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A fourth
determinant, Ag(y), is antithetical to Ag(x).
Six
* This work has been supported by
grants HL
16774 and
GM17173 of the U.S. National Institutes of Health.
The author is
indebted to Drs K. Berg, J. Hirschfeld, L. Beckman, D. C. Shreffler,
and F. Vogel for helpful comments on a first draft of this paper.
81
TABLE I
AG CHROMOSOME FREQUENCIES IN SWEDEN
(after Hirschfeld and Rittner, 1969)
Chromosome
xa|Lz
xal
x
ya z
yal
y
Frequency
0.0048
0.1935
0.0249
0.1549
0.1010
0.5210
TABLE II
GENE FREQUENCIES DEFINED BY x,y FACTORS OF
Ag SYSTEM
(after Giblett, 1969)
Alleles
Caucasoid
Negroid
Mongoloid
(N = 248)
(N = 54)
(N = 1205)
Agx
0.23
0.69
0.73
AgY
0.77
0.31
0.27
alleles appear to account for the population fre-
quencies and segregation in families (Table I). The
Ag(z) factor is apparently a subtype of a,, since
chromosomes xz and yz have not been observed.
All reported alleles have either the x or y factor, but
not both.
From limited gene frequency data, Agx
is the common allele in Africa and Asia, while Ag3
predominates in Europe (Table II).
The symbol Ag has been suggested for all ,6-
lipoprotein antigens detected by isoimmunization
(Buitler,
1967).
Patients
with
thalassaemia
are
especially good producers of antiserum, perhaps
because of the associated splenomegaly (Blumberg
et al, 1964).
The relation of many of these antisera
to the Ag system defined by a,, x, y, and z is unclear
(Hirschfeld,
1972).
Dausset et al (1968) report
1
I
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Review Article
Journal of Medical Genetics (1976).
13, 169-181.
The mucopolysaccharidoses
C. A. PENNOCK and I. C. BARNES
From the Department of Child Health, Bristol University; and the Department of Chemical Pathology,
Bristol Royal Infirmary
The group of inherited disorders referred to as
the mucopolysaccharidoses, of which Hurler's syn-
drome is the best known example, have been ex-
pertly reviewed and classified by McKusick in 1965,
1969, and reclassified in 1972.
The most recent
classification (Table I) resulted from observations
on skin fibroblasts made by Neufeld and her col-
leagues during their studies on the basic biochemical
defects in the mucopolysaccharidoses.
As a result
of this work, and research by other groups, the
actual enzyme defects in all the conditions shown in
Table I have been identified, and this has made the
antenatal diagnosis of these disorders a real possi-
bility.
These exciting developments which have
occurred during the past four years are reviewed in
the following paragraphs.
Mucopolysaccharide (glycosaminoglycan)
structure and nomenclature
Mucopolysaccharides
are
the
major
chemical
polymers of the ground substance and connective
tissue (in association with collagen, reticulin, and
elastin).
The reports published in the past are
often confusing since the terms mucopolysaccharide,
mucoprotein, mucin, mucus, and glycoprotein have
been used synonymously, but the position has been
clarified by Jeanloz (1960) who introduced the term
glycosaminoglycan (GAG).
This more clearly de-
fines the chemical nature of the mucopolysaccha-
rides (GAGs) as being high molecular weight poly-
mers of repeating dimers of an amino sugar usually
linked to a hexuronic acid.
The amino sugar is
either glucosamine or galactosamine, both of which
are usually either acetylated or sulphated at the
amino group, and both of which may also be sul-
phated either at carbon 4 or carbon 6 of the hexose
ring.
The hexuronic acid is either glucuronic acid
(that is, glucose with a carboxyl group at carbon 5),


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or iduronic acid (the C-5 epimer of glucuronic acid).
Several GAG chains of similar molecular weight
may be linked through a short neutral carbohydrate
linkage (usually galactose-galactose-xylose) to a pro-
tein core via a serine (or threonine) residue.
Full details of the chemistry of these polymers
have been given in a review by Muir (1969) and are
summarized in Table II.
Excretion of glycosaminoglycans
The term mucopolysaccharidosis was first sug-
gested by Brante in 1952 after finding that the liver
of two patients with Hurler's syndrome contained an
excess of chondroitin sulphate B (dermatan sul-
phate), a designation that was made permanent by
the demonstration of excess mucopolysacchariduria
by Dorfman and Lorincz in 1957, and confirmed by
Meyer and his colleagues in 1958.
The study of
urinary GAG excretion patterns gave the first indi-
cations of the biochemical pathogenesis of the muco-
polysaccharidoses, and contributed greatly to our
present understanding of the underlying defects.
169
(a) Normal GAG excretion.
The first sug-
gestion that GAGs might be present in normal urine
is thought to have been made by Moerner in 1895
who isolated a sulphated polysaccharide, which was
probably
chondroitin
sulphate
(McGale,
1969).
This finding was subsequently confirmed by Astrup
(1947) and Kerby (1954) who isolated an alchohol-
insoluble metachromatic material which was identi-
fied as chondroitin sulphate by DiFerrante and Rich
in 1956.
The latter subsequently showed that the
main GAGs excreted in normal urine are chon-
droitin-4-sulphate
and
chondroitin-6-sulphate,


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Annotation
Journal of Medical Genetics (1976).
13, 351.
Risks of miscarriage after amniocentesis
C. O. CARTER
From MRC Clinical Genetics Unit, Institute of Child Health, 30 Guilford Street, London WCIN IEH
An encouraging summary report has been re-
leased by the U.S. Department of Health, Education
and Welfare on the safety of amniocentesis and was
presented at the American Academy of Pediatrics
meeting in Washington in October 1975.
The re-
port was discussed by Dr Milunsky in 30 October
issue of New EnglandJournal of Medicine.
The collaborative study from 9 centres compared
the outcome of pregnancy in 1040 women under-
going the procedure and in 992
controls.
An
attempt was made to match the controls for mater-
nal age, parity, race, religion, socioeconomic status
and other features.
The most serious discrepancy
in matching is that 53.4% of the amniocentesis
group and only 34.9% of the controls were over the
age of 35 years.
The follow-up included neonatal
and one-year examinations of the children who were
the outcome of these pregnancies.
The most important finding was that fetal loss
(spontaneous abortion and stillbirth) for the amnio-
centesis group was 3.5% (36 cases) and for the con-
trol group 3.2% (32 cases) a statistically insignificant
difference.
Further no significant difference was
noted in the instance of congenital malformations,
not detected by amniocentesis, neonatal illness, or
development at 1 year of age.
Data are not given
on the incidence of Rhesus sensitization in the two
groups.
The overall accuracy of this screening
procedure is said to be 99%.
Nevertheless two
negative misdiagnoses
are reported, two infants
born with Down's syndrome after they had been
found to be normal on prenatal screening, and one
positive misdiagnosis, galactosaemia in a child who
at birth was found to be normal.
Fetal sex was in-
correctly assigned in three instances.
The findings
are to be published in full in a monograph from the
National Institute of Child Health and Human
Development.


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It should be emphasized that these are the results
of one, presumably selected, group of centres.
In
these centres, at least Dr Milunsky estimates, the
risk of abortion as a result of amniocentesis is pro-
bably not more than 0.5%.
The findings of the
MRC trial have not been published yet, but are
awaited with interest.
351


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Case Reports
Journal of Medical Genetics (1976).
13, 400-412.
Antenatal diagnosis of trisomy 13
with unexpected increase in alpha-
feto protein
Summary.
A
24-year-old
woman
who had previously given birth to an
infant with Down's syndrome was shown
by chromosomal analysis of the liquor
amnii
to be carrying
an infant with
trisomy
D.
Routine
examination
of
serum
and
liquor
alpha-feto
protein
(AFP) in the antenatal period showed
unexpected high
levels of both,
con-
sistent with a neural tube defect.
The
fetus, however, did not have evidence of
a neural tube defect but had scalp defects
which were presumed to have allowed
the leakage of AFP from the fetus into
the liquor amnii and hence into the
maternal serum.
Case report
This 24-year-old woman had her first infant, a female,
with classical Down's syndrome, in 1971.
At that time
she was 20 years old and her husband 24 years old.
The
infant's karyotype was 46, XX +21 and mother and
father had normal karyotypes.
A second pregnancy in
1972
was
terminated
at nine weeks
on
psychiatric
grounds.
She became pregnant for the third time in
September 1974 and was referred for amniocentesis on
15 January 1975.
She was in good
general
health.
Her blood group was Rhesus positive and she had no
history of hepatitis
or thyroid
disease.
Subsequent
screening for thyroid antibodies was negative, and her
serum complement was normal as were her immuno-
globulins.
There was no family history of aneuploidy
in her relatives or in those of her husband.
Liquor amnii was obtained without difficulty and
unexpectedly showed an increased AFP level of 70 ug/ml
(radioimmunoassay technique; normal upper limits 40
to 45 ,g/ml).
A simultaneous check at another labora-
tory by
a
different method
(single
radial immuno-
diffusion)
confirmed
the
raised
level.
Cytogenetic
studies on the liquor specimen showed the presence of a
fetus with trisomy D abnormality.
The mother was
therefore offered termination, and this was performed at
20 weeks' gestation.
A further specimen of liquor ob-


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tained before induction, and while the fetus was still alive,
showed that the AFP was still raised, 68 jug/ml in the
liquor; 187 ng/ml in the serum.
Necropsy
External features.
The fetus was female, weighing
240 g (Fig.
1).
At the vertex of the skull there was an
area of translucent, very thin skin, approximately 3 x 1
cm, the histological appearance of which is shown in
Fig. 2.
There was a similar smaller defect near the posterior
fontanelle.
There was micrognathia, low set ears, a
cleft palate, and polydactyly.
CNS.
The brain weighed 40 g and showed no gross
abnormality.
The
optic and
olfactory
nerves
were
normal.
Thorax.
There
was
anomalous
venous
drainage
with a small high ventricular septal defect.
Abdomen.
A Meckel's diverticulum was present.
The uterus was bicomuate with a single cervix.
The
right umbilical artery was absent.
All other organs
appeared normal on macroscopical and microscopical
examination.
The position of the scalp defects and their character-
istics were similar to those previously described
in
infants with trisomy 13.
Subsequent fibroblast culture
from the fetus confirmed trisomy 13.
One month after
00o


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journal of Medical Genetics (1976).
13, 439-448.
Pyloric stenosis in the
Oxford Record Linkage Study Area
PHILIPPA ADELSTEIN and JEAN FEDRICK
From the Unit of Clinical Epidemiology, Department of the Regius Professor of Medicine, University of Oxford
Summary.
The files of the Oxford Record Linkage Study were employed to
identify 220 infants presenting with infantile hypertrophic pyloric stenosis (IHPS)
in the 6-year period 1966 to 1971.
Information on these infants was obtained from
birth certificates and maternity notes.
The overall incidence was 2.5 per 1000 live-
births.
There was a distinct seasonal variation, with highest incidence to infants
born in the third quarter of the year as well as variation in incidence with area: the
cities had much lower rates of IHPS than the adjacent rural or small urban areas.
It was shown that the rates in the south and east ofthe area studied were far greater
than in the north and west.
In the present study there was no excess of primiparae, the peak maternal age
group was 20 to 24; there was a slight excess of parents of social classes I and II;
and a significant association with mothers who were Rhesus negative.
The rate of
IHPS among sibs was 85 per 1000.
Though there was the usual correlation with
the male sex (M: F ratio = 5.5: 1), there was no variation with birthweight and only
among the females was an association found with prolonged gestation.
There
appeared to be an inverse relation between gestation and age on admission to
hospital.
The disease of infantile hypertrophic pyloric
stenosis (IHPS) has become so amenable to present
methods of treatment that there have been relatively
few studies designed to elucidate the causes of the
disorder.
One of the major drawbacks to any study
of this kind is that the condition generally manifests
itself after discharge from maternity hospital. Thus
any information on factors connected with the rele-
vant pregnancy and social background must either
be obtained from retrospective inquiry ofthe mother


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or from a procedure oflinking with the records from
the relevant maternity hospital or domiciliary mid-
wife.
The problem, too, of obtaining an unbiased
control population can often be extremely time con-
suming.
The present study has the advantage of
employing the data banks of the Oxford Record
Linkage Study and in a sense may be considered to
be prospective.
Pyloric stenosis had been described in the medical
reports of the 18th century (Blair, 1717; Weber,
Received 26 January 1976.
1758; Armstrong, 1777), but was first recognized as
a clinical syndrome after a description of 5 cases by
Hirschsprung (1888) in Copenhagen.
At the turn of
the century several types of surgical procedure were
attempted with varying degrees of success, until in
1912 Rammstedt developed a very simple procedure
which has remained one of the most satisfactory
surgical operations to this day, with an extremely
low associated mortality.
Nevertheless there are a
few paediatricians who still prefer management by
medical means.
The
incidence
within
the
British
Isles
has
generally been reported as of the order of 2 to 3 per
1000 livebirths (Table I).
The only other European
areas recorded as having incidences ofover 1 per 1000
areGothenburgin Sweden and BudapestinHungary.
The rate in the southern countries of Europe is ap-
parently very low.
The one study from Malta
(Cachia and Fenech, 1966) suggested that the rate
there was as high as 0.9 because of the inter-
mingling of races resulting from the presence of
British servicemen on the island.
In the middle-
'39


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Journal of Medical Genetics, 1977, 14, 20-24
Heterozygote advantage for the
phenylketonuria allele
LETTEN FEGERSTEN SAUGSTAD
Vestheimgt. 6, Oslo 2, Norway
SUMMARY
Mean weight at birth of unaffected (normal homozygous and PKU heterozygous)
offspring of parents heterozygous for the phenylketonuria (PKU) allele averages significantly
above that of Norwegian neonates, with no significant difference in mean age of mothers or in mean
parity. It approaches the optimal birthweight-that which confers the minimum overall mortality
in the pre-, peri-, and postnatal periods. This near-optimal birthweight together with the possibly
higher effective fertility observed in PKU heterozygous couples (at least in those who married
before 1940), has apparently more than outweighed the disadvantages of the allelele in PKU
homozygous offspring as shown, for example, in an excessive number of pre- and perinatal deaths
among the total offspring of PKU heterozygotes, to say nothing of the PKU survivors who, often,
used to die young. The two effects-fertility and viability-apparently both contribute in the same
direction, to give a biological fitness in excess of 1 for the heterozygote. This heterozygote advantage
presumably explains the presence of the allele at frequencies above those to be expected from the
simple replacement of a homozygously-lethal allele by mutation alone.
The prevalence at birth of recessive disorders
is
affected inter alia by changes in inbreeding level and
by any
selective advantage
in the heterozygous
carrier. Heterozygote advantage has been observed
in man in sickle-cell anaemia and possibly in some
other disorders (see Motulsky,
1974; Stuart and
Burdon, 1974).
Evidence is presented for the view that heterozy-
gosity for the phenylketonuria (PKU) allele is ad-
vantageous in parents by rendering their unaffected
offspring more viable at birth, thereby improving the
chance of survival of the allele.
Material and methods
The mortality rate (incorporating the stillbirth rate)


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for infants before 1 month of age is lowest among
those with birthweights at a point somewhat above
the mean (Karn and Penrose, 1951; Fraccaro, 1955;
Rantakallio, 1968). This is also the case in regard to
all
births
in Norway
1967-1968
(Bjerkedal and
Bakketeig, 1972). There, the rate is lowest for birth-
weights in the neighbourhood of 4500 g (males), or
4000 g (females): while the average birthweight was
3512 g for males and 3391 g for females (Table 1).
Received for publication 12 March 1976
The chances for further survival to
1 year of age
appeared to be best for neonates of either sex that
had a weight at birth of approximately 4500 g.
Weights at birth of children with PKU born in
Norway between 1940 and 1973 and of their non-
PKU sibs were investigated, using the information in
the maternity hospitals (Saugstad, 1972). Controls
were all births in Norway between January 1967 and
January 1969 from the Medical Registration of
Births (T. Bjerkedal, 1973, personal communication),
which is based on forms completed on the ninth day
of life.
The number of pregnancies (including abortions
and pre- and perinatal deaths) of the heterozygous
mothers with PKU offspring were also investigated
and compared with a control series of 230 non-
primiparous women, of unknown heterozygosity for
PKU, consecutively admitted for delivery in Oslo in
1967. In addition, the numbers of liveborn offspring
in 36 families with PKU offspring born in Norway
before 1940 were investigated (Saugstad,
1975a).
The late Asbjorn F0lling kindly supplied information
on 22 of the 36 families diagnosed by him in 1932 to
1938 inclusive (F0lling et al., 1944). The remaining 14
of the 36 families were investigated by the present
author 1968 to 1971, when the reproductive histories
20


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Journal ofMedical Genetics, 1977, 14, 258-261
Partial trisomy 7p associated with familial 7p;22q
translocation
LINDA M. LARSON, WALTER A. WASDAHL, AND SYED M. JALAL
From the Department ofPathology, The Medical School; University ofNorth Dakota, and the Department of
Biology, University ofNorth Dakota, Grand Forks, North Dakota, U.S.A.
SUMMARY
A newly described partial trisomy of the short arm of chromosome number 7 is reported
in a familial translocation between 7 and 22. The unbalanced translocation was found in one family
member, the propositus, and the balanced form in 5 other members. The possibility of this trans-
location being a rare telomeric attachment previously undescribed in humans is discussed. Prominent
clinical features include general mental and motor retardation, microbrachycephaly, and cardiac and
oral abnormalities.
The advent of various banding techniques, parti-
cularly G banding, has enabled the accurate identi-
fication of several minute structural alterations in the
last few years. Described here is onesuch case inwhich
a small portion of the short arm of number 7 was
translocated to the long arm of chromosome number
22. This is one of the first reported cases involving
partial trisomy of the short arm of chromosome 7.
Familial studies of this condition have shown 5
balanced carriers and
1
affected individual in 3
generations. The propositus was a 15-month-old boy
with general mental and motor retardation. Physical
abnormalities
included high
palate,
split
uvula,
microbrachycephaly,
and
increased
transillumi-
nation of the frontal area of the skull.
Case reports
CASE IV.1
The propositus (Fig. 1) was the product of the first
pregnancy of an 18-year-old mother and a 22-year-
old father who were not related. At birth he weighed
2951 g and was 47 cm in length.
At 2 months of age a grade 2 systolic murmur was
heard at the apex of the heart and it was noted that he
had low set ears and a small mandible. At 15 months
of age he was referred.for chromosomal analysis


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because of his very retarded mental and motor
development and congenital heart abnormalities.
At this time physical examination showed weight
and height in the third centile and head circumference
in less than the third centile. Appetite and weight
Received for publication 17 August 1976
were poor from birth and he tired easily. His diet had
been mostly milk and few solids. There was increased
perspiration around the head and neck. He did not
smile, roll over, sit up, pull up, or stand but was able
to move his hand to his mouth. Other abnormalities
included high broad palate,
spilt
uvula, micro-
brachycephaly, and increased transillumination of
the frontal area of the skull. Heart abnormalities at
this time revealed a normal first sound and a second
sound that was
split, with accentuation of the
pulmonary closure. There was a grade 3/6 ejection
murmur along the upper left sternal border trans-
mitted into the lungs and a third heart sound along
the left sternal border followed by a grade 3 diastolic
murmur.
Electrocardiogram and echocardiogram revealed a
complete form of atrioventricular canal and evidence
of right ventricular hypertrophy without left ventri-
cular hypertrophy. Radiographs showed an enlarged
thymus and heart. An EMI scan showed hypoplasia
or atrophy of the brain with a dilated ventricular
system and enlarged subarachnoid spaces.
Results of laboratory tests for sweat chloride, total
thyroxine, and serum calcium were normal. Exami-
nation of urine was negative. Haemoglobin was 10-5
g/dl and cellular morphology of peripheral blood
showed hypochromia and microcytosis, suggestive
of chronic iron deficiency anaemia.
CASE iii.3
The father of the propositus was phenotypically
normal and in general good health. He was a high
school graduate and self-employed farmer.
258


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Journal of Medical
Annotation
Mendelian inheritance or transmissible ag4
lesson of Kuru and the Australia antigen
PETER S. HARPER
From the Department ofMedicine, Welsh National School of Medicine, Heath Park, Cardiff
The award of the 1976 Nobel prize in medicine to the
discoverers of two major forms of transmissible
disease-Kuru and the Australia antigen in relation
to hepatitis-might seem at first sight to be unrelated
to medical genetics. Yet not only was one of the
laureates, Baruch S. Blumberg, trained as a geneticist,
and the Australia antigen originally believed to be a
genetically determined serum protein system, but
Kuru itself and some other non-tropical encephalo-
pathies, now known to have a related aetiology,
were originally considered to have a hereditary basis.
The development of concepts in these two parallel
fields is of great interest in its own right, but for medi-
cal geneticists it is ofparticularrelevance, since it raises
a number of questions which may have much wider
significance. May other disorders now thought to be
genetically determined prove in reality to be infectious
diseases? May transmissible agents be closely in-
volved in determining the action of specific genes in
producing disease? It is worth looking critically at
some of the conditions where Mendelian inheritance
has been assumed to be the basis for familial aggre-
gation in the light of what has happened to our ideas
on the aetiology of Kuru and the Australia antigen.
Kuru
The fascinating story of the discovery and epidemio-
logical documentation of Kuru, and the steps which
led to the suspicion and elucidation ofa transmissible
viral agent as its basis, have been lucidly told in a
series of publications by Gajdusek and his colleagues
over the past 20 years (Gajdusek and Zigas, 1957,
1959; Gajdusek et al., 1966; Gajdusek, 1973, 1977).
The points of special interest to us here are threefold.
Why was a hereditary basis ofthe disorder considered
possible initially? Why was this explanation found


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inadequate, and an infective agent suspected? Is
there indeed a hereditary basis for susceptibility to
the disease ?
Kuru, a subacute, progressive, and invariably fatal
Received for publication 9 May 1977
neurological degeneration, is and appears always to
have been confined to a localised area of the New
Guinea highlands, occupied by the Fore people.
Gajdusek and Zigas
first
described
the
clinical
features in 1957, and
it was soon clear that the
disease was unique both clinically and epidemiolo-
gically.
A genetic basis for Kuru was proposed on the basis
of its restriction to a particular tribal group and
notable familial aggregation, with vertical trans-
mission from generation to generation. Gajdusek
and Zigas' original paper concludes:
'The peculiar sex and age distribution of cases, the
high familial prevalence in a closely intermarried
community, the phenomenon of anticipation (with
cases occurring in an earlier age in the second
generation) and occasional
family histories
in
which several siblings had died of the disease on
reaching approximately the same age, along with
the type of clinical picture that the disease presents
all support the suspicion that strong genetic factors
are operating in the pathogenesis. . .'
Gajdusek and Zigas (1957).
The genetic basis of Kuru was elaborated by Gaj-
dusek and Zigas (1959) and by Bennett et al. (1959)
and postulated an autosomal gene, fully penetrant
in the heterozygous female, but rarely in the male
unless present in homozygous state. Affected children
were considered to be homozygotes. Closer study,
however, showed discrepancies which were hard to
reconcile with Mendelian inheritance: though the
Kuru region was a sharply localised one the inhabi-
tants
were
heterogeneous,
showing
no
special
linguistic or physical differences from adjacent areas
free of the disease; furthermore the disease was of
relatively recent occurrence in the area, having shown
a rapid spread over a period of half a century, and
subsequently an equally dramatic decline, too rapid


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to be explained on a purely genetic basis. The sex
ratio, though equal in children, showed a distinct
female preponderance
in adults, while in adults
conjugal cases were frequent.
389


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Journal ofMedical Genetics, 1977, 14, 430-437
A 'new' syndrome of mental retardation with
characteristic facies and brachyphalangy
ALASDAIR G. W. HUNTER, PHYLLIS
J. McALPINE, NOREEN L. RUDD,
AND F. CLARKE FRASER
From the Division of Genetics, Department ofPediatrics, University ofManitoba and Health Sciences
Centre, Winnipeg, Manitoba; the Department ofGenetics, Hospitalfor Sick Children, Toronto, Ontario; and
the Department ofMedical Genetics, The Montreal Children's Hospital, Montreal, Quebec, Canada
SUMMARY
This paper describes 6 individuals, occurring in 3 generations of a single family, who were
affected by a distinct syndrome which included: retardation and microcephaly; a small oval face with
almond-shaped eyes, droopy eyelids, a small nose, and small downturned mouth; minor acral skeletal
anomalies, and short stature. Craniosynostosis, heart defects, and limited elbow extension were seen
less frequently. Expression was variable and parents who were in the direct vertical line of trans-
mission of the syndrome showed few, if any, overt signs of the disease. However, the metacarpal/
phalangeal profile of the parents showed a similar pattern to that seen in the affected individuals, and
it is suggested that this profile may be the most sensitive indicator of carrier status.
It is important to distinguish, within the hetero-
geneous category of 'mental retardation', those cases
with specific syndromes, so that the families con-
cerned can be advised more accurately about the
prognosis, both medical and genetic. This paper
describes a new familial syndrome appearing in 6
individuals over 3 generations, whose major features
include: retardation of varying severity, a charac-
teristic facies, and minor acral skeletal anomalies with
a characteristic pattern of phalangeal shortness. The
distribution of this syndrome in this kindred
is
Received for publication 7 March 1977
compatible with autosomal dominant inheritance
with reduced penetrance.
Family history
The family was of British extraction, and was


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ascertained independently through a girl in Montreal
(Fig. 1, V.14), and a boy in Toronto (Fig. 1, V.1) who
was studied as part of a project on craniosynostosis
(Family 9, Hunter and Rudd, 1977). The probands
were third cousins. There was considerable variation
in severity of expression of the syndrome among the
six retarded individuals, and all parents of affected
persons were of normal intelligence.
II
III
IV
V
VI
Fig. 1
Pedigree offamily
430
I


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Journal ofMedical Genetics, 1978, 15, 217-218
Linkage studies in Van der Woude syndromel
JOHN RUSSELL EASTMAN, DAVID BIXLER, AND VICTOR ESCOBAR
From the Departments ofOral-Facial Genetics and Medical Genetics, Indiana University School ofMedicine,
Indianapolis, Indiana 46202, U.SA.
SUMMARY
A newly ascertained kindred segregating Van der Woude syndrome through four
generations is described. Linkage studies using the methods of Ott (1974) were carried out using 19
marker loci.
Van der Woude syndrome has 3 primary manifes-
tations: (a) bilateral lower lip pits, (b) cleft lip with or
without palate, or (c) isolated cleft palate (Van der
Woude, 1954; Cervenka et al., 1967). The disease
entity segregates as an autosomal dominant trait with
70 to 80% penetrance (Van der Woude, 1954; Gorlin
and Pindborg, 1964; Cervenka et al., 1967). Variable
gene expression was shown by Cervenka et al. (1967)
who observed
lip
pits
in 69.6% of obligate gene
carriers but facial clefts in only 36% of the cases.
Congenital absence of second premolars has also been
reported in association with Van der Woude syndrome
(Schneider,
1973). A
single
previously
published
linkage study involving this syndrome observed no
linkage with 13 marker loci. Unfortunately no lod
scores were published (Schneider, 1973).
In the present study, linkage analysis was perfor-
med on a previously unreported family in which Van
der Woude syndrome was segregating.
Subjects and methods
A phenotypic
description of each family member
examined is given in the Fig. Blood group pheno-
typing
in
this family involved the ABO, Rhesus,
MNSs, Kidd, Kell, Duffy, and P traits. Haptoglobin
was determined from serum. Erythrocytes were used
in
determining
phosphoglucomutase,
acid
phos-
phatase,
6-phosphogluconate
dehydrogenase,
and
adenosine deaminase. Parotid saliva was used to deter-
mine amylase1, PA, PB, PR, and DB phenotypes. The
amylase2 phenotype was obtained from urine and the
ability to taste phenylthiocarbamide (PTC) was also
evaluated
with
PTC
solutions
to
varying
con-


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con-
centrations.
'This is publication number 77-12 from the Department of Medical Genetics
and was supported in part by the Human Genetics Center Grant PHS GM
21054 and the Oral-Facial Genetics Training Grant T22 DE 00007.
Received for publication 23 August 1977
Table
Lod scoresfor linkage with Van der Woude
syndrome: male andfemale scores combined
0o10
0.20
0.30
0.40
050
ABO
-0 19
0-04
0.07
0.03
0 00
Rh
0-84
0-52
0-26
0.06
0-00
MNS
-1-16
-0-63
-0-30
-0-11
0-00
Kidd
0-22
0-13
0-07
0-02
0-00
Kell
-0-03
-003
-0-03
-0-02
0-00
Duffy
0-03
0-14
0-13
0-07
0.00
p
-0-12
-0-05
-0-01
0-00
0-00
Hp
0-41
0-29
0-18
0.08
0-00
PGM,
-0-56
-0-24
-0.11
-0.04
0-00
ACP
0-30
0.20
0-11
0-04
0-00
6GPD
0.01
0-00
0-00
0-00
0.00
ADA
0.01
0-01
0-00
0.00
0.00
AMY,
0.00
0-00
0-00
0.00
0-00
PA
0.05
0.07
0.04
0.01
0-00
PB
0.00
0-00
0-00
0-00
0-00
PR
0-10
0.19
0-13
0-05
0.00
DB
0-29
0.23
0-16
0.08
0.00
AMY2
0.01
0.01
0.00
0.00
0.00
PTC
0-31
0.22
0-13
0-06
0-00
Computation of the likelihood and lod scores for
various recombination fractions was done by com-
puter analysis for each of the marker loci using a
recently
available
programme
(Ott,
1974)
which
computes the likelihood of linkage recursively,
as
proposed by Elston and Stewart (1971), starting with
the more recent generation and working back into the
pedigree.
Results
The lod scores for various recombination fractions are
given for each locus analysed in the Table.
Discussion
The results indicate that close linkage of Van der
Woude syndrome with any of the tested marker loci is
unlikely. Because of the small number of individuals
involved in the present study further investigations of
217


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Journal ofMedical Genetics, 1978, 15, 292-293
Linkage analysis in dominant
acrocephalosyndactyly 1
JOHN RUSSELL EASTMAN, VICTOR ESCOBAR, AND DAVID BIXLER
From The Departments ofOral-Facial Genetics and Medical Genetics, Indiana University School ofMedicine,
Indianapolis, Indiana 46202, USA
SUMMARY
Linkage analysis was performed on a previously reported family in which multiple
dominantly inherited acrocephalosyndactyly syndromes were present. An underlying axiom of linkage
analysis is that the trait analysed be monogenic. This prerequisite was presumptively established in the
single kindred analysed because acrocephalosyndactyly was observed in multiple cases in multiple
generations.
The acrocephalosyndactylies (ACS) are a clinically
similar
group
of disorders
manifesting
premature
craniosynostosis and varying degrees of brachydac-
tyly and syndactyly (McKusick, 1975; Gorlin et al.,
1976). McKusick (1975) most recently listed 4 types
of ACS, Pfeiffer, Apert, Chotzen, and Vogt, all of
which are dominantly inherited. The distinctness of
these categories has, however, been questioned by 2
lines
of evidence.
Firstly,
it
has
been
suggested
(Degenhardt, 1950) that Pfeiffer and Apert syndromes
involve the same gene defect based upon close clinical
similarity. That this is a viable possibility is shown by
Escobar and Bixler (1977a,b), who documented Apert,
Pfeiffer,
and
transitional
phenotypes
in
multiple
generations of a single family. Additionally, 2 other
families have been reported in which multiple ACS
types have been found in the same family (Robinow
and Sorauf 1975; Jackson et al., 1976). Secondly,
Escobar and Bixler (1977a) have recently reported a
unique
metacarpophalangeal
pattern
profile which
discriminates
2 ACS types (Pfeiffer and Chotzen)
from normal individuals, but not from each other.
Although most investigators consider the dominan-
tly
inherited ACS syndromes
to be the result of
different (though possibly
allelic) genes, the above
evidence raises a second possibility; this being that the


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multiple ACS phenotypes are the result of a single
gene with a highly variable expression. This hypothesis
is testable by performing linkage analysis on infor-
mative families, that is, those previously mentioned
which show multiple ACS types segregating within a
single kindred. This paper gives the results of such an
'This is publication number 77-50 from the Department of Medical Genetics,
and was supported in part by the Human Genetics Center Grant PHS GM
21054, and the Oral-Facial Genetics Training Grant T22 DE 00007.
Received for publication 23 August 1977
analysis performed on the family previously charac-
terised both phenotypically and radiographically by
Escobar and Bixler (1977a,b).
Methods and materials
The family involved
in this analysis
(Fig.
1) was
ascertained in the Department of Medical Genetics
through
a
proband
diagnosed
as
having
Pfeiffer
syndrome.
Detailed
phenotypic
findings
for
each
family
member
have
been
previously
published
(Escobar and Bixler, 1977b).
The marker loci employed in this analysis included
7 blood groups: ABO, Rhesus, MNSs, Kidd, Kell,
Duffy, and P traits. Three other traits were hapto-
globin, determined from serum, and the red blood cell
enzymes phosphoglucomutase and acid phosphatase.
Computation of the likelihood and lod scores for
various recombination fractions was done for each of
programme (Ott, 1974). This programme computes
the likelihood of linkage recursively,
as proposed
by
Elston and
Stewart
(1971),
starting
with
the
more recent generation and working back into the
pedigree.
Results
The lod scores for various recombination fractions are
given in the Table for each locus analysed.
Discussion
The
results shown
in the Table indicate that the
hypothesised single gene resulting in the dominantly
292


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Journal ofMedical Genetics, 1978, 15, 466-474
X-Y translocation in a retarded phenotypic
male
Clinical, cytogenetic, biochemical, and serogenetic studies
RENtE BERNSTEIN, JOAN WAGNER, JOY ISDALE, G. T. NURSE, A. B. LANE,
AND TREFOR JENKINS
From the Department ofHuman Genetics, School ofPathology, The South African Institutefor Medical
Research and University ofthe Witwatersrand, Johannesburg; and the Departments ofPaediatrics and
Radiology, University ofthe Witwatersrand, Johannesburg
SUMMARY
Cytogenetic studies on a mentally retarded boy revealed an X-Y translocation, karyotype
46,X,t(X;Y)(p22;ql 1). Only 5 other such cases have been reported and these were all females. The
unequivocal male phenotype suggested non-random inactivation of the normal maternally derived X
chromosome, and that the non-inactivated X-Y translocation chromosome included the locus for male
determination. Confirmation of this was provided by unassociated X and Y chromatin in interphase
cells, as well as by reverse banding after BrdU incorporation and autoradiography of metaphase
chromosomes. There was anomalous Xg blood group inheritance in the proband, indicating possible
localisation of the Xg locus to the terminal portion of the X short arm. Linkage of Xg and a form of
X-linked mental retardation is suggested. Close linkage of the Xg locus with the loci for aPgalactos-
idase, phosphoglycerate kinase, G-6-PD, and MPS II was excluded.
Cytologically
identifiable
translocation
of
the Y
chromosome to the X chromosome has been reported
very rarely (Khudr et al., 1973; Borgaonkar et al.,
1974; Van den Berghe et al., 1977). In all instances
where there was no free-lying Y chromosome, the
patients were phenotypic females. Two XX males with
presumptive morphological evidence of a Y to X
translocation have also been documented (Madan and
Walker, 1974; Wachtel et al., 1976).
We wish to report the investigation of a mentally
retarded child with a morphologically identified X-Y
translocation and an unequivocally male phenotype.
This
patient
afforded


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afforded
a valuable
opportunity
for
studying the pattern ofX inactivation in such cases, as
well as the location of the male determining genes of
the Y chromosome, and the linkage of genes possibly
located on the distal portion of the short arm of the X
chromosome, including the Xg locus.
Case report
The proband was first referred at the age of 4 years for
investigation of severe mental retardation associated
Received for publication 23 January 1978
with
skeletal
abnormalities
and short
stature. He
weighed 2.3 kg at birth, and was delivered normally at
term after a pregnancy uneventful except for a slight
show of blood at 16 weeks. The mother gave no
history of stillbirths or miscarriages at any time, or of
infection, drug ingestion, or irradiation during preg-
nancy. She had an ovarian cyst removed 3 months
before conception. The parents were unrelated and of
normal intelligence. The father was aged 26 and the
mother 23 years at the time of birth of the proband,
who was 3 years younger than his phenotypically
normal
brother.
The
family
history
was
non-
contributory, except that the father's sister was said to
have
a
son
suffering from hyperactivity,
slurred
speech, and incoordination of eye movements. The
father's height was 165 cm and his parents and sister
were also short in stature.
Limitation of elbow movements was noted in the
proband shortly after birth. His physical and mental
development was slow and all his milestones were
delayed. He first smiled and lifted his head between 4
and 6 months old, never crawled, presumably because
of his upper limb abnormalities, and first walked un-
assisted when nearly 4 years old. At 5 he still was not
466


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Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:44-48
Pain-related somatosensory evoked potentials in
cortical reflex myoclonus
Ryusuke Kakigi, Hiroshi Shibasaki, Ryuji Neshige, Akio Ikeda, Kousuke Mamiya,
Yasuo Kuroda
Abstract
To elucidate the sensitivity to pain stimuli
in
patients with
cortical
reflex myo-
clonus,
pain-related
somatosensory
evoked potentials (pain SEPs) following
CO2 laser stimulation and conventional
electrically-stimulated
SEPs
(electric
SEPs) were compared in four patients
with cortical reflex myoclonus. The P25
peak of electric SEPs was considerably
enhanced but the P320 potential of pain
SEPs was of normal amplitude in all
patients. After medication, myoclonus
was reduced and the amplitude ofP25 was
decreased, but P320 showed no change. In
our previous study of the scalp distribu-
tion in normal subjects, a subcortical site,
probably the thalamus, was considered to
be the generator source of P320. Because
most pain stimuli do not reach the cortex,
patients with cortical reflex myoclonus
are not sensitive to pain stimuli and P320
in pain SEPs is not enhanced.
Department of
Internal Medicine,
Saga Medical School,
Nabeshima,
Saga City 840-01,
Japan
R Kakigi
H Shibasaki*
R Neshige
A Ikeda,
K Mamiya,
Y Kuroda
*Present address: National
Institute of Neuroscience,
National Centre of
Neurology and Psychiatry,
Kodaira City, Tokyo 187,
Japan
Correspondence to:
Dr Ryusuke Kakigi,
Department of Internal
Medicine,
Saga Medical School,
Nabeshima, Saga City,
840-01, Japan
Received 31 March 1989.
Accepted 10 July 1989
There is a general concept that cortical reflex
myoclonus'
is
induced
mainly
by
muscle
stretch, touch or pressure.25 This is compatible
with the facts
that
cortical components of
electrically-stimulated somatosensory evoked
potentials (electric SEPs), which are generated
in the sensorimotor cortex as a result of as-
cending signals mediated through large mye-
linated
fibres,
are
considerably
enhanced
("giant") in most patients with cortical reflex
myoclonus.`'0
These
patients


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patients
might
be
sensitive to pain stimulation as well, but by
using a pin or needle,
it is difficult to give
"pure" pain stimuli without causing excitation
of cutaneous mechanoreceptors. A low power
and long wavelength CO2 laser beam induces
pain or heat sensation when applied to the skin.
Recently, we have investigated pain-related
SEPs (pain SEPs) by CO2 laser stimulation,
and as a result of various studies involving
ischaemic or anaesthetic conditions in normal
subjects, its ascending signals were considered
to be mediated through Ab fibres. " Bromm and
Treede using the microneurogram reached a
similar conclusion.'2
The object ofthis investigation was therefore
to elucidate the degree of sensitivity to pain
stimuli in cortical reflex myoclonus by analys-
ing pain SEPs.
Materials and methods
Four patients with cortical reflex myoclonus,
one with Ramsay Hunt syndrome, one with
sialidosis type 2, and 2 with unclassified pro-
gressive myoclonic
epilepsy, were
selected
according to the following three criteria;9 (1)
the amplitude of the P25, the initial cortical
positive potential recorded at or around the
somatosensory hand area of the scalp following
stimulation of the median nerve at the wrist,
was larger than the mean + 2 SD for normal
subjects. (2) An enhanced long-loop reflex (C
reflex'3) recorded even at rest (without volun-
tary contraction ofthe corresponding muscles),
and (3) the presence of cortical spikes pre-
ceding spontaneous myoclonic jerks using the
jerk-locked back averaging method.78"4 The
patients' profiles are summarised in table 1. No
neurological
dysfunction
other
than myo-
clonus, cerebellar ataxia or generalised convul-
sion was found. Thirty normal subjects (10
females and 20 males, mean age 46 years, range
18 to 75) were also studied. All subjects gave
informed consent.
In addition to using the conventional pin-
prick method, pain sense was also evaluated by
a specially made dolorimeter using a CO2 laser
beam,
to determine
the
exact strength of


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stimulus. Laser wavelength was 10 6 im, and
the diameter of the irradiated beam was ap-
proximately 2 mm. The stimulus was applied
to the dorsum of the hand, with increasing
power, once every 3 seconds. Subjects were
requested to tell the examiner each time they
felt mild touch (pre-pain threshold) and dis-
tinct sharp pain
"like
a pin-prick"
(pain
threshold). As the intensity above 20 5 mJ/mm2
was suspected to cause skin erythema, maxi-
mum power was set to that level. The test was
repeated at least three times and the lowest
threshold was adopted.
The electric stimulus was a constant voltage
square-wave pulse of0 2 ms duration delivered
to the left median nerve at the wrist. The
stimulus intensity was sufficient to produce a
definite twitch of the thumb.
Stimulus
intensity
of approximately
17-
20 mj/mm2 elicited sharp pain that subjects
tolerated without any discomfort and felt "like
a pin-prick". Stimulus duration was 10 ms.
To avoid habituation, irradiated sites were
changed slightly from stimulus to stimulus. A
red helium-neon laser was combined with the
CO2 laser to indicate the irradiated area. The
temporal delay between laser stimulation and
the onset of averaging was less than 1 ms. The
detailed
methods
were
described
in
our
previous study."
44


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Journal ofNeurology, Neurosurgery, and Psychiatry 1990;53:496-501
Saccadic function in spasmodic torticollis
R Stell, A M Bronstein, M Gresty, D Buckwell, C D Marsden
Abstract
Twelve patients with idiopathic
spas-
modic torticollis were compared with 19
normal controls on tests of saccadic eye
movements thought to depend upon nor-
mal basal ganglia function. The patients
were able to make random, predictive,
remembered, and self-paced saccades
equally as well as control subjects. This
suggests that those parts of the basal
ganglia which may be damaged in spas-
modic
torticollis,
are
separate
from
pathways
responsible
for
the normal
initiation and execution of saccades.
Medical Research
Council Neuro-otology
Unit, Institute of
Neurology, National
Hospital, Queen
Square, London
R Stell
A M Bronstein
M Gresty
D Buckwell
University
Department of
Clinical Neurology,
Institute of Neurology,
National Hospital,
Queen Square,
London
C D Marsden
Correspondence to:
Dr Rick Stell
MRC Neuro-otology Unit,
Institute of Neurology,
National Hospital for
Nervous Diseases,
Queen Square,
London WC1N 3BG,
United Kingdom.
Received 14 July 1989
and in revised form
11 October 1989.
Accepted 3 November 1989
The cause and pathophysiology of idiopathic
spasmodic torticollis, the most common form
of focal dystonia, is unknown. It is assumed to
be a disease of the basal ganglia by inference
as occasionally it is produced by lesions in this
region of the brain.' To date there have been
very few reports of abnormalities in ocular
motor function in torticollis. These have dealt
mainly
with
asymmetries
in
vestibular
responses
on caloric and rotational
tests.2 3
Whilst no gross abnormalities of oculomotor
function have been recognised,
there have
been no studies specifically focusing on the
saccadic subsystems requiring the integrity of
the basal ganglia for their production.
The saccadic ocular motor system utilises a
number
of
pathways
subserving
specific
functions, namely predictive and remembered
saccades,
as well
as
saccades
to voluntary


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visual and novel visual targets. In sub-human
primates,
pathways
traversing
the
basal
ganglia are important for the generation of
predictive
and
remembered
saccades.4
In
humans,
the
analysis
of
predictive
and
remembered saccades in diseases of the basal
ganglia,
such
as
Parkinson's
disease,
has
confirmed the presence of specific deficits in
this saccadic subsystem.56
We report the results of tests of saccadic
function known to be sensitive to basal ganglia
disease in a group of patients with idiopathic
torticollis and compare them to a group of
age-matched normal subjects.
Patients and methods
Twelve
patients
with
isolated
spasmodic
torticollis producing pure horizontal rotation
of the head were studied (table 1). Patients with
isolated rotation were chosen because we were
interested in right-left asymmetries of saccadic
function; if such an asymmetry were present it
would be most likely manifested in patients
with a lateralised disoider of motor control.
The direction of torticoilis referred to the side
to which the chin was displaced. There were 11
females and one male, with a mean age of 50-6
years (range 29-63). The mean disease dura-
tion was 9 6 years (range 1-25). Seven patients
had rotation of the chin to the left and five to
the
right. Three patients were not taking
medication at the time of the study, four were
taking benzhexol (Artane), three were taking
diazepam, one lorazepam and one mianserin.
All had been on the stated medications for at
least six months without any change in dosage.
All patients had previously received at least one
set of injections of botulinum toxin into the
appropriate neck muscles, and some had been
treated at regular intervals for up to two years.
The patients were compared to a group of 19
normal controls; seven females and 12 males
with a mean age of 43 years (range 30-65).
Eye movements were recorded with DC
electronystagmography
(ENG)
onto
paper
with an ink-jet polygraph (Mingograph) and
recordings
were
then
analysed
by
hand.


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by
hand.
Electrodes were placed near the inner and outer
canthi of each eye and a reference ground
electrode was placed onto the forehead. The
subject's head was supported by a head rest. In
addition, a binaural head clamp was used in
patients who
could
not keep
their heads
straight voluntarily. The recordings were made
with the head directed to face the screen and
with eyes in the primary gaze position.
Saccadic eye movements were made to a
target projected onto a screen 1-3 metres from
the patient by a video projector. The target, a
10 pixel diameter spot of light subtending an
angle of 1-30, was generated using a graphics
generator controlled by
a micro-computer.
The computer generated each of the target
displacement sequences, each sequence being
accessed by selection from an on screen menu.
An analogue signal of target displacement was
transformed to the paper recorder by a digital
to
analogue
converter,
so
that
latency
measurements could be made directly from the
recording.
The parameters of saccadic function exam-
ined were: random saccades, hidden predictive
saccades,
predictive
saccades,
remembered
saccades, and self-paced saccades. The target
moved in a square wave step fashion across the
screen in the horizontal plane for each of the
experimental conditions. Subjects and controls
performed all of the following experiments in
one session. Each experimental paradigm was
separated by a rest period ofapproximately two
minutes.
496


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Journal of Neurology, Neurosurgery, and Psychiatry 1990;53:519-521
SHORT REPORT
Vermal infarct with pursuit eye movement
disorders
Charles Pierrot-Deseilligny, Pierre Amarenco, Etienne Roullet, Rene Marteau
Abstract
Severe deficits of foveal smooth pursuit
and optokinetic nystagmus in all direc-
tions
were
electro-oculographically
recorded in an 80 year old woman. Mag-
netic resonance imaging (MRI) showed
an infarct involving the postero-inferior
part of the vermis (lobules VI to X) and
a portion of the left cerebellar hemi-
sphere, with apparent preservation of
the flocculus and the brainstem. The role
of the vermal lesion in these pursuit eye
movement disorders is discussed.
It has recently been shown that, besides the
flocculus, the posterior part of the vermis
(especially lobules VI and VII) is involved in
the control of pursuit eye movements in the
monkey.'2 Our case reports for the first time a
recent ischaemic lesion of the posterior vermis
and eye movement recordings, suggesting that
this cerebellar structure is also involved in the
control of pursuit eye movements in humans.
Service de Neurologie,
Hopital Saint-Antoine
and Unite INSERM
289, Hopital de la
Salpetriere, Paris,
France
C Pierrot-Deseilligny
P Amarenco
E Roullet
R Marteau
Correspondence to:
Dr C Pierrot-Deseilligny,
H6pital de la Salpetriere, 47
boulevard de l'Hopital,
75651 Paris cedex 13, France
Received 14 June 1989
and in revised form
22 September 1989.
Accepted 30 October 1989
Case report
An 80 year old woman experienced sudden
vertigo,
with
unsteadiness,
vomiting,
pos-
terior headache, without auditory symptoms.
For the previous five years she had received
treatment for high blood pressure. On admis-
sion her blood pressure was 160/80 mm Hg,
her pulse rate was irregular at 1 15 per minute.
There was no drowsiness. Vertigo increased
on change of head posture. Finger-to-nose
and rapid alternating movements of the left
upper limb were ataxic. Both eyes and head
were tonically deviated leftwards. However,


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oculocephalic movement allowed both eyes to
overcome this tonic deviation and reach the
extreme right position. Cranial nerves were
unaffected. There were no sensory or motor
deficits, all tendon reflexes were normal and
plantar
responses
flexor.
The
electrocar-
diogram showed atrial fibrillation. CT scan
performed
on
the
day
of admission
was
normal. In particular, there was no hydro-
cephalus,
which
suggested
that
there
was
no
compression
of the
brainstem
by
the
cerebellum.
MRI performed four days later showed an
infarct in the territory of the left posterior and
inferior cerebellar artery, mainly the territory
of its medial branch.3 All the inferior part of
the vermis was affected (lobules VI to X),
namely the clivus, the folium, the tuber, the
pyramis, the uvula and the nodulus (fig 1).
The inferior part of the left cerebellar hemi-
sphere was also damaged. The flocculus, the
different cerebellar peduncles and the brain-
stem were apparently spared. Moreover, the
brainstem did .not appear to be compressed.
There was only slight diffuse atrophy in the
cerebral hemispheres, without hydrocephalus.
The posterior headache lasted one day, ver-
tigo and left lateropulsion on walking cleared
up within several days and the
left tonic
ocular
deviation
progressively
disappeared
within ten days.
Oculographic study
Eye
movements
were
recorded
on
the
eleventh day after the onset of the symptoms,
while the patient was fully alert, cooperative
and attentive. She was not taking any other
medication than acetyl-salycylic acid. Direct-
current electro-oculography (EOG) was used,
for each eye separately, in darkness, with the
head immobilised. There was no nystagmus
when the patient looked straight ahead or in
the extreme positions. With eyes open, there
was no tonic deviation, but with eyes closed
there was a left conjugate eye deviation.
Horizontal eye movements Saccades to com-
mand and visually guided saccades had nor-
mal latency, velocity and amplitude (fig 2A).
In particular, no dysmetria was observed,


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whatever the position of the visual target (at
5°, 150, 250 and 350 away from the midline)
and
direction
of saccades
(left,
right,
or
returns to the midline).
Foveal pursuit of a small luminous target
moving sinusoidally at peak-to-peak ampli-
tude of 500 was largely saccadic in both direc-
tions (fig 2B). Both catch-up saccades and
smooth portions were larger leftwards than
rightwards but smooth eye movement veloci-
ties were similar in both directions. Smooth
movement gains (ratio of peak eye velocity to
peak stimulus velocity) were low, bilaterally,
compared to an age-matched control group,
for the two frequencies of stimulation used
(table). These gains were less than the lower
limit of the normal range (control mean-2
SD).
Optokinetic nystagmus (OKN) was elicited
using alternating black and white stripes mov-
ing at 30°/s across a screen covering 60° of the
visual field. It was severely impaired (fig 2C),
519


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Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:627-632
The effects of baclofen and cholinergic drugs on
upbeat and downbeat nystagmus
Marianne Dieterich, Andreas Straube, Thomas Brandt, Walter Paulus, Ulrich Buttner
Abstract
The GABAergic drug baclofen and the
cholinergic
drug
physostigmine
were
administered
to
patients
with upbeat
and
downbeat
nystagmus.
Baclofen
(orally, 5 mg three times daily) reduced
nystagmus slow phase velocity and dis-
tressing oscillopsia by 25-75% in four out
of five patients (two upbeat nystagmus;
two downbeat
nystagmus).
Physostig-
mine (1 mg single intravenous injection)
increased nystagmus in five additional
patients with downbeat (1) or positional
downbeat nystagmus (4) for a duration
of 15-20 minutes. The different interac-
tions of baclofen and physostigmine on
neurotransmission
subserving
vertical
vestibulo-ocular reflex could account for
these effects. The response to baclofen
appears to be a GABA-B-ergic effect with
augmentation
of
the
physiological
inhibitory
influence
of the
vestibulo-
cerebellum
on
the
vestibular
nuclei.
Similarly
baclofen
has
an
inhibitory
effect on the velocity storage mechanism.
Cholinergic
action
may
cause
the
increment of nystagmus by physostig-
mine.
Little
is known about neurotransmitters
involved, although pathways for upward and
downward VOR have been identified. Clinical
evidence suggests cholinergic and gabaergic
transmission.
Cholinergic drugs (physostig-
mine)
counteract
a
hyperactive
horizontal
VOR and disturbed fixation suppression of
caloric nystagmus in familial ataxia" " and
cerebellar
degeneration. 6
Anticholinergic
drugs (scopolamine or trihexiphenidyl) sup-
press
acquired
pendular
nystagmus
and
palatal
myoclonus. 7 The GABA-B-agonist
baclofen effectively suppresses periodic and
non-periodic alternating nystagmus.'20
In this report, we describe the effects of
baclofen (GABA-B-agonist) and physostig-
mine (cholinergic drug) in 10 patients with
acquired
upbeat
(2),
downbeat
(4),
or
positional downbeat nystagmus
(4). In one


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(patient 6), the effect of the anticholinergic
drug biperiden, which was injected 10 min-
utes after physostigmine injection, was tested.
It was found that baclofen inhibits upbeat and
downbeat nystagmus in some patients and this
has obvious clinical relevance. Physostigmine
on the other hand, appeared to change the
condition for the worse.
Department of
Neurology, Klinikum
Grosshadern,
University of Munich,
Munich, Germany
M Dieterich
A Straube
T Brandt
W Paulus
U Buttner
Correspondence to:
Dr Dieterich, Neurologische
Klinik, Klinikum
Grosshadern, Ludwig-
Maximilians Universitat,
Marchioninistrasse 15,
D 8000 Munich 70,
Germany
Received 19 July 1990
and in revised form
25 October 1990.
Accepted 15 November 1990
Upbeat
and
downbeat
nystagmus
in
the
primary position of gaze, with concomitant
oscillopsia, reflect an imbalance of vertical ves-
tibulo-ocular reflex tone in the pitch plane.'
Both
are
modulated
by
otolithic
input.23
Alternatively,
an imbalance of the
vertical
smooth pursuit system for downbeat nystag-
mus4 has been proposed. However, features of
the syndrome such
as fore-aft postural ins-
tability2 cannot be explained with this hypo-
thesis.
The pathways for upward- and downward-
vestibulo-ocular reflexes (VOR), from the ves-
tibular nuclei
to the oculomotor nuclei, are
partially
separated.5
The
vertical VOR
is
under the influence of the cerebellum, mainly
the vestibulo-cerebellum which projects on to
the vestibular nuclei.6 Upbeat nystagmus may
be induced by disrupting the upward VOR
pathways within the brachium conjunctivum7
or within structures of the caudal brainstem,
such as perihypoglossal nuclei89 and the ven-
tral
tegmental
pathway,'0
which
modulate
VOR. The downbeat nystagmus syndrome, as
demonstrated in monkeys, is caused by lesions
of either the floor of the fourth ventricle bet-
ween
the
vestibular
nuclei"
or
the
floc-
culus. 12
1
Patients and methods
Data for patients 1-10 are listed in table 1.
Patients 7-10 showed slight downbeat nys-
tagmus, with Frenzel's glasses, in the upright


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position of the head and positional downbeat
nystagmus in the head hanging position. After
physostigmine
application
(1 mg),
the
increased downbeat nystagmus was recorded
in the upright position with the eyes closed.
There was no history of previous drug treat-
ment in these patients.
Two healthy male subjects (aged 34 and 29
years
respectively)
were
used
as
controls.
Their eye movements were recorded with
electro-oculography (EOG) before and after
the intravenous injection of 1 mg physostig-
mine.
Horizontal and vertical eye position was
recorded
separately
by DC-EOG
with
a
resolution of 1 degree. The linearity of DC-
EOG for recording vertical eye movements
was
+ 30
degrees. The bandwidth of the
recording
system
was
0-30 Hz.
EOG
measurements
of
vertical
eye
movements
contaminated by lid artifacts were dismissed.
Eye movements and stimuli were stored on a
six channel tape recorder and printed on a
thermoprinter.
During recordings,
the subject
sat
in
a
627


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Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:1106-1109
SHORT REPORT
Saccade deficits after a unilateral lesion affecting
the superior colliculus
C Pierrot-Deseilligny, A Rosa, K Masmoudi, S Rivaud, B Gaymard
Abstract
A
70
year
old
patient with a small
haematoma largely restricted to the area
of
the
right
superior
and
inferior
colliculi
is
reported. Eye movements
were electro-oculographically recorded
17 and 80 days after the onset of the
haematoma. At the first examination,
latency
of
lateral
reflexive
visually-
guided saccades was asymmetrical, both
in the gap task (central fixation point
switched off200 ms before the onset ofthe
lateral target) and in the overlap task
(central
fixation
point
remaining
switched on). Furthermore, latency of
leftward saccades in the overlap task
was increased, and accuracy of these
saccades was impaired, at both examina-
tions. In the immobility task (fixation
straight
ahead
while
lateral
targets
suddenly
occurred) and
in
the
anti-
saccade task (saccade made away from
the lateral target), the percentages of
errors (saccades made
to the target)
were high at the first examination, and
noticeably lower at the second. These
results
suggest
that
the
superior
colliculus plays an important role both
in
the
triggering
and
inhibition
of
reflexive visually-guided saccades.
Service de Neurologie
and Unit6 INSERM
289, H6pital de la
Salpetri&re, Paris, and
Service de Neurologie,
H6pital Nord, Amiens,
France
C Pierrot-Deseilligny
A Rosa
K Masmoudi
S Rivaud
B Gaymard
Correspondence to:
Dr Pierrot-Deseilligny,
Service de Neurologie,
H6pital de la Salpetriire,
47 Bd de l'H6pital,
75651 Paris Cedex 13,
France.
Received 17 December 1990
and in revised form
19 March 1991.
Accepted 5 April 1991
The triggering of all types of saccades appears
to be performed by two suprareticular struc-
tures, the superior colliculus (SC) and the
frontal eye field (FEF), which both project
directly
on
to
the
brainstem
premotor
reticular formations.'2 In the normal
state,


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state,
however, the degree of involvement of each of
these two parallel pathways is different depen-
ding upon the types of saccade to be perfor-
med. Lesion studies in the monkey suggest
that the SC plays an important role in the
control of reflexive visually-guided saccades."
To date, only one patient with an isolated SC
lesion has been studied with saccade record-
imgs:'
spontaneous
saccades
and
reflexive
visually-guided
saccades
were
impaired.
There was also a limited lesion affecting the
SC
in
our
patient. Eye
movements
were
electrooculographically recorded using four
different paradigms, which tested both the
excitatory
and
inhibitory
mechanisms
involved during the
initiation of reflexive
visually-guided saccades. The results lead to a
better understanding of the role of the SC in
the initiation of these saccades.
Case report
A 70 year old diabetic man, treated with
oral medicines for 10 years, was admitted to
hospital
for
headache
and
a
slight
left
hemiparesis, which began the day before. He
also complained of intermittent slight vertical
diplopia,
occurring
in
downward
gaze.
Neurological
examination
on
admission
showed only a cerebellar syndrome in his
right arm. There was no obvious ocular motor
paresis, and convergence and pupillary reac-
tions were normal. His blood pressure was
220/100 mm Hg. A CT performed on the day
of admission, and an MRI performed 17 days
later, showed
a
lesion
affecting
the
right
superior and inferior colliculi and possibly the
right brachium conjunctivum suggestive of a
small haematoma (fig A, B, C). The headache
lasted three days. Eye movements were recor-
ded twice, 17 days and 80 days after the onset.
During
these
two
recording
sessions
the
patient was alert and cooperative. His vertical
diplopia still occurred occasionally in down-
ward gaze, being due to a slight paresis of the
left superior oblique muscle (Lancaster test).
There was no diplopia when the eyes moved
horizontally
in
the
different
saccade
paradigms. Visual attention was tested in the
first
recording
session,


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session,
according
to
a
procedure previously described;7 there was no
visual neglect. A second MRI was performed
the day before the second recording session,
showing a small cicatricial lesion affecting the
right superior and inferior colliculi (fig D).
Eye movement recordings
Eye movements were recorded by
direct-
current
electro-oculography
(EOG)
in
complete darkness with four electrodes (two
horizontal temporal, and two vertical on one
eye). The head was immobilised by a head-
rest with
a
restraining mechanism
at the
temples.
Four
saccade
paradigms
were
studied.
The overlap task tested the triggering of
reflexive visually-guided saccades. A central
fixation point was switched on throughout the
task. The subject was instructed to fix this
point, and to look as quickly as possible at a
lateral target, suddenly occurring 250 away
from the central point, either right or left,
1106


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Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal in patients with clinical and pathological diagnosis ofAlzheimer's disease


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Journal ofNeurology, Neurosurgery, and Psychiatry 1992;55:190-194
Association of atrophy of the medial temporal lobe
with reduced blood flow in the posterior
parietotemporal cortex in patients with a clinical
and pathological diagnosis of Alzheimer's disease
K A Jobst, A D Smith, C S Barker, A Wear, E M King, A Smith, P A Anslow,
A J Molyneux, B J Shepstone, N Soper, K A Holmes, J R Robinson, R A Hope,
C Oppenheimer, K Brockbank, B McDonald
Radcliffe Infirmary,
Oxford OX2 6HE
University
Department of
Clinical Neurology
K A Jobst
A Wear
E M King
A Smith
University
Department of
Pharmacology
A D Smith
Department of
Neuroradiology
C S Barker
P A Anslow
A J Molyneux
Department of
Neuropathology
B McDonald
University
Department of
Nuclear Medicine,
John Radcliffe
Hospital, Oxford
B J Shepstone
N Soper
K A Holmes
Littlemore Hospital,
Oxford
J R Robinson
K Brockbank
University
Department of
Psychiatry,
Warneford Hospital,
Oxford
R A Hope
C Oppenheimer
Received 11 March 1991 and
in revised form 10 June 1991.
Accepted 18 July 1991
Abstract
A combination of medial temporal lobe
atrophy,
shown
by
computed
tomo-
graphy, and reduced blood flow in the
parietotemporal cortex, shown by single
photon emission tomography, was found
in 86% (44151) of patients with a clinical
diagnosis of senile dementia of the Alz-
heimer type (SDAT). The same combina-
tion ofchanges was found in four out of 10
patients
with
other
clinical
types
of
dementia and in two out of 18 with no
evidence of cognitive deficit. Of the 12
patients who died, 10 fulfilled histopatho-
logical criteria for Alzheimer's disease,
nine ofthem having a clinical diagnosis of
SDAT, and one a clinical diagnosis of
multi-infarct dementia. All 10 patients
with histopathologically diagnosed Alz-
heimer's disease had shown a combina-
tion ofhippocampal atrophy and reduced
parietotemporal blood flow in life. In 10
patients (nine with SDAT) out of 12 in
whom
the
hippocampal
atrophy
was
more noticeable on one side of the brain
than on the other the parietotemporal


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perfusion deficit was also asymmetrical,
being greater on the side showing more
hippocampal atrophy. These results sug-
gest that the combination of atrophy of
the hippocampal formation and reduced
bloodflowin the parietotemporal region is
a feature of dementia of the Alzheimer
type and that the functional change in the
parietotemporal region might be related
to the loss ofthe projection neurons in the
parahippocampal gyrus that innervate
this region of the neocortex.
CT has shown that many patients with a
clinical diagnosis of senile dementia of the
Alzheimer
type
(SDAT)
display
more
appreciable cerebral atrophy than expected for
their age.' Functional changes in the brains of
demented patients have been found by meth-
ods that show cerebral blood flow, or uptake of
glucose, oxygen
or radioligands:
the most
frequent finding is a functional deficit in the
posterior parietal and temporal lobes ofthe cor-
tex.2"
Single photon emission tomography
(SPET) has recently been used to show that the
functional deficits in the posterior parietal and
lateral temporal lobes are related to the degree
of cognitive decline,"8 but such findings are
difficult to reconcile with neuropathological
studies showing that the most severely affected
parts of the brain in Alzheimer's disease are in
the medial lobe, mainly the amygdala, the
hippocampal formation and adjacent parahip-
pocampal gyrus.>'3 Atrophy of these areas can
be revealed in life by CT studies in which the
scan angle is adjusted to give a clearer view of
the medial temporal lobe, and such studies in
patients with a clinical diagnosis ofAlzheimer's
disease have, indeed, shown severe damage to
structures in the medial temporal lobe.'""6
However, atrophy of the medial temporal lobe
is also found in other conditions-notably,
epilepsy and hypoxia,'7 schizophrenia,'8 and
amnesia'9-and so is not unique to dementia of
the Alzheimer's type.
In none of the CT and SPET studies des-
cribed above were the two procedures carried
out in the same patients. The purpose of our


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report is to describe CT studies ofthe temporal
lobe and SPET studies of perfusion of the
cortex in the same group of patients. We
wished to see whether there was any relation
between atrophy of the medial temporal lobe
and a perfusion deficit in the parietotemporal
cortex and, if so, whether such a relation was
associated with Alzheimer's disease defined
clinically and, when possible, by histopatho-
logical criteria. Preliminary findings have been
reported.20
Patients and methods
Patients were recruited,
after having been
given a full explanation of the study protocol,
from general practitioners and hospital based
services, with some subjects entering them-
selves. Ethical approval for the study was
obtained
from
both
the
Central
Oxford
Research and the Psychiatric Sector Research
ethics committees. Informed consent was ob-
tained from those without cognitive deficit, and
for those with a significant deficit it was given by
a close relative. Subjects were referred with
varying degrees of mental deterioration and
memory loss, many for detailed screening with
a view to making a diagnosis. Diagnoses were
made according to DSM-III-R criteria. Drug
treatment remained unchanged during screen-
ing.
190


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Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:65-68
Abstract
Following an all-night fast, 45 patients
with Parkinson's disease were examined
using certain motor items present in the
United Parkinson's Disease Rating Scale.
All were given a single tablet of carbidopa
25 mg and levodopa 250 mg and re-exam-
ined 90 minutes later. In addition to this
evaluation, 23 of these patients underwent
further scoring over a 4-hour period. A
significant negative correlation was found
between age and one important aspect of
drug-derived
benefit:
magnitude
of
response. In contrast, age had no appar-
ent influence on duration of benefit from
the
drug.
Although
baseline
(fasting)
scores were predictably correlated with
duration
of
disease,
magnitude
of
response was not adversely influenced by
this variable. Not all Parkinsonian signs
were equally influenced by age. Whereas
the poor response ofgait and bradykinesia
appeared to be dependent on age, no such
effect was noted on rest tremor scores.
The data indicate that in patients with
Parkinson's disease treated long term,
factors associated with age rather than
duration of disease may have a stronger
adverse
influence
on
magnitude
of
response to levodopa.
(J Neurol Neurosurg Psychiatry 1993;56:65-68)
Department of
Neurology, Boston
University School of
Medicine, Boston,
Massachusetts, United
States, Department of
Neurology, Boston
Veterans
Administration
Medical Center,
Boston,
Massachusetts, United
States
R Durso
K Isaac
L Perry
M Saint-Hilaire
R G Feldman
Correspondence to:
Raymon Durso, Department
of Neurology, Boston
Veterans Administration
Medical Center, 150 South
Huntington Avenue, Boston,
MA 02130, United States.
Received 17 July 1991
and in revised form
3 February 1992 and
28 April 1992.
Accepted 2 May 1992
A well-documented finding regarding limita-
tions of levodopa use in Parkinson's disease is
the observation that treatment is most effica-
cious during the early years of therapy and
that, later, many patients experience a sig-
nificant decline
in the


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in the
effectiveness of the
drug.' 2 Two
factors
that
characterise
this
decline
are,
firstly,
a
shorter
duration
of
response and, secondly, an inability to main-
tain the same quality of improvement. The
reduction
in
the
duration
of response
to
levodopa is clinically manifested as wearing
off, end-of-dose deterioration or the on-off
phenomenon. There is considerable agreement
that these limitations in duration of benefit are,
at least in part, related to disease progression
(that
is,
a continuing loss of cells
in the
nigra).36 In this regard, a diminished capacity
of nigral terminals to synthesize and store
dopamine, or both,78 may play an important
role. There is less consensus about factors that
may limit the magnitude of the response to
levodopa. Using data obtained from patients
participating in pharmacological studies at the
65
Boston Veterans Administration Medical Cen-
ter and University Hospital, we analysed the
duration and magnitude of response to levo-
dopa in relation to several potential factors that
might influence its efficacy. This opportunity
was
available
because
all
participants had
received
the same dose of carbidopa and
levodopa without concomitant administration
of other medications and all had been scored
using motor items
present
in
the United
Parkinson's Disease Rating Scale (UPDRS).
Patients and methods
Examination scores from 45 patients (39 males
and
six females)
with Parkinson's
disease,
having participated in either of two pharmaco-
logical studies, were analysed with regard to
their age at the time of study; their age at time
of disease onset; the duration of the disease
and the daily levodopa dose. The duration
of levodopa
therapy
was
not
specifically
addressed as essentially it was identical to the
duration of disease in our patient population.
The diagnosis of Parkinson's disease had been
agreed upon by
at
least two
neurologists
experienced in movement disorders and all
patients exposed
to levodopa had demon-
strated sustained, significant benefit from the


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drug. Individuals with pyramidal, cerebellar or
prominent autonomic signs were excluded, to
minimise inclusion of the diagnosis of multi-
systems degeneration. Prior approval for these
projects had been given by the Research and
Development Human Studies Subcommittees
of both the Boston Veterans Administration
Medical Center and the Boston University
Hospital.
The
two
pharmacological
studies
from
which subjects were evaluated employed iden-
tical methodologies except for frequency of
observations following carbidopa and levodopa
administration.
One
patient
group
(22
patients) was scored immediately preceding
administration of carbidopa and levodopa and
90 minutes after. The other group (23 patients
underwent multiple examinations immediately
before and 30, 60, 90, 120, 180, 240 minutes
after administration. No single patient partici-
pated in both studies. On the day of investiga-
tion, patients were fasted and all medications
withheld from midnight. Studies were con-
ducted in both outpatient and inpatient set-
tings. At 9am subjects were evaluated using
motor examination
items
in
the UPDRS.
These
examinations
were
also
videotaped.
Scoring was done by either one of two inves-
tigators (RD or KI). A separate analysis of the
Age influences magnitude but not duration of
response to levodopa
Raymon Durso, Kathryn Isaac, Linda Perry, Marie Saint-Hilaire, Robert G Feldman


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J7ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:85-93
Severe psychiatric disturbance and abnormalities
of the corpus callosum: review and case series
Anthony S David, Alisa Wacharasindhu, W Alwyn Lishman
Abstract
The association between developmental
defects of the corpus callosum and major
psychiatric disturbance is discussed with
a review of published cases. Seven new
cases are presented, of which four had
clear psychotic symptoms, two receiving a
diagnosis
of
schizophrenia.
Of
the
remainder, one had a developmental dis-
order
affecting
social
interaction
and
speech which could be classed as Asper-
ger's syndrome, one had a personality
disorder with depressive and conversion
symptoms, and the last was an adolescent
boy with severe behavioural problems.
The difficulties in determining the precise
relevance of the
callosal anomalies
to
these clinical manifestations are discussed
especially since the prevalence of such
anomalies in the population is uncertain.
(y Neurol Neurosurg Psychiatry 1993;56:85-93)
Department of
Psychological
Medicine, Institute of
Psychiatry and King's
College Hospital,
London, UK
A S David
A Wacharasindhu
Section of
Neuropsychiatry,
Institute of Psychiatry,
London, UK
W A Iishman
Correspondence to:
Dr David, Department of
Psychological Medicine,
King's College Hospital,
Denmark Hill, London SE5
9RS, UK
Received 18 December 1991
and in revised form
3 April 1992.
Accepted 13 April 1992
The corpus callosum (CC) contains the largest
nerve fibre tract in the human brain, connect-
ing the cerebral hemispheres with one another.
It is estimated to contain nearly 200 million
fibres. The CC together with the anterior and
hippocampal commissures form the forebrain
commissures. The tract develops intimately in
association with the fornix, hippocampal com-
missure, hippocampal formation, septum pel-
lucidum and cingulate cortex, beginning to
form shortly after the anterior commissure.
Details of the anatomy and embryology of
the CC have been well described.''
Abnormal


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Abnormal
morphologies of the CC can be classified into
acquired
and
congenital
defects.
Acquired
changes
can
result from
trauma,
tumours,
hydrocephalus, vascular accidents and white
matter diseases.' Complete agenesis is a rare
developmental anomaly of unknown cause and
is associated with a wide variety of genetic
defects,
in particular trisomies of chromo-
somes, 8, 13 and 18.67 Agenesis has also been
considered a marker of intrauterine metabolic
upsets such
as hyperglycinaemia,8 and may
result from insults such as intrauterine infec-
tions and exposure to toxins.3
-
The partial
forms of agenesis usually affect the posterior
portions and are presumed to reflect the action
of pathogenic influences occurring after the
initial development of the commissures, that is,
after the sixteenth week of gestation.
Agenesis is frequently accompanied by other
developmental defects. These encompass com-
mon midline abnormalities (for example, cleft
palate),
although
other
ocular
and
spinal
abnormalities
may
occur.6 The
associated
brain anomalies which have been reported
include interhemispheric
cysts with hydro-
cephalus (Dandy-Walker malformation), lipo-
mas of the CC or interhemispheric fissure,
invariably
associated
with
partial
agenesis,
absence of the inferior cerebellar vermis, and
disorders of neuronal migration."2 The cingu-
late gyrus is invariably abnormal and limbic
structures may also be affected.
The main function of the CC
is
inter-
hemispheric
integration:
connecting
corre-
sponding regions of the cerebral cortex in the
two
hemispheres.
Crudely,
it
serves
as
a
conduit
for
transfer
of
sensory
informa-
tion,'3-15 although the precise nature of the
information transferred and its overall influ-
ence on the activity of the hemispheres is a
topic of continued research and speculation.'6
It has been noted repeatedly that in agenesis of
the CC there is an absence of most aspects of
the disconnection symptoms which affect sub-
jects who have had
surgical separation of
the
commissures-the
"split-brain
opera-
tion"." 1


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tion"." 1
This has been attributed to the
presence of alternative pathways connecting
the hemispheres such as the anterior com-
missure, which
is frequently
intact despite
callosal
agenesis,
or
subcortical
channels.
Other compensatory mechanisms may also
play a part such as the duplication of those
specialised functions which are usually dis-
tributed asymmetrically between the hemi-
spheres, such as speech. Nevertheless, some
failures of interhemispheric communication
have been noted such as reduced transfer of
maze learning from one hand to another,'9
impaired matching of visual patterns between
the right and left visual fields20 and reduced
transfer of incongruent word
stimuli
in
a
colour naming task,2' (but see22).
The prevalence of callosal agenesis is diffi-
cult to quantify. Widely varying estimates in the
literature, ranging from 0 004% to 2-64%,
reflect the different study populations (tables 1
and 2). Thus paediatric neurology services will
give higher rates than necropsy studies of
unselected members of the population. Sim-
ilarly, the rates of associated abnormalities and
clinical problems reflect the setting in which
cases are evaluated. All that can be stated is
that
certain presentations, namely learning
disability
and
epilepsy
are
rather
com-
mon,3 17 30
the
latter
usually
estimated
at
around 40%. Despite most cases coming to
light because of the need
to investigate
a
manifest neurological syndrome, many series
85


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Ideomotor apraxia without aphasia and aphasia without apraxia: the anatomical for double dissociation


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26ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:286-289
Ideomotor apraxia without aphasia and aphasia
without apraxia: the anatomical support for a
double dissociation
Costanza Papagno, Sergio Della Sala, Anna Basso
Abstract
This study aimed to verify the existence of
a
double
aphasialapraxia
dissociation.
Apraxic
patients
without
aphasia and
aphasic
patients without apraxia were
included in a consecutive series ofpatients
with cortical or subcortical CT docu-
mented vascular lesions in the left hemi-
sphere. Of 699 patients, 10 were found to
be apraxic but not aphasic and 149 aphasic
but not apraxic. These findings indicate an
aphasialapraxia double dissociation. This
suggests that praxis and language make
use of two different, partly overlapping
networks.
(J Neurol Neurosurg Psychiatry 1993;56:286-289)
MRC Applied
Psychology Unit,
Cambridge, UK
C Papagno
Department of
Neurophysiology, S
Paolo Hospital, Milan
and Neuropsychology
Unit, Clinica del
Lavoro Foundation,
Medical Center of
Veruno, Italy
S Della Sala
Istituto di Clinica
Neurologica, Milan
University, Milan,
Italy
A Basso
Correspondence to:
Dr Papagno, Presidio
Ospedaliero, via Verdi 2,
20038 Seregno, Milano,
Italy
Received 6 June 1991
and in final revised form
29 June 1991
Accepted
10 July 1992
The term "apraxia" encompasses various dis-
orders affecting the purposeful execution of
deliberate
movements
which
cannot
be
explained by elementary motor-sensory defi-
cits, perceptual and comprehension impair-
ment
or
severe
mental
deterioration.
Ideomotor apraxia
is
a form of apraxia in
which the implementation of the gesture in a
precise motor programme
is disrupted.
In
right handed subjects ideomotor apraxia
is
associated with lesions in the left hemisphere2 3
which is also dominant for language and has
therefore often been associated with aphasia.
Ajuriaguerra
et
al 4 reported
that 90%
of
patients with ideomotor apraxia also had apha-
sia.
Conversely
32
of 60
(53%)
aphasic
patients5 were also apraxic.
The
association
between
aphasia
and


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and
apraxia is often due to the encroachment of the
lesion upon contiguous
structures, differen-
tially
specialised
for language and
praxis.'
Aphasia has often been reported in the absence
of apraxia5 which supports this theory. The
opposite pattern (apraxia without aphasia) has
rarely been reported.
Liepmann6 (quoted by Ajuriaguerra et al 4)
reported 7 non-aphasic patients with poorly
specified disturbances of praxis, 6 of whom
had right hemiplegia and therefore presumably
a left-hemisphere lesion. Recently, Goodglass
and Kaplan7 reported 5 mildly apraxic though
non-aphasic patients with left brain damage,
Heilman et al8 reported a non-aphasic, right
handed man who was examined three months
after
a left-hemisphere
stroke who showed
ideomotor apraxia and agraphia, and Selnes et
ae
described
a patient with transient fluent
aphasia with an auditory comprehension defi-
cit and persistent apraxia and dysgraphia three
years after frontoparietal ischaemia. Selnes et
allo described an 81 year old right handed
man, affected by myasthenia gravis who, one
month after a massive left-hemisphere stroke,
showed marked limb apraxia coupled with
dyscalculia, right neglect, anosognosia, agra-
phia but no aphasia, except for mild dysno-
mia.
One apraxic patient out of 40 non-aphasic
subjects with left brain damage was reported
by De Renzi et al.5 Agostoni et al" described a
patient (case 5) who sustained an ischaemic
lesion of the internal capsule and caudate
nucleus, and was not aphasic. To find support
for the notion of dissociability between aphasia
and apraxia, Kertesz et al'3 studied a series of
143 patients who had sustained a cortical or
subcortical stroke of the left-hemisphere and
who had been examined at least three months
afterwards. In 2 severe and 7 moderate aphasic
patients, praxis was spared and in one case of
mild aphasia, praxis was moderate. Kertesz et
all3 did not observe apraxia in non-aphasic
patients. Junque et all4 reported a right handed
patient who had ideomotor apraxia but not


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aphasia, after a massive left-hemisphere infarc-
tion. Recently Della Sala et all' reported a
patient (case 29) with apraxia and without
aphasia in a series of patients with left hemi-
sphere subcortical lesions.
In this study we aimed to verify the existence
of a double dissociation between aphasia and
apraxia. For this purpose we systematically
searched for apraxic non-aphasic subjects and
vice versa in a consecutive series of patients
with cortical or subcortical left-hemisphere
vascular lesions.
Material and methods
Subjects
Among the patients examined at the Aphasia
Unit at Milan University between 1979 and
1988,
we
selected
the
699
right
handed
patients with CT documented vascular lesion
in the left-hemisphere (CT without enhance-
ment performed
at least
15 days after the
stroke).
Neuropsychological investigation
All subjects had the following neuropsycho-
logical examination at different intervals after
stroke:
1) Ideomotor apraxia
A 24 item test for ideomotor apraxia, which
consists of half nonsymbolic and half symbolic
movements, half requiring the holding of a
static position and half the execution of motor
286


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Peripheral neuropathy the presenting feature of tyrosinaemia I and effectively treated with inhibitor of 4-hydroxyphenylpyruvate dioxygenase


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Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56: 1129-1132
LESSON OF THE MONTH
Peripheral neuropathy as the presenting feature of
tyrosinaemia type I and effectively treated with an
inhibitor of 4-hydroxyphenylpyruvate dioxygenase
T C Gibbs, J Payan, E M Brett, S Lindstedt, E Holme, P T Clayton
Abstract
A 21 month old girl presented with a
short history of frequent falls and a right
sided foot drop. She went on to suffer
recurrent episodes of distal weakness in
her arms and legs with hyporeflexia.
Electrophysiological studies were consis-
tent with inflammatory
demyelinating
polyradiculoneuropathy (IDP) and treat-
ment with corticosteroids appeared to
lead to an improvement. However, the
development ofhypertension, evidence of
tubulopathy, and hepatomegaly led to re-
evaluation. A diagnosis of type I tyrosi-
naemia was made, based on increased
urinary excretion of succinylacetone and
decreased
activity
of fiumarylacetoac-
etase in her cultured skin fibroblasts. A
low tyrosine diet did not prevent life-
threatening exacerbations of neuropathy
but intravenous haemarginate appeared
to aid her recovery from one exacerba-
tion.
An
immediate
improvement
in
strength was seen after starting treat-
ment with 2-(2-nitro-4-trifluoro-methyl-
benzoyl)-1,3-cyclohexanedione
(NTBC),
an inhibitor of 4-hydroxy-phenylpyru-
vate
dioxygenase.
A
liver
transplant
was performed but the patient died of
immediate postoperative complications.
Tyrosinaemia needs to be considered in a
child with recurrent peripheral neur-
opathy because (i) the signs of liver dis-
ease and renal tubular dysfunction may
be subtle;
(ii) acute exacerbations may
be life threatening; (iii) specific forms of
treatment are available.
(7 Neurol Neurosurg Psychiatry 1993;56:1129-1132)
Tyrosinaemia type I (McKusick no 276700)
usually presents with symptoms attributable
to hepatic or renal tubular dysfunction, or
both.'
Tyrosinaemia
can
be
detected by
neonatal amino acid screening,2 or by more
specific screening procedures based on the
accumulation
of


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of
succinylacetone
or
its
effects.34 Succinylacetone, which accumulates
in this disorder, is a potent inhibitor of por-
phobilinogen synthase and patients usually
show increased urinary excretion of 5-amino-
laevulinic acid (&-ALA).
Neurological crises resembling acute por-
phyria have been well described in children
with tyrosinaemia,'7 but we are only aware of
one case in which a neurological symptom
(ataxia) was
the presenting
feature.8 This
report describes a patient with tyrosinaemia
type I in whom recurrent weakness due to a
peripheral
neuropathy was
the
presenting
symptom. A number of different forms of
treatment were attempted and the results are
presented.
Case report
Our
patient was
the
first
child born
to
unrelated Asian parents. There was no family
history
of
neurological
disease.
Neonatal
screening excluded hyperphenylalaninaemia
and hypothyroidism but the methods used
were not capable of picking up tyrosinaemia.
The patient had started walking at 16 months
and was apparently well until 21 months of
age. At about this time her parents noticed
she tended to fall over and had a right-sided
foot drop.
At 26, 29, and 32 months, she had an
acute illness characterised by a fever, irritabil-
ity, leg pains, a right-sided limp, and colicky
right iliac fossa pain. Examination revealed
distal weakness in her arms and legs, bilateral
foot drop, and decreased reflexes with absent
ankle jerks. Nerve conduction studies were
performed at 30 and 33 months (see below).
A diagnosis of a chronic relapsing form of
polyneuropathy was made because of the
nature and variability of the results of motor
conduction studies and the persisting normal-
ity of sensory conduction. High dose daily
oral corticosteroids led to an improvement in
her symptoms. Any attempt to reduce the
dose of prednisolone to less than 17-5 mg per
day over the next 18 months led to exacerba-
tion of her symptoms. The response to treat-
ment was gratifying but certain features of the
case remained unexplained as indicated in


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table 1 (26 months, 29 months).
At 3-5 years the patient was noted to have
developed palmar erythema. She was cushin-
goid,
hypertensive
(170/120),
and
had
stopped growing. Examination revealed clini-
cal cardiomegaly and echocardiography con-
firmed biventricular hypertrophy. A firm liver
edge was palpable 2-5 cm below the costal
margin. She had a wide-based
gait,
distal
muscle weakness with areflexia, and flexor
Hospital for Sick
Children, Great
Ormond Street,
London WClH 3JH
Medical Professorial
Unit
T C Gibbs
P T Clayton
Department of
Neurology
J Payan
E M Brett
Department of
Clinical Chemistry,
Gothenburg
University, Sahlgren's
Hospital, Sweden
S Lindstedt
E Holme
Correspondence to:
Dr P Clayton.
Received 26 October 1992
and in final revised form
18 February 1993.
Accepted 26 February 1993
1129


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9'ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:990-996
Motor recovery after acute ischaemic stroke: a
metabolic study
V Di Piero, F M Chollet, P MacCarthy, G L Lenzi, R S J Frackowiak
Abstract
The metabolic changes occurring after
ischaemic stroke were measured to inves-
tigate the functional anatomy of clinical
motor recovery. Positron emission tomog-
raphy (PET) and the
steady-state
15O
technique was used to compare resting
relative
metabolic
distributions
at
the
onset of functional deficit with those fol-
lowing recovery. Ten patients were studied
with repeat scans. Motor recovery was
associated
in
some
patients
with
an
increase of relative oxygen metabolism in
anatomical structures normally involved
in motor function in the affected hemi-
sphere, particularly in the cortical motor
areas. In those patients without such met-
abolic changes in the cortex of the dis-
eased hemisphere, relative increases in
cortical metabolism in the contralateral
hemisphere were associated with better
motor recovery than in patients with no
relative
cortical metabolic
increase
in
either hemisphere. There was no correla-
tion between the degree of improvement
in motor function and the severity of
motor deficit at onset, the size and site of
the lesion and the metabolic changes in
the infarcted zone. No particular pattern
of global metabolic changes was observed
after recovery. Thus different relative pat-
terns of metabolic recovery were seen in
patients with different lesions and evi-
dence was found for the participation of
contralateral structures in the recovery
process in some patients.
(7 Neurol Neurosurg Psychiatry 1992;55:990-996)
A demonstrably effective therapeutic approach
to acute cerebral ischaemia has
still to be
defined. This is partly due to an incomplete
understanding of the mechanisms leading to
ischaemic
cell death and partly to an even
greater ignorance about the mechanisms of
functional recovery following cerebral infarc-
tion. Research in the area of functional rehabil-
itation
is
doubly


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is
doubly
difficult
because
of the
multiple variables that affect outcome and the
difficulty of selecting homogeneous patient
populations with respect to mechanism and
extent of infarction.1 Methods of selecting
groups of patients that might benefit from
intensive rehabilitation treatment and what
forms,
if any, such treatment should
take
remain to be defined. One step would be the
establishment
of the
functional
anatomical
basis for such recovery. The investigation of
such aspects of human functional recovery has
been mainly
clinical and pathological with
attention directed principally at the ischaemic
lesion. The results have been contradictory.25
Cerebral blood flow (CBF) has been the
principal
functional
parameter
investigated
with the development of functional neuroim-
aging techniques. However, in the acute phase
of stroke there is profound mismatch between
cerebral
metabolism
and
blood
flow
with
various degrees of relative or absolute hyper-
aemia, -' which means that CBF does not
reflect cerebral function in the early phase of
injury. The mismatch is responsible for the low
prognostic value of CBF unless the measure-
ment is made within a very few hours of onset
of the acute ischaemia.9"-1 Positron emission
tomography (PET) can be used to measure
human brain metabolism in vivo thus provid-
ing more direct evidence of cerebral function
in the acute phase of stroke.
The aim of our study was to evaluate the
metabolic changes occurring after ischaemic
stroke in the acute and recovered phase and to
investigate correlations with clinical recovery
of motor function.
Materials and methods
We studied 5 male and 5 female patients, mean
(SD) age 54-3
(8 7) years, presenting with
motor dysfunction due
to
acute ischaemic
infarction in a cerebral hemisphere. Comatose
patients or those suffering from other neuro-
logical conditions were excluded. The study
had the approval of the Hammersmith Hospi-
tal ethics committee and the Administration of
Radioactive Substances Advisory Committee


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of the Department of Health, UK. Written
informed consent was obtained in each case
from the patient or the nearest relative. All but
one patient (case 8-table 1) had no history of
cerebrovascular
disease.
Clinical
evaluation
included a full neurological examination, an
assessment ofmotor function using the motric-
ity index (MI) of Demeurisse et al, 2 of general
function using the Barthel
scale,'3
a Mini
Mental State test'4 and a formal neuropsycho-
logical evaluation. The MI is a published scale
based upon
the MRC
grading of muscle
strength,
especially
designed
to
evaluate
"patients' progress in motor recovery ... and
correlations with other clinical data".'2 The
scale reflects motor performance using three
movements
in each limb with appropriate
weighting to give a 0-100 scale, with 100
representing normality. Scores from 0 to 32
MRC Cyclotron Unit,
Hanmersmith
Hospital, London, UK
V Di Piero*
R S J Frackowiak
F M Chollett
Cattedra di
Neuropatologia e
Psicopatologia,*
Dipartimento di
Scienze Neurologiche,
Universita degli Studi
"La Sapienza", Rome,
Italy
G L Lenzi
Service de
Neurologie,t HBpital
Purpan, Toulouse,
France
Department of
Radiology,
Hammersmith
Hospital, London, UK
P MacCarthy
Correspondence to:
Professor Frackowiak, MRC
Cyclotron Unit,
Hammersmith Hospital, 150
Ducane Road, Lond6n W12
OHS, UK
Received 13 February 1991
and in final revised form
31 October 1991.
Accepted 14 December
1991
990


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06ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:1046-1053
Hysteria following brain injury
Peter Eames
Abstract
Of 167 patients referred to a unit treating
severe behaviour disorders after brain
injury, 54 showed clinical features closely
resembling those of gross hysteria as des-
cribed by Charcot. Close correlation was
found with very diffuse insults (hypoxia
and hypoglycaemia), but not with severity
of injury or with family or personal his-
tory of hysterical or other psychiatric
disorder. The findings may have implica-
tions for the understanding of the nature
of hysteria.
(7 Neurol Neurosurg Psychiatry 1992;55:1046-1053)
Burden Neurological
Hospital, Bristol BS16
lQT
P Eames
Correspondence to:
P Eames
Received 13 February 1991
and in revised form
24 December 1991.
Accepted 24 February 1992
"Hysteria" is a difficult term, partly because it
embraces several distinct ideas. The complex-
ity is well illustrated byVeith' and in two recent
multi-author books.23 In addition to the diffi-
culties of characterising the central idea of
hysteria, problems arise from the fact that a
range of disorders is subsumed. Four semi-
separable syndromes may be identified: hyster-
ical personality disorder, Briquet's syndrome
or "the stable syndrome of hysteria,"4 the
more focal presentations of dissociation still
usually referred to as "conversion hysteria,"
and what might be
called "Charcot's
syn-
drome" or "gross hysteria." Charcot described
a large number of individuals, mainly but not
exclusively inpatients, who for much if not all
of the time showed a wide and varying range of
usually
gross disturbances
of function and
behaviour that could not be explained on a
basis of demonstrable pathology of the central
nervous system and were thus considered to be
"simulations."5 It was his view, however, that
these simulations were compulsive rather than
voluntary, and were the result of an as yet
unrecognised kind of organic brain disturb-
ance.
In
a
private
hospital
unit
specifically
designed
for
treating
patients
with


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with
severe
behaviour disorders following brain injury,6 it
is the routine practice
to make systematic
observations and ratings ofbehaviours,7 and all
observations
are pooled and discussed
reg-
ularly by the whole treatment team. As a result,
a particular patient with severe hypoxic brain
injury from an anaesthetic accident (see below)
was ultimately recognised to be presenting a
wide
array
of
behaviours
that
could
be
explained only on a basis of gross hysteria. (It
was interesting that
it took several months
before the team suddenly realised the nature of
these disturbances. In retrospect it seemed that
the emotive aspects of severe brain injury of
this kind had elicited what amounted to a
mental set against accurate identification ofthe
problem.)
Case history
Case A
At the age of 26, A, a female schoolteacher,
underwent
planned
cholecystectomy.
The
operation went well, but during the immediate
recovery period she became cyanosed. Urgent
investigation revealed that the lines supplying
nitrous oxide and oxygen had been reversed on
the other side of the wall of the theatre. With
appropriate treatment cardiorespiratory func-
tion soon became normal, but she remained
unconscious for some days, emerging very
gradually, and continuing to seem confused for
many months. It became apparent that she was
cortically blind, with gross disturbance of eye
movements, and there was a diffuse movement
disorder with dystonic quadriparesis, and later,
mild choreoathetosis. She soon became disin-
hibited in talk and behaviour, and required
constant supervision. She began to produce an
almost continuous stream of "empty" phrases
("Nurse, darling, I'm hungry, I'm thirsty, I
want to go to the toilet, nurse.
. .").
A succession of "special" nurses all devel-
oped the habit of responding to each of these
utterances in a reassuring manner. She grad-
ually regained mobility (though this was awk-
ward and hampered by her visual deficit) and
also control of bowel and bladder. Several
attempts at formal rehabilitation were blocked


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by her disordered behaviour.
When case A was seen some two and a half
years after the injury constant utterances inter-
fered with all activities, although she was able
to cooperate with physical examination
to
some extent. There was no apparent response
to visual stimuli, though for most of the time
she kept her eyes closed. Eye movements were
severely disrupted, with searching nystagmus.
Speech was slightly dysarthric and often tele-
grammatic. There was no paresis, but most
movements were dyspraxic, and there was
plastic rigidity of all limbs; slight choreoathe-
totic movements were seen at rest and on
effort. Reflexes were normal. CT had shown
mild diffuse cortical atrophy and moderately
enlarged ventricles, but an electroencephalo-
gram was normal.
She was admitted to a single room in a
general psychiatric unit and had one to one
nursing. It was thought she had considerable
potential for further rehabilitation if the behav-
iour disorder could be overcome. The constant
1046


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16ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:1086-1088
SHORT REPORT
Propriospinal myoclonus in multiple sclerosis
R Kapoor, P Brown, P D Thompson, D H Miller
Abstract
The clinical and electrophysiological fea-
tures of segmental myoclonus affecting
the right arm and upper trunk are des-
cribed in a patient with multiple sclerosis.
Electrophysiological
studies
suggested
that the myoclonus was propagated from a
generator site in the cervical cord, where
lesions were found using MRI. The spread
of electromyographic
activity
in
each
myoclonic jerk was slow and variable.
These findings are characteristic of pro-
priospinal myoclonus, which has not been
associated with multiple
sclerosis pre-
viously.
(7 Neurol Neurosurg Psychiatry 1992;55: 1086-1088)
University
Department of
Clinical Neurology,
National Hospital for
Neurology and
Neurosurgery, Queen
Square, London, UK
R Kapoor
P Brown
P D Thompson
D H Miller
Correspondence to:
Dr Kapoor
Received 18 November
1991.
Accepted 23 January 1992
The types of myoclonus that arise from various
generator sites in the nervous system can be
distinguished
on
clinical and
neurophysio-
logical grounds.
In cortical myoclonus,
for
example, discharges in the sensorimotor cortex
are conducted rapidly in the pyramidal tracts,'
leading to focal or multifocal jerks. In myoclo-
nus of brainstem origin, reticular firing causes
more generalised axial jerks due to rostral and
caudal
spread
of
activity
in
reticulospinal
pathways.2 3
In
contrast,
spinal myoclonus
tends to be focal and segmental, with little
spread of activity from spinal generator sites,
which
produce
jerks
of longer
and
more
variable duration than those of supraspinal
origin.' 5
Recently, an additional form of spinal myo-
clonus has been described in which a spinal
generator
recruits
axial muscles
via
slowly
conducting propriospinal pathways to produce
extensive jerks of the trunk.6 Whereas segmen-
tal spinal myoclonus can occur with numerous
disorders
including multiple
sclerosis,5
few


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few
cases of propriospinal myoclonus have been
described. In one, a cervical cord lesion was
present, but lesions were not found in the
others.6We now report a patient with multiple
sclerosis
in whom propriospinal myoclonus
was documented
and
in whom
associated
lesions of the cervical cord were found on
MRI.
Case report
A right handed white woman developed right
optic neuritis when aged 23 years. The follow-
ing year there was an episode of left optic
neuritis. She then noted a fine postural tremor
(which responded to propranolol), together
with irregular, involuntary jerking of the right
shoulder and arm, and sometimes of the leg.
This could be preceded by a tingling sensation
over the back of the neck. The muscle jerking
persisted, and when aged 25 years she also
developed Lhermitte's symptom and altered
sensation over the left side of her face. This
progressed over four weeks to include urinary
urgency, an unsteady gait and finally a burning
discomfort of the right leg. There was no
additional past or family history of neuro-
logical disease, she was otherwise asympto-
matic and took no regular medications.
At this point the general and state examina-
tion were normal. The corrected visual acuities
were 6/6 on the right and 6/9 on the left, with
impaired colour perception on the left (9 of 13
Ishihara plates were identified). There were
bilateral, paracentral scotomata and both op-
tic discs were pale. A
left relative afferent
pupillary defect and convergence nystagmus
affecting only the left eye were noted. Spino-
thalamic sensation was impaired in the first
and second divisions of the left fifth cranial
nerve, but the corneal reflexes and remaining
cranial nerves were normal.
In the limbs, there were spontaneous, irregu-
lar jerks of the right shoulder and arm leading
to elevation and abduction of the right shoul-
der associated sometimes with a grunt. They
were preceded by a tingling sensation over the
neck but could not be suppressed voluntarily.
Similar jerks were elicited by taps to the right


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shoulder and by pinprick over the proximal
right arm. More violent jerks spread to involve
trunk and hip flexion on the right. Limb tone
and coordination were normal but there was
mild pyramidal weakness of the left leg. The
tendon
reflexes
were
uniformly
brisk,
the
abdominal reflexes present and the left plantar
response
was
extensor.
Sensory
testing
revealed no
objective
abnormalities
in
the
limbs.
Investigations
All routine haematological and biochemical
tests were normal. After the episode of left
optic neuritis the auditory evoked potentials
were also normal, but the visual evoked poten-
tials were delayed bilaterally (full field pattern
evoked P100 latencies 125 ms on the right,
131 ms
on
the
left). The CSF
contained
0 58 g/l protein, glucose
3-3 mmol/l
(blood
glucose 5*1 mmol/l) and 11 white blood cells/
mm3
(all
mature
lymphocytes).
Electro-
1086


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NEURAL REGENERATION RESEARCH｜Vol 18｜No. 8｜August 2023｜1709
NEURAL REGENERATION RESEARCH
www.nrronline.org
Perspective
In vitro microglia models: the era of 
engineered cell microenvironments
Background: The most widely employed approach 
by cell biologists to performing in vitro cell culture 
assays is the one using 2D plastic culture ware 
systems, which allows reproducibility and ease 
of use. Moreover, this method is cost-effective. 
However, in most cases, these flat surfaces lead 
to the formation of unrealistic 2D cell monolayers, 
which do not reproduce the complex configuration 
characteristics of native tissues in terms of 
dimensionality, rigidity, and topography. For this 
reason, a new generation of interdisciplinary 
scientists, working across microengineering and 
cell biology has started to develop engineered 
cell microenvironments (Huang et al., 2017) by 
employing advanced materials and fabrication 
approaches (Fan et al., 2019) over the last two 
decades. Depending on the level of resolution 
of the adopted manufacturing technique, the 
geometrical features of these structures can 
reach micrometric or even sub-micrometric 
dimensions comparable to the ones of cellular 
somas or cellular filopodia, therefore fostering 
cell-biomaterial interactions. The developed 
structures are pivotal for a better investigation 
of fundamental mechanobiology (Lemma et 
al., 2019), the optimization of in vitro disease 
modeling, drug/treatment screening (Gao et al., 
2021), and tissue engineering (Mani et al., 2022).
Among all tissues in our body, brain tissue is 
one of the most complex. Several efforts have 
been made (Accardo et al., 2019) to create 
physiologically relevant and biomimetic artificial 
niches that are able to efficiently host different 
neuronal and glial cell lineages. Among these, 
microglia are the resident macrophages of 
the central nervous system and contribute to 
maintaining the brain’s homeostasis. In addition, 
they have a vital role in tissue repair. Activation


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and dysfunction of microglial cells are associated 
with neurodegenerative diseases, such as 
Alzheimer’s disease and Parkinson’s disease. 
In the human brain, four main phenotypes of 
microglia are reported, namely ramified, primed, 
reactive and amoeboid. The ramified or “resting” 
phenotype is the most abundant in the healthy 
brain and features a cellular morphology with 
multiple extensively ramified processes that 
probe chemical or physical cues that indicate 
the presence of a foreign body or cellular debris. 
Microglia that display an amoeboid or “activated” 
phenotype secrete pro-inflammatory mediators 
and neurotoxins, initiating a pro-inflammatory 
signal cascade that results in phagocytosis, 
among other things. This amoeboid phenotype 
is characterized by a flat cellular morphology, a 
wide cell body, and few (i.e., less than three) or 
no branched primary processes. One of the main 
issues when primary microglia are isolated from 
the brain and are seeded in 2D plastic culture 
ware systems is that they display either round, 
globular-like, or flat, amoeboid-like, morphologies 
(Figure 1A; Jeong et al., 2013). Although progress 
has been made in the optimization of microglia 
Ahmed Sharaf, Raissa Timmerman, Jeffrey Bajramovic, Angelo Accardo* 
employed technique for the fabrication of cell 
scaffolds called electrospinning (Figure 1C-i), able 
to generate polymeric nanofibers using electric 
fields, was employed to assess the response 
of primary microglia (which have a higher pre-
clinical relevance compared to the BV-2 cell line), 
isolated from Wistar rat pups (Pires et al., 2015), 
in presence of poly(trimethylene carbonate-co-ε-
caprolactone) (P(TMC-CL)) fibers. A comparison 
between flat P(TMC-CL) films and P(TMC-CL) 
fibers showed that cells cultured on P(TMC-
CL) films were larger and featured an increased 
circularity compared to microglia cultured on 
fibers. This can be considered as an indication 
of a more pro-inflammatory profile. However,


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when media from the primary microglia culture 
was introduced to astrocytes, astrogliosis was 
not exacerbated, signifying that microglia were 
not activated. Thus, it is important to mention 
that the association between microglia activation 
states and the display of distinct morphologies 
are not always linked. In another recent work, the 
addition of conditioned medium of BV-2 microglia 
grown within 3D graphene foams obtained by 
chemical vapor deposition (Figure 1C-ii) promoted 
neurosphere formation, which was not observed 
when neurons were exposed to conditioned 
medium from 2D cultured microglia, suggesting 
possible applications in the field of regenerative 
medicine (Jiang et al., 2016).
All the above-mentioned studies employed 
microglia cell lines or primary microglia coming 
from rodent models. However, in order to have 
more clinically relevant models for prospective in 
vitro disease modeling, drug-screening assays, or 
even neural tissue engineering purposes, it is of 
paramount importance to evaluate the behavior 
of microglia that are closer to human microglia. 
A recent advancement, making use of primary 
microglia isolated from adult rhesus macaques, 
reported for the first time how micro- and nano-
metric 2.5D and 3D structures, fabricated via 
two-photon polymerization, directly influenced 
primary microglia morphology and branching 
(Figure 1C-iii and D; Sharaf et al., 2022). Two-
photon polymerization is a manufacturing 
in vitro culture conditions, e.g. the elimination of 
serum from the culture medium, in vitro microglia 
are still characterized by an activated phenotype 
(Bohlen et al., 2017; Timmerman et al., 2022). This 
limits the potential of performing fundamental 
neuromechanobiology investigations, and of 
developing in vitro disease models or in vitro 
drug-screening studies that involve microglia. In 
order to overcome this limitation, research has 
been emerging over the last decade showing 
that micro- and nano-engineering approaches


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represent a powerful tool to create controlled and 
reproducible microenvironments able to guide the 
fate of microglia and to optimize current in vitro 
microglia models.
Engineered microglia environments: The 
guidance of microglia morphology and phenotype 
via engineered microenvironments can take place 
by exploiting four different parameters: substrate 
geometry, topography (e.g., roughness), stiffness, 
and biochemical coating (Figure 1B). A decade 
ago, excimer laser processing of thin hydrogenated 
amorphous silicon films deposited by plasma-
enhanced chemical vapor deposition on glass 
substrates already enabled the formation of silicon 
micro and nano-structures (between 2 nm and 2.3 
μm) resulting in substrates with various roughness 
which influenced the morphology of a murine 
microglial cell line (BV-2) (Persheyev et al., 2011). 
On amorphous flat silicon, BV-2 cells tended to 
adopt a rounded morphology with flat protrusions 
whereas in the presence of laser-processed 
silicon micro- and nano-structures, these cells 
displayed a more elongated, bipolar shape. The 
manufactured features are sensed by microglia via 
lamellipodia and filopodia in a process known as 
mechanosensing. More recently, another widely 
A
B
C
D
Figure 1 ｜ Schematic representation of the various features of in vitro microenvironments, the processes used to 
fabricate them, and their effect on microglia.
(A) Microglia phenotypes observed in vivo and in vitro. (B) Overview of the parameters of in vitro microglia 
engineered microenvironments and their interplay therein. (C) Examples of processes employed to fabricate in vitro 
engineered microglia microenvironments (i) electrospinning, (ii) chemical vapor deposition (CVD), and (iii) two-photon 
polymerization (2PP). (D) An example of the effect of engineered microenvironments where nanopillar arrays, providing 
a topography and stiffness that resemble those of the native cell environment, fostered the expression of a ramified


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phenotype in primate-derived microglia compared to the amoeboid one on flat surfaces. Created with BioRender.com.


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Journal of Medical Genetics 1989, 26, 18-27
New mutation to Huntington's disease
GERHARD WOLFF*, GUNTHER DEUSCHLt, THOMAS F WIENKER*,
KONRAD HUMMEL:, KLAUS BENDER*, CARL H LUCKINGt,
MARTIN SCHUMACHER§, JURG HAMMERII, AND GODEHARD OEPEN¶
From *Institut fur Humangenetik und Anthropologie, tNeurologische Klinik und Poliklinik, lInstitut fur
Blutgruppenserologie,
§Radiologische
Universitatsklinik,
Sektion Neuroradiologie, and
¶Psychiatrische
Klinik und Poliklinik,
University of Freiburg
i Br,
Federal Republic of Germany; and IlInstitut fur
Medizinische Genetik,
University of Zurich, Switzerland.
SUMMARY
We report a large family with an isolated case of Huntington's disease (HD), which is
probably the result of a new mutation. The patient developed clinical signs typical of HD at the
age of 36. The clinical course of the patient's disease is documented by several clinical admissions
over a period of 14 years at present. The family history is strikingly negative with the parents
having been clearly unaffected into their 80s and with 13 older and two younger, living, healthy
sibs. Extensive testing of polymorphic markers (blood groups, red cell and serum proteins, HLA
antigens) showed no indication of non-paternity, but rather gave strong support to the hypothesis
that the proband is a full sib. In addition, DNA typing for several RFLPs known to be closely
linked to the HD gene locus indicated that several clearly unaffected sibs share one or the other
or both of the patient's haplotypes. This is further evidence in favour of the hypothesis of a
new mutation at the HD locus.
The posterior probability of a new mutation to HD in the patient exceeds 99%, even if an
a priori probability of non-paternity of 10% and a mutation rate of HD of 10-7 is assumed.
Huntington's
disease
(HD)
is
an
autosomal
dominantly inherited neurodegenerative
disorder
with a variable age at onset but full penetrance by
old age. The defect causes specific neuronal loss,
leading to progressive motor disturbance, psycho-


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logical manifestations, and intellectual deteriora-
tion.1 2 The mutation rate
is among the lowest
known for human disorders,3 the estimated number
of mutants per million
gametes varying between
013x 10-6 and 9 6x 10- .4
Calculated
mutation
rates
using
the
'direct'
method, based on the proportion of cases without a
detectable family
history,
are
clearly maximum
estimates owing
to
the
inherent
difficulties
in
defining a mutant case.5 6 Wendt and Drohm,7 in
their study of 4024 HD patients, found no mutant
case after having tested for paternity by examining
blood groups of all living unaffected parents and
after having excluded those cases where the parents
died before outliving their risk.
In a review of data on mutation rates to HD,
Shaw and Caro8 came to the conclusion that new
Received for publication 18 January 1988.
Revised version accepted for publication 5 May 1988.
mutants make up only around 0-1% or less of all
cases.
Twelve possible cases of new mutation to HD, in
which the parents were living or died healthy at
advanced age, have been reported to date,5 9-19 but
none of them meets all of the criteria suggested by
Stevens and Parsonage16 to designate a case of a
new mutation: (1) clinical cardinal features in the
proband and similarly affected offspring; (2) both
parents having outlived most of their risk; (3) suffi-
cient information about the health status of the
parents; and (4) proof of paternity.
Not surprisingly, there is no definite proof of a
new mutation in HD.
It seems impossible that a
specific case will meet all the postulated criteria.
Clinical symptoms being unspecific with a wide
differential diagnosis,20-22 late onset, and the diffi-
culty
in
most sporadic
cases
of establishing
a
convincing negative family history, cause inherent
problems, which led Reed and Neel5 to the conclu-
sion
that specific instances of mutation
in
this
disorder will not be demonstrable.
However, proving a new mutation in a sporadic
case may be of great importance to the family, that


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CURRENT
OPINION Chronic and delayed neurological manifestations of
persistent infections
Darshan Pandya and Tory P. Johnson
Purpose of the review
Persistent infections capable of causing central nervous system (CNS) complications months or years after
the initial infection represent a major public health concern. This concern is particularly relevant
considering the ongoing coronavirus disease 2019 pandemic, where the long-term neurological effects are
still being recognized.
Recent findings
Viral infections are a risk factor for the development of neurodegenerative diseases. In this paper, we
provide an in-depth exploration of the prevalent known and suspected persistent pathogens and their
epidemiological and mechanistic links to later development of CNS disease. We examine the pathogenic
mechanisms involved, including direct viral damage and indirect immune dysregulation, while also
addressing the challenges associated with detecting persistent pathogens.
Summary
Viral encephalitis has been closely associated with the later development of neurodegenerative diseases
and persistent viral infections of the CNS can result in severe and debilitating symptoms. Further, persistent
infections may result in the development of autoreactive lymphocytes and autoimmune mediated tissue
damage. Diagnosis of persistent viral infections of the CNS remains challenging and treatment options are
limited. The development of additional testing modalities as well as novel antiviral agents and vaccines
against these persistent infections remains a crucial research goal.
Keywords
autoimmune, encephalitis, neurological impairments, persistent infections, post-acute sequelae of SARS CoV-2
infection
INTRODUCTION
The central nervous system (CNS) is comprised of
long-lived cells and is capable of modulating inflam-
matory processes [1] providing an ideal location in
which pathogens can persist [2]. However, not all
pathogens require presence in the CNS to cause
neurologic disease. Emerging evidence from the


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severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) pandemic (COVID19) has reinforced
the concept that infections, irrespective of their
anatomical location, can contribute to neurological
disease in both acute and late phases [3].
Delayed onset of neurological issues due to
infections can occur months or years after the initial
infectious insult as highlighted by the recent strik-
ing finding that viral encephalitis is associated with
significant risk of later development of dementia
[4
&&] and that vaccination against some viruses
can decrease the risk of developing dementia [5].
However, several barriers exist in distinguishing if
the neurological symptoms are due to persistent
infectious agents or postinfectious inflammatory
sequelae. First, persistent infections, especially those
in the CNS, are often underdiagnosed as they are not
readily detected by conventional tests. Clinically,
these may account for a significant proportion of
the approximately 40–50% of cases of encephalitis
that have no identifiable cause [6–9]. Second,
during persistent infections there is ongoing inflam-
mation which can mimic autoimmune or autoin-
flammatory processes leading to misdiagnosis of
Section of Infections of the Nervous System, National Institute of Neuro-
logical Disorders and Stroke, National Institutes of Health, Bethesda,
Maryland, USA
Correspondence to Tory P. Johnson, Room 7C-120; Building 10, 10
Center Drive, Bethesda, MD 20892, USA. Tel: 301.827.9783;
e-mail: tory.johnson@nih.gov
Curr Opin Neurol 2023, 36:198–206
DOI:10.1097/WCO.0000000000001154
Written work prepared by employees of the Federal Government as part
of their official duties is, under the U.S. Copyright Act, a “work of the
United States Government” for which copyright protection under Title
17 of the United States Code is not available. As such, copyright does
not extend to the contributions of employees of the Federal Government.
www.co-neurology.com
Volume 36  Number 3  June 2023
REVIEW


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91
J Med Genet 1992; 29: 91-97
Fetal hydrops
P A Boyd, J W Keeling
Abstract
Seventy-two
fetuses
or
neonates
with
non-immune
hydrops
were
examined
between 1983 and 1988. The commonest
association was chromosome abnormal-
ity; 11 fetuses had a 45,X karyotype and 11
autosomal trisomy. Chromosome abnor-
mality was suspected in a further 20 on
necropsy findings but chromosome cul-
ture was not possible or unsuccessful. In
11 cases there was histological evidence of
infection; seven babies had major struc-
tural anomalies and six affected fetuses
were twins. In six (8%) the cause of hyd-
rops was not determined compared with
eight (16%) of cases examined between
1976 and 1982. Hydrops was diagnosed
more frequently while the fetus was alive,
before 20 weeks' gestation, and associated
with chromosome anomaly than found
previously.
Departments of
Medical Genetics,
Churchill Hospital,
Headington, Oxford
OX3 7LJ.
P A Boyd
Department of
Paediatric Pathology,
John Radcliffe
Maternity Hospital,
Oxford.
J W Keeling*
*Present address:
Department of Paediatric
Pathology and
Cytogenetics, Royal
Hospital for Sick
Children, Edinburgh
EH9 lLF.
Correspondence to
Dr Boyd.
Received 17 April 1991.
Accepted 2 July 1991.
Effective prevention of rhesus
disease has
shifted the emphasis of the investigation of the
pregnancy complicated by fetal hydrops to-
wards non-immunological causes.' The increas-
ing availability of obstetric ultrasound and its
use in the investigation of pregnancies which
are 'large for dates' or have a clinical diagnosis
of polyhydramnios has resulted in a larger
proportion of cases of fetal hydrops being
diagnosed while the fetus is still alive. The
more frequent use of ultrasound for dating
purposes
in the second trimester, together
with opportunities for a detailed fetal anomaly
scan around 20 weeks' gestation, means that
many hydropic fetuses are now recognised at
an asymptomatic stage. This enables a wider
range of investigations to be undertaken. Elu-
cidation of the underlying cause or association


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of hydrops should be possible in
a larger
proportion of cases.
We report our experience with fetal hydrops
during the last five years and compare gesta-
tional age at diagnosis, method of diagnosis,
and pathological findings in the hydropic fetus
with those examined in the same unit between
1976 and 1982.2
Material and methods
Cases of fetal hydrops from pregnancies which
terminated in both the second and third tri-
mesters were identified from the files of the
Department
of Paediatric
Pathology, John
Radcliffe Maternity Hospital (JRH), Oxford.
These comprised fetuses from women who
were booked for delivery at that hospital and
those referred for pathological examination.
Referral was often prompted by prenatal in-
vestigations
undertaken
in
Oxford,
either
ultrasound examination at the JRH or through
the Department of Medical Genetics.
Fetal hydrops was defined as generalised
subcutaneous oedema with an effusion in at
least one body cavity. After pathological ex-
amination each case was allotted to one of six
groups: proven chromosome anomaly, dys-
morphic features (two or more) suggestive of
chromosome anomaly but without cytogenetic
diagnosis, infection, visceral anomaly, compli-
cation
of twin pregnancy, and
idiopathic.
Clinical and pathological details were con-
sidered first within each group and then the
groups were compared with each other. They
were finally compared with cases of fetal hyd-
rops seen between 1976 and 1982.
Results
Pertinent clinical details of each pregnancy
and
the
results
of
prenatal
ultrasound
examination and chromosome culture are pre-
sented in table 1, grouped according to patho-
logical findings in the fetus. A comparison
between the groups is made in table 2 and
gestational age at diagnosis, status at delivery,
and pathological associations are compared
with cases reported previously in table 3.
CHROMOSOME ANOMALY
The commonest association of fetal hydrops
seen during the present study was chromo-
some anomaly. There were 22 such fetuses


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(table 1). The hydropic state in all fetuses in
this group was identified by ultrasound scan.
In seven this was during a scan before amnio-
centesis. Amniocentesis was indicated because
of advanced maternal age in six and for known
maternal balanced translocation in one case. In
13 of the remaining 15 women, a hydropic
fetus was identified on routine scan, and in two
women a detailed scan was performed because
of raised
maternal
serum
alphafetoprotein
level and a history of intrauterine growth re-
tardation, respectively.
Half of the fetuses with chromosome anom-
aly exhibited a 45,X karyotype. In 10 of the 11,
postnuchal fluid accumulation was described
in the scan report and two were already dead
when the scan took place. Examination of these
fetuses after delivery showed that 10 out of 11
exhibited tubular hypoplasia of the distal aor-
tic arch (Haa). In case 11, material was not
available for review. The only other cardiac
anomaly was a persistent left superior vena
cava (PLSVC). Three fetuses had horseshoe
kidney and a further fetus had unilateral in-
complete renal rotation, the renal pelvis facing
arteriorly.
Three of five fetuses with trisomy 21 had
cardiovascular
malformations.
These
were


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J Med Genet 1993; 30: 1-26
REVIEW ARTICLE
The morbid anatomy of the human genome:
chromosomal location of mutations causing
disease
Victor A McKusick, Joanna S Amberger
Abstract
Information is given in tabular form de-
rived from a synopsis of the human gene
map which has been updated continu-
ously since 1973 as part of Mendelian
Inheritance
in
Man
Johns
Hopkins
University Press, 10th ed, 1992) and of
OMIM (Online Mendelian Inheritance in
Man, available generally since 1987). The
part of the synopsis reproduced here
consists of chromosome by chromosome
gene lists of loci for which there are asso-
ciated disorders (table 1), a pictorial rep-
resentation of this information (fig la-d),
and an index of disorders for which the
causative mutations have been mapped
(table 2).
In table 1, information on genes that
have been located to specific chromoso-
mal positions and are also the site of
disease producing mutations is arranged
by chromosome, starting with chromo-
some 1 and with the end of the short arm
of the chromosome in each case.
In table 2 an alphabetised list of these
disorders and the chromosomal location
of the mutation in each case are pro-
vided. Both in the 'Disorder' field of table
1 and in table 2, the numbers 1, 2, or 3 in
parentheses after the name of the dis-
order
indicate
that
its
chromosomal
location was determined by mapping of
the wildtype gene (1), by mapping of
the clinical phenotype
(2), or by both
strategies (3).
(J Med Genet 1993;30:1-26)
The fields in the listing by chromosome (table
1) are as follows:
Location
-
that
is,
chromosomal
site
(p = short arm; q = long arm; numbers = band;
ter = end).
Symbol - The symbol approved by
the
Nomenclature Committee of the Human Gene
Mapping Workshops and their successor orga-
nisation is given first; alternative symbols are
included.
Status
-
C = confirmed;
P = provisional;
L= 'in limbo' (that is, tentative or inconsis-
tent). The 'in limbo' entries are not listed in
fig 1.
Title - name of gene locus.
MIM# - This is the number in McKusick's


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Mendelian Inheritance in Man, 10th ed (1992)
and its continuously updated online version
OMIM. (For historical reasons, the number
may sometimes indicate location of the entry in
the 'dominant catalogue' because the wildtype
gene was characterised and mapped before the
recessive disorder resulting from mutation at
that site. The practice is to create only one
entry in OMIM for each gene locus.)
Method of mapping
A = in situ DNA-RNA or DNA-DNA anneal-
ing ('hybridisation'), for example, ribosomal
RNA
genes
to
acrocentric
chromosomes;
kappa light chain genes to chromosome 2.
AAS = deductions
from
the
amino
acid
sequence of proteins,
for example, linkage
of delta and beta globin loci from study of
hemoglobin Lepore.
C = chromosome
mediated
gene
transfer
(CMGT), for example, cotransfer of galacto-
kinase and thymidine kinase.
Ch = chromosomal
change
associated
with
particular phenotype and not proved to repre-
sent linkage (Fc), deletion (D), or virus effect
(V), for example, loss of 13q14 band in some
cases of retinoblastoma.
D = deletion or dosage mapping (concurrence
of chromosomal deletion and phenotypic evid-
ence of hemizygosity), trisomy mapping (pres-
ence of three alleles in the case of a highly
polymorphic locus), or gene dosage effects
(correlation of trisomic state of part or all of a
chromosome with 50% more gene product).
Includes
'loss
of
heterozygosity'
(loss
of
alleles) in malignancies. Examples: acid phos-
phatase- 1
to
chromosome
2;
glutathione
reductase to chromosome 8. Includes DNA
dosage, for example, fibrinogen loci to 4q2.
Dosage mapping also includes coamplification
in tumour cells.
EM= exclusion mapping, that
is, narrowing
the possible location of loci by exclusion of
parts of the map by deletion mapping, extended
to include negative lod scores from families
with marker chromosomes and negative lod
scores with other assigned loci, for example,
support for assignment of MNSs to 4q.
Center for Medical
Genetics, The Johns
Hopkins University
School of Medicine,
Blalock Building,


key: chroma:document
string_value:
Room 1007, 600 N
Wolfe Street,
Baltimore, MD
21287-4922, USA.
V A McKinsick
J S Amberger
Correspondence to
Dr Amberger.
Received 12 October 1992.
I


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ARTICLE
Intracellular trafficking of HLA-E and its regulation
Wanlin He1, Ester Gea-Mallorqu´ı1, Huw Colin-York2, Marco Fritzsche2, Geraldine M. Gillespie1, Simon Brackenridge1,
Persephone Borrow1, and Andrew J. McMichael1
Interest in MHC-E–restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian
immunodeficiency virus (SIV) infection in a vaccine model. The development of vaccines and immunotherapies utilizing human
MHC-E (HLA-E)–restricted CD8+ T cell response requires an understanding of the pathway(s) of HLA-E transport and antigen
presentation, which have not been clearly defined previously. We show here that, unlike classical HLA class I, which rapidly
exits the endoplasmic reticulum (ER) after synthesis, HLA-E is largely retained because of a limited supply of high-affinity
peptides, with further fine-tuning by its cytoplasmic tail. Once at the cell surface, HLA-E is unstable and is rapidly
internalized. The cytoplasmic tail plays a crucial role in facilitating HLA-E internalization, which results in its enrichment in
late and recycling endosomes. Our data reveal distinctive transport patterns and delicate regulatory mechanisms of HLA-E,
which help to explain its unusual immunological functions.
Introduction
MHC-E is a highly conserved non-classical major histocom-
patibility complex class I (MHC-I) molecule. Although HLA-E
(human MHC-E) cell surface expression is universal, it is
normally low compared with classical HLA-Ia molecules
(D’Souza et al. 2019). The main function of HLA-E is to present
a highly conserved peptide VL9 (VMAPRTL/VV/L/FL), which
is derived from the leader sequences of other HLA-I (HLA-A/
B/C and G) molecules, to CD94/NKG2 receptors on natural
killer (NK) cells (Borrego et al., 1998; Braud et al., 1998a).
Thus, MHC-E regulates NK cell functions, a role that is con-
served across mammals.
MHC-E can also present different pathogen-derived pep-
tides to CD8+ T cells, though reports are scarce compared with


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classical MHC-Ia molecules. HLA-E can activate CD8+ T cells
through the presentation of Mycobacterium tuberculosis (Mtb)
peptides (Heinzel et al., 2002). Among the 36 Mtb-derived
peptides shown to bind to HLA-E, 11 are recognized by CD8+
T cells (Joosten et al., 2010). The CD8+ T cells activated by
these peptides in Mtb infection exhibit HLA-E–restricted cy-
totoxic activity against mycobacterium-infected cells (van
Meijgaarden et al., 2015). HLA-E can also present Salmonella
typhi (S. typhi) peptides to CD8+ T cells and inhibit S. typhi
pathogenesis (Fresnay et al., 2016; Rudolph et al., 2019;
Salerno-Gonçalves et al., 2004). A BZLF1 peptide derived from
the EBV can also bind to HLA-E and activate CD8+ T cells
(Garc´ıa et al., 2002; Ulbrecht et al., 1998). HLA-E–restricted
presentation of human cytomegalovirus (HCMV) UL40-derived
peptide, with an identical sequence to the human VL9 peptide,
can stimulate specific CD8+ T cells that effectively recognize and
kill HCMV-infected cells (Mazzarino et al., 2005; Pietra et al.,
2003). Recent studies of a simian immunodeficiency virus (SIV)
vaccine that enabled 55% of rhesus macaques (RMs) to clear in-
fection following an SIV challenge have sparked renewed interest
in MHC-E (Hansen et al., 2011; Hansen et al., 2013; Hansen et al.,
2016). This vaccine, vectored by a particular strain of rhesus cy-
tomegalovirus (RhCMV68-1) with key gene deletions and en-
gineered to express SIV genes, stimulates an MHC-E–restricted
CD8+ T cell response that is critical for the effective and long-
lasting protection observed in vaccinated RMs (Hansen et al.,
2016; Malouli et al., 2021).
HLA-E–bound pathogen-derived epitopes offer potential
advantages for vaccine-elicited CD8+ T cell responses. Many
pathogens downregulate surface HLA-Ia molecules to evade
immune recognition (Antoniou and Powis, 2008), which
poses a significant challenge for vaccines targeting CD8+ T cell
responses. However, HLA-E is usually resistant to such
downregulation and is frequently upregulated, thus preserv-


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ing the HLA-E–NKG2A axis, which enables pathogens to avoid
NK cell–mediated lysis (McMichael and Picker, 2017). This
retained or augmented surface expression ensures the effi-
cacy of HLA-E–restricted CD8+ T cells if they can be elicited by
vaccination. The typical low surface expression of HLA-E may
prevent or limit natural HLA-E–restricted T cell priming in
most infections, making prior immune escape unlikely and
facilitating the therapeutic application of HLA-E–restricted
T cells. There are only two dominant alleles of HLA-E that
.............................................................................................................................................................................
1Nuffield Department of Medicine, Center for Immuno-Oncology, University of Oxford, Oxford, UK;
2Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Correspondence to Andrew J. McMichael: andrew.mcmichael@ndm.ox.ac.uk; Simon Brackenridge: simon.brackenridge@ndm.ox.ac.uk; Persephone Borrow:
persephone.borrow@ndm.ox.ac.uk.
© 2023 He et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Rockefeller University Press
https://doi.org/10.1084/jem.20221941
1 of 18
J. Exp. Med. 2023 Vol. 220 No. 8
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Linkage of internal minisatellite loci chromosome and exclusion of autosomal dominant retinitis pigmentosa proximal rhesus


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1JMed Genet 1990; 27: 14-16
Linkage of internal minisatellite loci on chromosome 1
and exclusion of autosomal dominant retinitis
pigmentosa proximal to rhesus
Chris F Inglehearn, Surinder S Papiha, Marcelle Jay, Alan F Wright, Anthony T Moore,
Shomi S Bhattacharya
Abstract
We report the exclusion of a locus for autosomal
dominant
retinitis
pigmentosa
proximal
to
the
rhesus locus in a single large pedigree. In addition,
a
previously
unreported
linkage
is
described
between
two
chromosome
1
markers,
which
confirms that a highly variable minisateilite locus is
placed internally on chromosome 1.
Retinitis pigmentosa is an inherited human disorder
characterised by
progressive
degeneration
of the
retina, leading to loss of visual field, night blindness,
and ultimately to complete loss of sight late in the
disease
process.' There
are X linked, autosomal
dominant,
and
autosomal
recessive
forms,
with
phenotypic heterogeneity in all categories. Families
falling into the autosomal dominant retinitis pigmen-
tosa (ADRP) category can be further subdivided on
the basis of age of onset, penetrance, and persistence
of a measurable rod electroretinogram. 4 Several
reports have suggested that an ADRP locus is linked
to rhesus on chromosome lp, but with lod scores no
higher than 1-89 at a recombination fraction of 0-2 in
male meioses and 0 4 in female meioses.5-8 In one
large Irish pedigree such a location has been excluded,
consistent with the hypothesis that phenotypic varia-
tion in ADRP is the result of underlying genetic
heterogeneity.9 We report linkage data using two
Department of Human Genetics, University of Newcastle
upon Tyne, 19 Claremont Place, Newcastle upon Tyne
NE2 4AA.
C F Inglehearn, S S Papiha, S S Bhattacharya
Moorfields Eye Hospital, City Road, London.
M Jay
MRC Human Genetics Unit, Western General Hospital,
Edinburgh.
A F Wright
Addenbrooke's Hospital, Hills Road, Cambridge.
A T Moore
Correspondence to Dr S S Bhattacharya.
Received for publication
11 August 1989.


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Revised version accepted for publication 8 September
1989.
VNTR probes derived from chromosome 1 in a single
large family in which regional ADRP'
has been
diagnosed. One of these probes, YNZ2, obtained
from Yusuku Nakamura, detects a moderately variable
locus, DIS57, with at least eight alleles'0 approxi-
mately 11 cM proximal to rhesus on chromosome
ip."1 The other, known as pMSl, was donated by
Professor Alec Jeffreys and is a truly hypervariable
sequence (at least 33 alleles, none of which attain a
significant population frequency) detected by finger-
printing probe 33 15.12 This probe has been assigned
to lp33-35 by in situ hybridisation,'3 but has as yet
not been genetically mapped.
Materials and methods
Genomic DNA prepared from lymphocytes of subjects
in family ADRP5 was digested at 65°C with TaqI, size
fractionated on a 1% agarose gel, and capillary blotted
onto nylon filters (Hybond N, Amersham). Filters
were prehybridised in 7% SDS and 0 5 mol/l sodium
phosphate
buffer
at 68°C
for
30 minutes,
then
hybridised in the same buffer overnight with 32p
labelled probes. Washes were at 65°C in 0- 1 x SSC and
0-1% SDS.
Results and discussion
Lymphocyte DNA from subjects in the pedigree
shown in fig 1, known as ADRP5, were digested with
TaqI, southern blotted, then probed first with pMSl
and then with YNZ2. The lod scores obtained from
analysis of the results are shown in the table. When
calculating the lod scores for linkage between each
probe and ADRP, all subjects classed as unaffected,
who were either under the age of 25 or had not been
seen by an ophthalmologist, were excluded. Large
negative lod scores betweenADRPand YNZ2 exclude a
locus for ADRP proximal to rhesus in this family.
Further experiments are under way in this laboratory
to test this family with a suitable probe distal to
rhesus, and also to analyse four other large ADRP
families, one cone-rod dystrophy pedigree, and one
family with Sorsby's macular degeneration with these
14


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Search for consanguinity within and families of patients with trichothiodystrophy associated with xeroderma pigmentosum


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J Med Genet 1990; 27: 21-25
Search for consanguinity within and among families
of patients with trichothiodystrophy associated with
xeroderma pigmentosum
Fiorella Nuzzo, Gianna Zei, Miria Stefanini, Rita Colognola, Augusta Silvana Santachiara,
Paola Lagomarsini, Stefano Marinoni, Laura Salvaneschi
Abstract
The association of two rare hereditary disorders,
trichothiodystrophy
(TTD)
and
xeroderma
pigmentosum (XP), was found in four patients from
three families, apparently unrelated but living in the
same
geographical
area.
In
order
to
test
the
hypothesis of a common ancestor, consanguinity
within and among the families was checked using
three
different
approaches:
reconstruction
of
genealogical trees, typing of blood markers, and
surname analysis.
The
results
of the
three
types
of analyses
strengthen the hypothesis that, in at least two out of
the three families, the genetic defect determining
the TTD/XP phenotype is identical by descent, as a
consequence of remote inbreeding. This implies
that if two mutations are responsible for the two
diseases they are at linked loci or affect the same
gene.
The hereditary disorders xeroderma pigmentosum
(XP) and trichothiodystrophy (TTD) have both been
found to be present in patients showing clinical and
cellular photosensitivity, typical of XP, in addition to
clinical
traits of TTD
(brittle hair with reduced
sulphur content,
ichthyosis,
physical and mental
retardation). '
At present, 19 photosensitive TTD patients have
been
reported; DNA
repair
studies
have
been
performed
in
cells
from
10
patients
and
Istituto di Genetica Biochimica ed Evoluzionistica, CNR,
Via Abbiategrasso 207, 27100 Pavia, Italy.
F Nuzzo, G Zei, M Stefanini, R Colognola, P Lagomarsini
Dipartimento di Genetica e Microbiologia 'A Buzzati-
Traverso', Universita di Pavia, Italy.
A S Santachiara
Istituto per l'Infanzia, Trieste, Italy.
S Marinoni
Centro Trasfusionale AVIS, Pavia, Italy.
L Salvaneschi
Correspondence to Dr Nuzzo.
complementation analysis showed the presence of the


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XP group D (XP-D) mutation in all of them.2 3
XP
and TTD
are
both
autosomal
recessive
disorders
resulting
from
single
gene
defects.
Homozygote frequency is very low: XP occurs in 1
out
of
250 000
subjects,
the
XP-D
patients
comprising
about
10%
of
all
the
XP
cases
investigated.4 5 The incidence of TTD is unknown; a
total
of
81
patients
(with
and
without
photosensitivity) from 51 families has been reported
since 1963.2 Thus, the presence of the homozygous
conditions for both mutations is a highly improbable
event
and
alternative
explanations
should
be
considered for the occurrence of the complex XP-D/
TTD phenotype.
The four patients described by Stefanini
et al,'
belonging to three families, apparently unrelated but
living
in
the
same
geographical
area,
offer
the
opportunity to investigate some genetic aspects, in
particular the identity of the defect.
We checked consanguinity within and among the
three families using different approaches, namely the
reconstruction of genealogical
trees, the study of
blood genetic markers, and the analysis of surnames.
Materials and methods
The families studied (families 1, 2, and 3) originated
from, and currently live in, small towns no more than
100 km apart, located in an area of about 1600 km2 in
the plain behind the Alps in north-east Italy (Veneto
and Friuli-Venezia Giulia regions).
Data
for
the
construction
of
pedigrees
and
surnames were obtained by direct interview and from
registers of births, marriages, and deaths and area
statistics. Data on consanguinity in these regions were
obtained from the list of consanguineous marriages
available for the period 1911 to 1964 (Moroni and Zei,
unpublished data).
Blood samples were obtained from three patients
affected by XP-D and TTD (one from family 1, two
from family 2), from their parents, from the parents
of a dead affected child (from family 3), and from
relatives in the three families. The subjects examined,
that is, 11 from family 1, 12 from family 2, and eight
from family 3, are shown in fig 1.


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Received for publication 14 December 1988.
Revised version accepted for publication 27 June 1989.
21


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J Med Genet 1990; 27: 73-77
Original articles
An exclusion map of Marfan syndrome
Susan H Blanton, Mansoor Sarfarazi, Hans Eiberg, Jacques de Groote, Peter A Farndon,
Michael W Kilpatrick, Anne H Child, F Michael Pope, Leena Peltonen, Clair A Francomano,
Catherine Boileau, Marion Keston, Petros Tsipouras
Abstract
The combined genetic data between the Marfan
syndrome and 75 informative loci on 18 autosomes
were used to construct an exclusion map for this
disorder. Data are also presented for a further two
unmapped markers. The most likely location of the
Marfan syndrome gene is highlighted and all the
unexcluded areas of the genome are displayed in a
graphical form. This exclusion map shows that
almost 75% of the genome has been excluded as a
likely location for the Marfan syndrome gene in
Department
of Pediatrics,
University
of Connecticut
Health Center, Farmington, CT 06032, USA.
S H Blanton*, M Sarfarazi, P Tsipouras
Institute of Medical Genetics, University of Copenhagen,
Denmark.
H Eiberg
Clinical Genetics Unit, Birmingham Maternity Hospital,
Birmingham.
J de Groote, P A Farndon, M W Kilpatrick
Department
of
Cardiological
Sciences,
St
George's
Hospital Medical School, London.
J de Groote, A H Child
Clinical Research Centre, Harrow, Middlesex.
J de Groote, F M Pope
Laboratory
of Molecular
Genetics,
National
Public
Health Institute, Helsinki, Finland.
L Peltonen
Division of Medical Genetics, Johns Hopkins Medical
School, Baltimore, MD, USA.
C A Francomano
Unite 73, INSERM, Paris, France.
C Boileau
Clinical Genetics Service, Western General Hospital,
Edinburgh.
M Keston
Correspondence to Dr Sarfarazi.
*Present address: Graduate School of Biomedical Sciences,
University of Texas Health
Sciences
Center,
Houston,
TX 77225, USA.
Received for publication 16 August 1989.
Revised version accepted for publication 26 October 1989.
the majority of the families studied. Apart from
chromosomes 8, 13, 21, and 22, for which no data
were
available, other regions not excluded yet


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include Sp, 6p, 9p, 10p, 12p, 15, 17p, 18, and 20p.
Future linkage analysis using markers located in the
highlighted regions
should
facilitate
the
identi-
fication of the site of the Marfan syndrome gene.
Marfan
syndrome
(MS)
is
a
serious
heritable
disorder of connective tissue associated with signi-
ficant morbidity and mortality.' The mapping of the
gene for MS will help significantly in our eventual
understanding of its pathogenesis and, more impor-
tantly, it will be essential in the design of a rational
therapy. Since 1976 a number of reports on linkage
studies in MS have appeared, none of which showed
linkage of MS to a marker.
More recently (June 1989) various groups involved
in linkage analysis in MS were invited to participate in
the first International Genetic Linkage Workshop on
Marfan syndrome. At the meeting it was agreed that
a significant advance towards the mapping of the gene
would be made by the pooling of all linkage data for
MS to date. In particular, this would avoid unnecessary
duplication of negative results and highlight those
areas of the genome not yet studied.
As a result of this meeting a consortium of those
involved with MS was formed. This paper presents a
more
detailed
exclusion map
for MS
based on
previously published reports, and on the data provided
by other members of the consortium; some of the
individual data sets are given in full in the other
papers in this issue of the Journal.
Source of linkage data
The linkage data presented here were compiled either
during
the
first
International Workshop by
the
collaborating consortium groups or were subsequently
sent to us. In addition previously published data were
incorporated. The pooled data on MS consist
at
present of 77 markers on 18 autosomes. Seventy-five
of these markers have been localised with various
degrees of confidence and the remaining two (APOH
and C6) are still unmapped. These two markers have
been excluded from our analysis. Three of the groups
73


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8
Med Genet 1990; 27: 82-85
Linkage data for Marfan syndrome and markers on
chromosomes
1 and 11
Jacques de Groote, Peter A Farndon, Michael V Kilpatrick, Anne de Paepe,
J W Oorthuys,
Norman C Nevin, Anne H Child, F Michael Pope
Abstract
Six large families with classical Marfan syndrome
were studied using markers on chromosomes 1 and
11. Two of three families tested showed negative
scores using DIS7 but a third family gave a positive
score (0.92) at 0=0*1. The other chromosome 1
markers typed (MUCI, NGFB, DIS8) excluded
close linkage. Negative lod scores with two chromo-
some 11q22 markers (DIIS84, DIIS148) excluded
at least 20 cM in this area (Z= <-2), which was
chosen for study as two enzymes responsible for
coliagen degradation (coliagenase and stromelysin)
are localised to this region.
Marfan syndrome is a dominantly inherited connective
tissue disorder affecting primarily the skeletal, ocular,
and cardiovascular systems. The estimated prevalence
is 6/100 000, with 25% of cases resulting from new
Dermatology Research Group, Clinical Research Centre,
Harrow, Middlesex.
J de Groote, F M Pope
Clinical Genetics Unit, Birmingham Maternity Hospital,
Birmingham.
P A Farndon, M V Kilpatrick
Facultair Centrum voor Medische Genetica, Universitair
Ziekenhuis, Gent, Belgium.
A de Paepe
Kindergeneeskunde,
Academisch
Ziekenhuis
bij
de
Universiteit van Amsterdam, The Netherlands.
J W Oorthuys
Department of Medical Genetics, Belfast City Hospital,
Belfast.
N C Nevin
Department
of
Cardiological
Sciences,
St
George's
Hospital Medical School, Cranmer Terrace, London
SW17 ORE.
A H Child
Correspondence to Dr Child.
mutations.' The gene shows a high penetrance. The
condition is heterogeneous2 and shows great intra-
familial variability of expression.
A typical Marfan syndrome patient is characterised
by an asthenic build, being unusually tall with a high
arched palate, long thin extremities, arachnodactyly,
chest wall deformities (pectus carinatum, excavatum),
scoliosis, and joint hypermobility. Common ocular


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abnormalities range from myopia to bilateral lens
dislocation and retinal detachment. Eighty percent
have cardiovascular involvement ranging from mitral
valve prolapse to aortic root dilatation and aneurysm.
Most of the premature deaths result from aortic
dissection, although beta blocker therapy decreases
the rate of dilatation of the aortic root, while elective
surgical replacement prolongs life, with an 87% five
year postoperative survival rate.3
The primary defect of Marfan syndrome remains
unknown, and no laboratory or prenatal diagnostic
test
is available. Although many abnormalities of
connective tissue have been reported,"7 none of the
putative genes coding for major connective tissue
fibrillar components has been found to be linked in
family studies.812
To date, however, the following loci have been
excluded in the families studied: COLIAI, COLIA2,
COL2AI, COL3AI, COL6AI, COL6A2, COL6A3,
and tentatively, elastin.
In
1979, Mace's study of 17 families with
19
conventional markers yielded a maximum lod score of
1F38 at 0=0-25 between the rhesus blood group locus
on chromosome 1 and Marfan syndrome.'3
In our present study, we report exclusion data for
four loci on chromosome 1 and two loci on chromo-
some
11. Linkage studies were performed for six
families with classical Marfan syndrome, that
is,
members classically affected in at least two out of
three major systems (table 1) with a pedigree showing
autosomal dominant inheritance.
The two main enzymes responsible for collagen
degradation are collagenase (localised to 1 1q21-q22. 1)
and stromelysin ( l1q22.2-q22.3).14 It is possible that
excessive degradation of collagen (and other com-
ponents of connective tissue) could be the primary
cause of Marfan syndrome. A regulatory gene for
collagenase or stromelysin or both becomes a new
Received for publication 8 September 1989.
Revised version accepted for publication 30 October 1989.
82


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8J Med Genet 1990; 27: 86-90
Linkage analysis in Marfan syndrome
Robin C Schwartz, Susan H Blanton, Catherine A Hyde, Thomas R Sottile Jr, Louanne Hudgins,
Mansoor Sarfarazi, Petros Tsipouras
Abstract
We have analysed 40 marker loci on 13 chromo-
somes for linkage with Marfan syndrome. None of
the loci was linked to the Marfan syndrome locus
at 0=0.00. This study provides
a basis for an
exclusion map and for further coliaboration
in
mapping of the locus.
Marfan syndrome (MS) is an autosomal dominant
disorder of the connective tissue, characterised by
cardiovascular,
musculoskeletal,
ocular,
and
pul-
monary abnormalities. This condition is estimated to
have a prevalence of 4 to 6 per 100 000 persons and
imparts
significant
morbidity
and
mortality.' 2
Although the clinical manifestations of this disorder
have been very well described,' to date there is only
one documented genetic defect in one family. This
was originally reported by Byers et al3 to be a small
polypeptide insertion in the a2 chain of type
I
collagen, and has recently been shown by Phillips et
a14 to be a single nucleotide change that results in a
substitution of glutamine for arginine at position 618
in the triple helical domain of the protein. However,
the causal relationship between
this finding and
the phenotype remains unclear. Despite numerous
histological,
ultrastructural,
and
biochemical
investigations 9 and genetic linkage studies using
conventional protein and cell surface markers,'0 11 as
well as the candidate gene approach,'2-'7 the under-
lying genetic basis of MS has eluded definition.
For this reason, we developed the strategy of using
restriction fragment length polymorphisms (RFLPs)
that are associated with random probes throughout
the genome to map the MS locus. We present the
results of our analysis of 10 three generation families
here.
Department
of Pediatrics,
University
of Connecticut
Health Center, Farmington, CT 06032, USA.
R C Schwartz, S H Blanton*, C A Hyde, T R Sottile Jr,
L Hudgins, M Sarfarazi, P Tsipouras


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Correspondence to Dr Tsipouras.
*Present address: Graduate School of Biomedical Sciences,
University of Texas Health
Sciences Center, Houston,
TX 77225, USA.
Received for publication 16 August 1989.
Revised version accepted for publication 26 October 1989.
Materials and methods
PEDIGREES
Ten three generation families with MS
were
as-
certained, in which the proband had involvement
of the cardiovascular, musculoskeletal, and ocular
systems. One of us (PT) personally examined 100
affected and unaffected subjects included in
this
study.
The
clinical
evaluation
usually
included
anthropometric measurements, clinical examination,
a dilated slit lamp examination by an ophthalmologist,
and an echocardiogram. The diagnosis of MS was
made if a subject had at least two major manifesta-
tions and one minor manifestation, as described in
table 1, which summarises the clinical features of this
condition. The phenotype in all families was con-
sistent with the above diagnostic criteria. Family 1
lacked aortic dilatation but certain persons had mitral
valve prolapse. In family 6 the lenses were only mildly
Table
I
Major
syndrome.
and minor manifestations of Marfan
Major
Minor
System
findings
findings
Ocular
Ectopia lentis
Myopia
Retinal detachment
Cardiovascular
Aortic regurgitation
Mitral valve prolapse
Aortic root diameter
(clinically and on
dilatation
echocardiogram)
Musculoskeletal
Kyphosis
Tall stature
Pectus deformity
Arachnodactyly
Upper to lower
Joint laxity
segment ratio at
least 2 SD below
mean for age
Pulmonary
Pneumothorax
Table 2
Structure of MS pedigrees.
Phase
Family
No of
No of
Potential
known
no
affected
unaffected
meioses
meioses
MS1
17
11
28
19
MS2
3
2
5
2
MS3
11
8
19
4
MS4
6
6
12
5
MS6
10
4
14
7
MS7
5
0
4
1
MS8
4
1
4
1
MS9
3
1
3
2
MS1O
14
4
18
1
MS11
12
5
17
15
Total
85
42
124
57
86


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2
Med Genet 1990; 27: 240-243
Alphafetoprotein in midtrimester Down's syndrome
fetal serum
Mary J Seller
Abstract
Serum alphafetoprotein was estimated in fetuses
with and without Down's syndrome or with other
chromosome abnormalities from the 17th to the
28th week of pregnancy. In normal fetuses, the AFP
level declines steadily during this period. Before 20
weeks, there was no difference in the serum AFP
levels of the three groups of fetuses. After 20 weeks,
the serum AFP level in cases of Down's syndrome
declined more rapidly than normal. This was not
observed
in
fetuses
with
other
chromosome
abnormalities.
This suggests that low maternal
serum alphafetoprotein levels used for prenatal
screening for Down's syndrome in the early second
trimester cannot be explained by low levels in the
Down's fetuses themselves.
It is now well established that midtrimester maternal
serum alphafetoprotein (MSAFP) levels tend to be
lower
than normal when
the
fetus
has Down's
syndrome. 1-6 Some workers have found that the
amniotic fluid alphafetoprotein (AFAFP) levels are
below the normal median in such cases too,2 58 while
others have found them to be normally distributed.
'4
The mechanism for these low AFP levels in the
maternal serum, and possibly the amniotic fluid, is
not yet known, but one suggestion has been that
Down's syndrome fetuses produce less AFP than
normal fetuses.9 My previous studyl'
suggested that
this is not so; consequently, I have examined this
point further by determining the serum AFP levels in
midtrimester
fetuses
with
and
without
Down's
syndrome.
Materials and methods
Fetal blood samples were obtained from two sources
and the results were analysed separately. In one case,
Division of Medical and Molecular Genetics, United
Medical and Dental Schools of Guy's and St Thomas's
Hospitals, Guy's Campus, London SEI 9RT.
M J Seller
Received for publication 12 April 1989.
Revised version accepted for publication
I November 1989.
fresh
fetal
blood was
obtained
by
percutaneous


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umbilical cord sampling (cordocentesis) from the 18th
to
28th week
of pregnancy
for
diagnostic
fetal
karyotyping. In the other, postmortem blood samples
were obtained by cardiac puncture from
fetuses
received for postmortem examination after prosta-
glandin termination of pregnancy, or after a mid-
trimester spontaneous abortion, between 17 and 26
weeks of gestation.
After either means of collection, the blood samples
were spun at 6000 rpm for 10 minutes. The serum was
diluted 1 in 200,
1 in 100, or 1 in 50 with distilled
water according to gestational age, and the AFP level
was quantified by one dimensional crossed antigen-
antibody electrophoresis (the rocket technique)."
Cordocentesis
samples
from
fetuses
without
Down's syndrome were divided into two groups and
their results were also analysed separately. Group 1
(41 samples) comprised fetuses which were completely
normal, both chromosomally and developmentally.
These were derived from patients undergoing the
procedure for raised maternal age who presented too
late for amniocentesis, or where the amniotic cell
culture had failed, or where the fetus was at risk for a
blood disorder. Group 2 (49 samples) consisted of
fetuses who were chromosomally normal but who had
a developmental defect, such as diaphragmatic hernia,
hydrocephalus, congenital heart defect, or exomphalos,
or there was an obstructive uropathy or Rhesus
incompatibility.
Samples were also received from
fetuses with renal agenesis,
ascites, hydrops, and
intrauterine
growth
retardation,
but
they
were
excluded from the study.
All postmortem specimens of fetuses with Down's
syndrome were derived from termination of preg-
nancy after prenatal diagnosis. Seven fetuses without
Down's syndrome also came from terminations: five
had a neural tube defect and two were normal. Serum
AFP
results from
these were pooled with those
obtained
from
16
spontaneous
abortions
of
an
apparently
normal
fetus
(group
3).
Only
those
abortuses that were fresh, showing no sign of early


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maceration, were selected for study, in an attempt to
obtain a comparable group to those from terminations,
where the fetuses were presumably alive up to the
time of the induction. Unfortunately, because of
departmental
policy
not
to perform chromosome
240


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7
Med Genet 1991; 28: 704-707
Cerebrocostomandibular syndrome in four sibs, two
pairs of twins
Vassiliki Drossou-Agakidou, Alexandros Andreou, Vassiliki Soubassi-Griva,
Maria Pandouraki
Abstract
We report four sibs, two pairs of twins, with
cerebrocostomandibular syndrome (CCMS).
The family history was negative. All four
babies
had
the
characteristic
features
of
CCMS, including Pierre-Robin anomalad and
rib dysplasia. Cerebral involvement was evid-
ent in two of the patients who had suffered
perinatal asphyxia. The presence of the syn-
drome in all four sibs together with the negat-
ive family history in previous generations is
consistent with Mendelian autosomal reces-
sive inheritance with high penetrance.
The cerebrocostomandibular syndrome (CCMS) is
a rare dysmorphic syndrome
first described by
Smith et all in 1966. At least 34 cases of the syn-
drome have been reported to date.23 It is character-
ised primarily by defective costal development and
features of the Pierre-Robin anomalad."2 Cerebral
maldevelopment or malfunction is common among
the reported cases.2 We describe the syndrome in
four sibs, consisting of two pairs of twins. To our
knowledge, this is the first report ofCCMS in twins.
Case reports
The mother was a 23 year old primigravida at the
birth of the first pair of twins. The father was 28
Department of Neonatology and Neonatal Intensive
Care Unit, Aristotelian University of Thessaloniki,
Greece.
V Drossou-Agakidou, V Soubassi-Griva
Neonatal Intensive Care Unit, Ippokration Hospital
of Thessaloniki, Greece.
A Andreou
Department of Radiology, Ippokration Hospital of
Thessaloniki, Greece.
M Pandouraki
Correspondence to Dr Drossou-Agakidou, 52 Neapoleos
Street, 54454 Thessaloniki, Greece.
years old and non-consanguineous. The parents
were clinically and radiologically normal and there
was no history of malformations in the family (fig 1)
or of exposure to any known teratogenic agents
during the pregnancies. Prenatal ultrasound indic-
ated polyhydramnios in both pregnancies, but no


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malformations were detected. Both pairs of twins
were delivered by caesarian section at 38 weeks'
gestation.
CASES 1 AND 2 (II1i AND III-2)
The first pair of twins (cases 1 and 2), two boys, had
two placentas and the same ABO and rhesus blood
groups, so that we cannot be certain about the
zygosity. Both babies had low Apgar scores and
required resuscitation. Endotracheal intubation was
impossible and they both received oxygen by face
mask and ambu bag. Soon after birth they developed
severe respiratory distress which improved after the
insertion of nasopharyngeal tubes. Both babies had
features of the Pierre-Robin anomalad (severe mic-
roretrognathia, glossoptosis, and cleft palate). The
chest radiograph of case 1 showed a funnel shaped
thorax with
11 pairs of ribs (no 12th pair was
identified) and discontinuity of the posterior arcs of
both fifth ribs (fig 2). The chest radiograph of case 2
was similar with discontinuity of the right fifth rib
only (fig 3).
Both babies had clinical signs of mild postasphyx-
ial
encephalopathy and
feeding
difficulties,
for
which they needed gavage feeding. Case 1 was doing
well, breathing through the nasopharyngeal tube,
until the 50th day of life, when he was found dead in
1
2
3
4
Received for publication 13 December 1990.
Revised version accepted for publication 7 March 1991.
704
Figure 1
Family pedigree.


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Cancer family syndrome: cytogenetic investigations, in vitro tetraploidy, and biomarker studies in large family


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I MedGenet 1990; 27: 441-445
Cancer family syndrome: cytogenetic investigations, in
vitro tetraploidy, and biomarker studies in a large
family
Ginevra Guanti, Francesco Susca, Giuseppe Cristofaro, Maria Lucia Caruso, Serafina Massari,
Rosa Porsia, Alessandro Stella, Italo Giorgio
Abstract
Fifty-five members of a family with the cancer
family syndrome (CFS) were investigated for the
foliowing potential biomarkers for cancer prone-
ness: (1) cytogenetics of peripheral blood lympho-
cytes and skin fibroblasts; (2) in vitro tetraploidy of
dermal fibroblast monolayer cultures; (3) quantita-
tive
serum
immunoglobulin
determinations;
(4)
study of genetic linkage with respect to eight blood
group markers including Kidd.
Biological specimens were
obtained from
14
patients affected with cancer, 21 subjects at risk,
and 20 healthy subjects. None of the markers
tested in this family, in order to identify a biomarker
for the status of CFS gene carrier, was found to be
useful. Our search for linkage to other biological
markers (DNA RFLPs and NK cells) is in progress.
Colon cancer is the second most common internal
malignancy. About 5 to 10% of all colon cancers have
been estimated to occur in families with an inherited
susceptibility, as seen in Gardner's syndrome, familial
polyposis
coli,
Turcot's
syndrome,
and
Lvnch's
syndrome
types
I and
II.
Investigation
of such
families may help us to understand the aetiology of
malignancy and help in selecting subjects at risk for
more intensive surveillance and earlier detection of
tumours.
We report here the results of a series of genetic
Istituto
di
Genetica,
Universita
degli
Studi,
Via G
Amendola 165/A, 70126 Bari, Italy.
G Guanti. S Massari, R Porsia. A Stella
Istituto Scientifico Gastroenterologico De Bellis, Castel-
lana, Italy.
F Susca, G Cristotaro, M L Caruso,
I Giorgio
Correspondence to Dr Guanti.
studies on a large family with a hereditary predis-
position to non-polypotic colon cancer syndrome or
Lynch's syndrome type 11.1 Its main features include


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early age of onset of tumours, increased frequency of
adenocarcinomas of the colon, mainly proximal loca-
tion of colorectal tumours,
a high occurrence of
gastric, endometrial, and multiple primary malignan-
cies, and an autosomal dominant mode of inheritance
of the susceptibility to colorectal and other neoplasias.
Potential markers for cancer proneness,2 that is,
cytogenetic
studies of peripheral lymphocytes,
in
vitro
tetraploidy
of dermal
fibroblast monolayer
cultures, quantitative serum immunoglobulin deter-
minations, and red cell blood groups, were investigated
in this study.
Materials and methods
The family was identified by one of us (GC) in 1985
when a 26 year old subject reported that many
relatives
had
colon
cancer.
Once informed,
the
consenting members of the family were interviewed
and
all available medical and other vital records
reviewed. Retrospective clinical data were obtained
from interviews with members of the fourth and fifth
generations, who identified the names of members of
the first and second generations. Medical records and
pathology
documents
were
then
retrieved
from
physicians as well as hospitals throughout the geo-
graphical catchment area where the majority of the
family lived. The relative lack of population mobility
among this kindred, coupled with availability of
medical records in the area, made possible clinical
and pathological documentation on relatives with or
without cancer. The same members were then offered
a clinical examination, gastroscopy and colonoscopy,
and laboratory analyses. Several subjects accepted and
were evaluated accordingly. The diagnosis of persons
in generation VII of the family was provisional
because most of them were children under the age of
puberty or under the age of risk. The pedigree is
shown in the figure. The clinical phenotypes have
been previously published.3
In order to investigate the possible existence of
Received for publication 9 October 1989.
Revised version accepted for pbtilication
I February
1990.
41


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J Med Genet 1990; 27: 475-479
Review article
Cystic fibrosis screening and community genetics
B Modell
Cystic fibrosis (CF), the commonest serious recessively
inherited disease of Caucasians,
is fast becoming
preventable. The gene in which mutation can lead to
CF, the cystic fibrosis transmembrane conductance
regulator (CFTR), has recently been identified, and a
deletion of three DNA base pairs that removes a
phenylalanine residue from position 508 of the protein
product accounts for 60 to 80% ofCF mutations in the
UK population.' This mutation can be detected by
relatively simple DNA methods.2 3 Consequently,
geneticists are now confronting an imminent need to
set up
population
screening
for CF
carriers,
a
challenge that, if appropriately seized, could greatly
improve the delivery of genetics services as a whole.
At present, clinical geneticists are mainly concerned
with diagnosis, counselling, and prenatal diagnosis for
families referred to them. Relatively few have yet
been drawn into the issues of population screening
and the outreach approach to the community that it
entails. However, a recent report of the Royal College
of Physicians (RCP)4 pointed out the existence of a
range
of 'community
genetics
services',
that
is,
preventive
genetics
services
based on population
screening that are often delivered by obstetricians and
others,
rather
than by
clinical
geneticists.
They
include (1) neonatal screening for phenylketonuria,
congenital hypothyroidism, and other disorders; (2)
screening in pregnancy for rhesus blood group and
viral infections, maternal serum AFP screening, the
offer of fetal karyotyping
to older women,
and
midtrimester ultrasound scanning for fetal anomalies;
(3) population screening for carriers of haemoglobin
disorders or Tay-Sachs disease.
The RCP report noted many shortcomings in the
delivery of these services and proposed that they
Perinatal Centre, Department of Obstetrics and Gynae-
cology, UCH School of Medicine, 86-96 Chenies Mews,
London WC1E 6HX, and Department of Public Health


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and Policy, London School of Hygiene and Tropical
Medicine.
B Modell
should be improved, not only by increased resource
allocation
but
also
by
appropriate
regional
and
national organisation, public education and profes-
sional training, and service monitoring.
Increased
involvement
of clinical
geneticists
in delivery
of
community genetics services was strongly recom-
mended,
especially
with
regard
to
organisation,
monitoring, information, and counselling. The new
developments in CF are likely to bring this about,
since
clinical
geneticists
will
necessarily
play
a
prominent
part
in organising national
screening,
because of the large numbers and the DNA tech-
nology involved. The time has come
to plan
a
comprehensive prevention programme for CF, based
on a national policy and including laboratory services,
infrastructure
for
screening,
information
for
the
public, education for health professionals, prenatal
diagnosis, and service monitoring.
Carrier screening and prenatal diagnosis for
recessively inherited disorders
In dominant or X linked conditions, such as Hunting-
ton's chorea or haemophilia, the family history is the
key
to
identifying
carriers,
but with
recessively
inherited conditions, like cystic fibrosis or the haemo-
globin disorders, the issues of carrier screening are
very different.
(1) The number of carriers vastly exceeds the
number of affected children: about a hundred times
more CF carriers than patients are born annually.
When carrier screening is possible and desirable, the
large numbers imply that screening and counselling
must be integrated into primary health care.
(2) Most affected
infants
are born
to couples
without a family history. Population screening, when
it is possible, is the only way to detect most carriers.
Few of the carriers so detected will be familiar with
the major disease.
(3) When prenatal diagnosis is possible but carriers
cannot be detected, only the second affected birth to
the same couple can be avoided. For the past few


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years, this has been the situation with CF. Though
such 'retrospective' prevention is very beneficial for
475


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I Med Genet 1990; 27: 697-700
Exclusion of autosomal dominant polycystic kidney
disease type
II (ADPKD2) from 160 cM of
chromosome
1
Shrawan Kumar, William J Kimberling, Patricia A Gabow, Yin Y Shugart, Sandra Pieke-Dahl
Abstract
Autosomal dominant polycystic kidney disease is a
heritable disorder and recent studies have shown
genetic heterogeneity,
with some,
but not
all,
families showing linkage with markers on chromo-
some 16p. Members of a large ADPKD family,
unlinked to chromosome 16, have been typed for 12
marker loci located on both arms of chromosome 1.
Multipoint analysis excluded ADPKD2 from the
region
between DIS81 (pTHH33)
and D1S67
(pHHH106) on the long arm and between Rh and
PGMI on the short arm. This excludes the disease
locus from about 61% of chromosome
1.
Autosomal
dominant
polycystic
kidney
disease
(ADPKD) is a systemic disorder characterised by
cysts in the kidneys, liver, pancreas, and ovaries and
by structural abnormalities in the gastrointestinal
tract, vascular tree, and cardiac valves. ADPKD is
one of the most common genetic disorders, occurring
with a frequency of about 1:1000, and is responsible
for 8 to 9% of end stage renal disease in Europe and
North America. 1-3
One gene responsible forADPKD has been localised
on the short arm ofchromosome 16 by virtue ofshowing
tight linkage between the cluster of genes coding for
the a chain of haemoglobin4 and the gene for the
enzyme
phosphoglycolate
phosphatase
(PGP).5 6
However, subsequent studies showed genetic hetero-
geneity in ADPKD with the observation of a lack of
Department of Genetics, Center for Hereditary Com-
munication Disorders, Boys Town National Research
Hospital, 555 North 30th Street, Omaha, Nebraska 68131,
USA.
S Kumar, W
J Kimberling, Y Y Shugart, S Pieke-Dahl
Department of Medicine, University of Colorado Health
Sciences Center, Denver, Colorado 80262, USA.
P A Gabow
Correspondence to Professor Kimberling.
Received for publication
11 April 1990.
Accepted for publication 9 May 1990.


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linkage with chromosome 16 markers in someADPKD
families.'7'0 The type of ADPKD localised to the
short arm of chromosome 16 is known as ADPKD1,
while the type unlinked to chromosome 16 is known
as ADPKD2. In the latter case, there is a possibility
that families with 'ADPKD2' may also be genetically
heterogeneous in which case further subdivision may
be warranted. The proportion of families unlinked to
chromosome 16 (ADPKD2) has been estimated to be
7%.11
The discovery of the linked markers has provided a
method for diagnosis of ADPKD before the develop-
ment of detectable renal cysts. This method also
permits prenatal detection of gene carriers. However,
the accuracy of prediction by linkage is dependent
upon the relative frequency of the unlinked type of
ADPKD. The greater the proportion of ADPKD2,
the greater the likelihood of diagnostic error. This is
especially true in small families since large families
can provide enough information to verify the presence
of linkage with known chromosome 16 markers. This
difficulty in small families could be largely avoided if
the linkage relationship of the ADPKD2 gene were
known. Hence, we have continued our studies on
localising the ADPKD2 gene. The present paper
concerns the results of analysis of several markers,
spanning chromosome 1, used for linkage studies with
the ADPKD2 gene.
Materials and methods
The family studied in the present investigation is a
large kindred with over 250 members. The original
ancestors emigrated to America from Sicily and the
family has been followed by the Renal Division at the
University of Colorado Health Sciences Center for the
past 20 years. The pedigree has already been published
elsewhere.7 The diagnosis ofADPKD was confirmed
by ultrasonography. Any persons having at least one
cyst in each kidney and at least two cysts in one
kidney was considered affected. 12
Genomic DNA was isolated from either lympho-
cytes or transformed lymphoblasts. The digestion of 5
to 10 ,tg of DNA from each family member was


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7
Med Genet 1990; 27: 760-779
Medical genetics around the world
Medical genetics in South Africa
Trefor Jenkins
Medical practice in South Africa is firmly grounded in
the British tradition. The country's
first medical
faculty was established at the South African College
(soon to become the University of Cape Town) in
1917 and, although the second followed in Johannes-
burg three years later, another 23 years. were to elapse
before another came into being. Today there are
seven medical schools (eight
if one includes the
small, recently established one at Umtata in Transkei,
one of the 'independent' homeland states), which,
between them, produce some 900 doctors each year.
Before 1918 South Africans went to British medical
schools to train, although preclinical courses were
offered at the South African College from 1911. Many
of the country's medical academics have pursued
specialist training in the United Kingdom, with
smaller numbers'proceeding to the USA or Holland
for postgraduate studies. There are approximately
20 000 registered doctors in South Africa (95% are
white and 85% are male) and the doctor:population
ratio was 1:1344 in 1985 (up from 1:2157 in 1960),
which compares with 1:650 in the UK, 1:520 in the
USA, and 1:10 500 in Kenya. (For these and the
following statistics relating to medical practice in
South Africa I am indebted to Kirsch and Benatar.')
In the major urban areas of South Africa the ratio is
1:875 but in the 'homelands' (rural areas inhabited
almost exclusively by black people) it is much less
favourable. In Transkei it is 1:19 000 and in Qwa
Qwa, another of South Africa's national states, it is
1: 1 16 000. In the 1940s the ratio ofgeneral practitioners
to specialists was 7:1, but the figure has gradually
fallen until it is now 3:1. In western Europe the ratio
is 1:1. Successful completion of a six year course and a
one year internship makes the candidate eligible for
MRC Human Ecogenetics Research Unit, Department of
Human Genetics, School of Pathology, South African


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Institute for Medical Research, Hospital Street, PO Box
1038, Johannesburg 2000, and University of the Wit-
watersrand, Johannesburg, South Africa.
T Jenkins
registration as a general practitioner. Specialisation
requires four to five years of recognised training and
passing an examination.
Medical genetics is not a recognised speciality and
the handful of South African medical geneticists are
specialists
in
internal
medicine,
paediatrics,
or
pathology, who have subsequently undergone further
training as geneticists either in South Africa or in the
USA. There may be a need for medical genetics to
become a recognised speciality in South Africa, but
until more academic departments are brought into
being this is unlikely to occur. Medical scientists with
PhD degrees in biological subjects can register with
the South African Medical and Dental Council (the
equivalent of the General Medical Council in the
United Kingdom) as Medical Natural Scientists. One
is head of a university medical genetics department
and others are in administrative positions with the
Department
of National
Health and
Population
Development (DNHPD) Genetic Services Division.
Tertiary health care is of a high standard; the
academic hospitalshavethe full rangeofsub-specialities
and 'high-tech' medicine is as much in evidence in
these hospitals as it is in the teaching hospitals of
Europe and North America. There is considerable
debate within the profession about the appropriateness
of much of this training because, in the first place,
large numbers of the medical graduates leave the
country within afew years ofqualifyingand, secondly, a
large proportion of the population (more than 50%)
lives in rural areas, and there is a reluctance on the
part of doctors to work in these relatively remote
areas.
The infant mortality rates (IMRs) (death occurring
within the first year of life per 1000 births) in South
Africa averaged over 1981 to 1985 are 12-3 for white,
17-9
for Indian,
51-9
for
'Coloured'
(or mixed


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(or mixed
peoples), and 94 to 124 for African populations.2 The
figure for Africans can be broken down to show a
value of 25-6 for those resident in Soweto and 130 for
those in the Transkei; the IMR for 'Coloureds' shows
a 2-6 times higher rate in rural compared with urban
areas. The commonest causes of death in the 1 to 12
760


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Brit. J. Ophthal. (I975) 59, 573
Glaucoma-induced changes in the ciliary ganglion
SHASHI KAPOOR AND M. SOOD
From the Department of Ophthalmology, Jawaharlal Institute of Postgraduate Medical Education and Research,
Pondicherry-6, India
The ciliary ganglion
is a parasympathetic relay
station, related to the innervation of the uvea. It is
composed
mainly
of
parasympathetic
ganglion
cells (Kurus, 1956). It has been shown to undergo
degenerative
changes
after corneal
cauterization
(Bach,
I899; Bernheimer,
I897;
Marina,
I899),
iridectomy (Warwick, I954), exenteration (Warwick,
I954),
and
evisceration
(Tobari,
I97I)
but
its
relationship
with
glaucoma
is
still
uncertain.
Changes in intraocular pressure have been found
on stimulation of the ciliary ganglion (Lele and
Grimes, I960; Schmerl and Steinberg, 1949). The
aim of the present study was to find out what
happens to the ciliary ganglion in experimental
glaucoma.
Material and methods
Glaucoma was induced experimentally in one of the
eyes of seven rhesus monkeys by inserting a hypodermic
needle (26 gauge) into the anterior chamber through
the temporal limbus under paraldehyde anaesthesia.
The needle was connected to a saline reservoir which
was elevated so as to maintain the intraocular pressure
Address for reprints: Dr Shashi Kapoor, Department of Ophthal-
mology, Jawaharlal Institute of Postgraduate Medical Education
and Research, Pondicherry-6, India
at 75 mm for iz hours, after which the animals were
killed. The globe, optic nerves, and ciliary ganglia were
then examined histopathologically. Sections of io ,tum
thickness were stained with haematoxylin and eosin
and methyl green pyronin.
Results
The
ciliary ganglion
comprises many ganglion
cells. In a normal ciliary ganglion, each cell has a
central nucleus, uniformly distributed Nissl gran-
ules in the cytoplasm, and a complete ring of glial
cells around it (Figs i and 2).
The
histopathological
changes
seen
in
the
ciliary ganglia after 12 hours of acute glaucoma were


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string_value:
eccentric displacement or extrusion of the nucleus,
and
chromatolysis
in
the
form
of
peripheral
clumping or disappearance of the Nissl granules.
No change was observed in the interstitial cells
(Figs 3-5). The changes are summarized in the
Table.
Discussion
The relationship of the ciliary ganglion
to the
innervation of the uvea has been demonstrated by
the experiments of Tobari (I97i) and Warwick
Table
Ganglion cell changes in experimental acute glaucoma
Animal
Nucleus
Nissl granules
Abnormal
Normal
1328
1369
1274
I288
1509
1350
I I85
No.
337
358
324
347
365
338
288
9303
2357
(0)
20-24
20-73
20-27
2I*22
I9-48
20-04
19.55
20-2
(average)
Cells
examined
478
452
413
449
489
465
376
Abnormal
Normal
No.
(%)
56
422
88-28
43
409
90-48
44
369
89.33
53
396
88-20
72
417
85-27
62
403
86-66
41
335
89-o8
3122
371
2751
88-2
(average)
2
3
4
5
6
7
Total
Cells
examined
I665
1727
1598
I635
I874
i688
'473
ii66o


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INSIGHTS
TB granuloma: CD30 co-stimulation for CD4+ T cell
co-operation
Abigail R. Gress1 and Tyler D. Bold1
Tuberculosis granuloma T cells express an array of mediators including the CD30 co-stimulatory receptor and its ligand,
CD153. CD4 T effector cells require signals through CD30, potentially provided co-operatively by other T cells, to completely
differentiate and protect against disease (Foreman et al., 2023. J. Exp. Med. https://doi.org/10.1084/jem.20222090).
A new study by Foreman et al. (2023) re-
veals a novel mechanism by which T cells
co-operate through co-stimulation in the
granuloma to develop protection against
tuberculosis (TB). Adaptive immunity
against the intracellular pathogen Myco-
bacterium tuberculosis (Mtb) epitomizes the
canonical paradigm of the CD4 T helper
1 (Th1) cell, with IFN-γ help for macro-
phages at the forefront of its functional
armamentarium. But there is still more to
understand
about
precisely
how
these
lymphocytes protect hosts against TB dis-
ease, particularly at the site of primary lung
infection, in the organized immunologic en-
vironment of the granuloma. Foreman et al.
(2023) have found that signaling in CD4
T cells through the CD30 co-stimulatory
receptor
via
its
ligand
CD153,
both
highly expressed by T cells in the gran-
uloma, is essential for the development
of protective T cells in TB (Foreman
et al., 2023).
To identify T cell protective mecha-
nisms that function at the site of TB in-
fection, Foreman et al. (2023) explored the
transcriptome
of
bulk
CD4
and
CD8
T cells isolated from lung granulomas of
Mtb-infected rhesus macaques, compar-
ing these cells to T cells in either the blood
or bronchoalveolar lavage ﬂuid from the
same infected hosts. Granuloma T cells
differentially expressed an array of hom-
ing receptors, cytokines, chemokines, and
transcription factors when compared to
T cells from these other two anatomic
sites. This included 887 genes in CD4
T cells and 849 in CD8 T cells that were
speciﬁcally expressed in the granuloma, a


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ﬁnding that offers strong justiﬁcation for
the targeted study of T cells recruited to
Mtb-infected tissues across hosts.
Compared to naive T cells in the blood,
granuloma CD4 and CD8 effector T cells
differentially expressed a large array of co-
stimulatory molecules including TNFRSF8
(CD30), TNFRSF4 (OX40), and TNFRSF9 (4-
1BB). Interestingly, the ligands for several
of these receptors, TNFSF8 (CD30L/CD153)
and TNFSF9 (4-1BB-L), were also differen-
tially expressed only in granuloma CD4
T cells. Further data analysis correlating the
expression of genes relative to the bacterial
burden
of
individual
lung
granulomas
conﬁrmed that TNFRSF8 (CD30) was one of
the most highly expressed genes in both
granuloma CD4 and CD8 T cells indepen-
dent of the potential confounding variable
of bacterial load, suggesting that it may play
an important role in protection.
A previous publication from the same
group found that CD153, the ligand for
CD30, is highly expressed by a protective
CD4 T cell population in the lung paren-
chyma of Mtb-infected mice and is re-
quired for CD4 T cell–mediated protection
in the mouse model of TB (Sallin et al.,
2018). The authors further investigated
the mechanistic role of CD30 in T cell–
mediated
protection
using
the
mouse
model. Similar to CD153−/− mice, CD30−/−
mice succumbed earlier to Mtb infection
than wild-type mice. However, both mu-
tant strains maintained similar frequen-
cies of Mtb-speciﬁc T cells in the lungs,
indicating that neither protein is neces-
sary for the generation or initial differ-
entiation of antigen-speciﬁc effector cells.
Despite this, the authors found that donor
CD4 T cells isolated from either CD30−/− or
CD153−/− mice failed to protect T cell–
deﬁcient recipient mice, suggesting that
both elements of this co-stimulatory sig-
naling axis must be expressed by T cells
for protection (Foreman et al., 2023).
In their previous study focused on
CD153, the authors hypothesized that
CD153 expressed on CD4 T cells could
mediate protection against Mtb by stim-


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ulating CD30 on infected macrophages
(Sallin et al., 2018). To test this in the
present study, the authors used mixed
Insights from Abigail R. Gress and Tyler D. Bold.
.............................................................................................................................................................................
1Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
Correspondence to Tyler D. Bold: tbold@umn.edu.
© 2023 Gress and Bold. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the ﬁrst six months after the
publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0
International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Rockefeller University Press
https://doi.org/10.1084/jem.20230547
1 of 3
J. Exp. Med. 2023 Vol. 220 No. 8
e20230547


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Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:706-708
Short report
Concordant cerebral oligodendroglioma in identical
twins
NCA ROELVINK,* W KAMPHORST,t D LINDHOUT,T HPONSSEN*
From the Departments ofNeurosurgery,* Pathologyt and the Institute ofHuman Genetics,: Free University,
Amsterdam, The Netherlands
SUMMARY A case of concordant oligodendroglioma in monozygotic twins is reported. The twins
were also concordant for uterine leiomyoma and one twin partner had fibroadenoma and lipoma of
the breast and myelofibrosis. As very few cases of concordant glioma in monozygotic twins have
been published and no such cases in dizygotic twins, a genetic influence in the aetiology of glioma
can only be suggested.
Four histologically proven cases of concordant gli-
oma in monozygotic twins have been published so far,
amongst
which
there
was
no
case
of
oligo-
dendroglioma.' 4 Study of concordant and discor-
dant brain tumours may shed light on the con-
tribution of genetic and non-genetic factors to the
pathogenesis of these tumours. Therefore, we report
on a twin pair concordant for oligodendroglioma and
uterine leiomyoma.
Case histories
The female twins were born in 1928. The parents were
healthy and non-consanguinous. At time of delivery pater-
nal age was 36 years and maternal age 38 years. Data about
placenta(s) and the composition of fetal membranes were
not available. The twins were of identical resemblance from
their early childhood till in their fifties. Both had blood-
group A Rhesus factor positive and they were right handed.
They were reared and lived together till 1952. The younger
sister
is hypermetropic and has concomitant convergent
squint of the left eye. The family history was negative for
hereditary diseases.
Twin A
This twin has had hypermetropia, convergent squint and
amblyopia of the left eye from early childhood. She acquired
pulmonary tuberculosis during the second world war, com-
Address for reprint requests: NCA Roelvink, Free University Hospi-
tal, Department of Neurosurgery, de Boelelaan


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1117,
1007 MB
Amsterdam, The Netherlands.
Received 26 March 1985 and in revised form 24 August 1985.
Accepted I September 1985
plicated by abdominal tuberculosis at the age of 26. She
remained without offspring. At the age of 38 a uterine lei-
omyoma was removed. The first symptoms suggesting brain
pathology consisted of paresthesiae in the right arm and leg
at the age of 56 years. No other neurological abnormalities
were evident. There were no signs of phacomatoses. Cyto-
genetic analysis of peripheral lymphocytes showed a normal
karyogram (46, XX). On computed tomography of the brain
an irregular hypodense area was seen in the left parietal lobe.
At craniotomy a slight bulging of the left parietal bone was
apparent. Only partial removal of the tumour was possible.
Histological
examination
showed
it
to
be
an
oligo-
dendroglioma, grade B' (figs a). Radiotherapy was given
with a megavolt apparatus at a dose of 6120 cGy in 34 ses-
sions in 49 days. Twelve months after surgery there are still
no clinical or CT scan signs of tumour recurrence.
Twin B
She
had
had
hypermetropia,
convergent
squint
and
amblyopia of the right eye from early childhood. She had 4
children one of whom had an ovarian cyst. At the age of 30
and 47 years she suffered from psychiatric disturbances
which were explained by environmental circumstances. At
the age of 38 a uterine leiomyoma was removed. The first
unequivocal symptom pointing to brain pathology was an
attack of vertigo after a sudden head movement at the age of
56 years. No neurological abnormalities or signs of pha-
comatoses were found. Computed tomography of the brain
showed a hypodense mass with hyperdense spots in the right
frontal lobe. At craniotomy frontal lobectomy was carried
out for radical removal of the tumour. Histological exam-
ination revealed an oligodendroglioma, grade D' (fig, b).
Radiotherapy was given with a telecobalt apparatus at a
dose of 5000cGy in 20 sessions in 21 days.
Six months after surgery severe anaemia was discovered.
706


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Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:1030-1038
Limb apraxia in patients with damage confined to the
left basal ganglia and thalamus
E DE RENZI,
P FAGLIONI, M SCARPA, G CRISI
From the Departments ofNeurology and Radiology, University ofModena, Italy
SUMMARY Limb apraxia was investigated with standardised tests in 14 patients whose CT scan
provided evidence of a vascular lesion confined to the left basal ganglia, or the thalamus, or both,
and not involving the cortex or adjacent white matter. Five patients were severely impaired in
imitating movements and pantomiming object use. Four of them also performed poorly when tested
with real objects. In two patients the lesion was primarily thalamic and in three the lesion was
primarily in the lenticular nucleus and the posterior limb of the internal capsule. Patients without
apraxia generally had smaller injuries, but there were exceptions. Apraxia is currently conceived of
as due to damage of cortical areas and their cortico-cortical connections, but the present data
suggest that the model should be enlarged to include the deep nuclei and the pathways running
through them.
The introduction of CT examination in neurological
practice has opened new avenues
to
the under-
standing of the anatomical basis of higher nervous
function disorders. On the basis of CT results, it has
been discovered that deep hemispheric structures,
play a hitherto unsuspected role in the genesis of
symptoms that were thought to be the province of the
neocortex
and
the
underlying
white
matter.
Depending on the side of lesion, Aphasia`6 and uni-
lateral neglect' 2 7-10 have been reported to result
from damage restricted to the striatum, or the thal-
amus, or both, suggesting that the circuits subserving
language and lateral attention must be enlarged to
include these structures. No comparable evidence has
hitherto been reported for apraxia, a condition tradi-
tionally attributed to the involvement of parietal and
frontal cortical areas of the hemisphere dominant for


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speech and/or to the fibre bundles connecting them
within the same hemisphere and through the corpus
callosum with the premotor cortex of the contra-
lateral hemisphere." -
l
Our interest in the relationship between left deep
nuclei damage and movement organisation disorders
was first aroused by a patient who had severe limb
apraxia following a haematoma slhown by CT scan to
Received 25 June 1985 and in revised form 28 October 1985.
Accepted 2 November 1985
Address for reprint requests: Dr E De Renzi, Clinica Neurologica,
Via Del Pozzo 71, Modena 41 100, Italy.
involve the left thalamus, the posterior limb of the
internal capsule and the posterior part of the lenticu-
lar nucleus. Alerted by this case, we searched the files
of left brain-damaged patients examined with apraxia
tests in the course of previous studies and for whom
there was CT scan documentation that the lesion was
confined to the deep nuclei, sparing the cortex and the
underlying white matter. Fourteen such cases (inclu-
sive of the one originally examiined) were recovered;
in five of them there was unequivocable evidence of
limb apraxia. We report in detail the five positive
cases and contrast them with those not showing
apraxia.
Methods
The 14 patients of the present study were, with one excep-
tion, admitted to the wards in the early days of their disease
and were tested for apraxia within 10 to 50 days of the onset
of their illness. They were all alert and cooperative at the
time of testing. Four patients had a haematoma and 10 had
a softening of the left hemisphere in an area between the wall
of the third ventricle medially and the external capsule
laterally.
Lesion sites were assessed with CT scan sections at 00 to
the canthomeatal line. In describing the lesion we will make
reference to the three sections where the basal ganglia are
represented (Sections 10, 9 and 8 of Matsui and Hirano's
Atlas'5) and will designate them as the inferior, middle and
superior section, respectively.
Praxis evaluation was based on the performance on a


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Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:1165-1170
Local cerebral glucose utilisation in chronic alcoholics:
a positron tomographic study
YVES SAMSON,* JEAN-CLAUDE BARON,*t ANDRE FELINE,:
JACQUES BORIES,§ CHRISTIAN CROUZEL*
From Service Hospitalier Frederic Joliot CEA, Departement de Biologie (Orsay),* Clinique des Maladies du
Systeme Nerveux, La Salp&triere,t Service de Psychiatrie, H6pital Kremlin Bicetre,t Service de
Neuroradiologie, La Salpetriere,§ Paris, France
SUMMARY
Using positron tomography,
a study of regional cerebral glucose utilisation
was
performed prospectively in a highly selected group of six neurologically unaffected primary chronic
alcoholics. In this group, neuropsychological, behavioural and CT scan anomalies were comparable
with those previously reported in more extensive studies. With respect to age-matched control
values, cerebral metabolic rate was not significantly modified in the selected cortical, subcortical and
cerebellar regions of interest. However, the metabolic regional distribution index, which reflects the
distribution pattern of glucose utilisation, was selectively and significantly decreased in the medio-
frontal area, pointing to a limbic metabolic dysfunction apparently linked to chronic alcoholism.
Even in apparently neurologically unaffected sub-
jects, chronic alcohol abuse may be associated with
some
degree
of
cerebral
dysfunction.
Neuro-
psychological studies have demonstrated impairment
of several motor, spatio-visual and memory func-
tions,
despite
approximately
preserved
IQ.' -
Changes
in cerebral blood flow have been
also
reported.68 Although pathological studies reported
only equivocal cortical alterations in chronic alcohol-
ics,5 9 10 the occurrence of widened cortical
sulci
(cerebral atrophy) has been demonstrated in vivo by
numerous CT
scan
studies. " - 16
However,
the
precise mechanism of the reported morphological
and neuropsychological
changes,
and
the
inter-
relationships
among
the
two,
remain
largely


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largely
unknown.2 Experimentally, alterations of neuronal
membranes,17 alteration of dopaminergic and gab-
aergic systems,'8-2' as well as selective vulnerability
of hippocampal neurons,22 23 have been reported,
strengthening the hypothesis that alcohol alters neu-
ron function and even perhaps structure. The present
study was an attempt to determine by means of posi-
tron tomography (PET) if abnormal cerebral glucose
utilisation (CMRGIu) could be found in a clinically
homogeneous
sample
of
highly
selected
neu-
rologically unaffected chronic alcoholics.
Address for reprint requests: Yves Samson, Service Hospitalier
Frederic Joliot Hopital d'Orsay, 91406 Orsay, France.
Received 13 August 1985 and in revised form 9 December 1985.
Accepted 15 December 1985
Methods
Six subjects admitted to the psychiatric department of a gen-
eral hospital were prospectively selected on the following
criteria: 30-60 years of age, chronic dependence on alcohol
(DSM III), present hospital admission directly related to
alcoholism, right handedness, provision of informed con-
sent. Criteria of exclusion were: preexistent psychiatric, neu-
rological
or severe physical
disease (including alcohol-
related
encephalopathy),
head
trauma
with
loss
of
consciousness, seizures, clinically obvious hepatic cirrhosis
or insufficiency and drug abuse.
Neurological and psychiatric clinical examination, includ-
ing a standardised questionnaire about drinking history and
sociobehavioural alterations was performed for each sub-
ject, as well as EEG, CT and routine biological laboratory
tests.
Neuropsychological
testing
was
also
performed,
including performance and verbal IQ determination, cog-
nitive tasks (Wisconsin Cards Sorting test), Rey's figure
copy and delayed reproduction, Weschler memory test or
battery 144,24 Luria series.
Using
the
'8F-fluoro-2-deoxy-D-Glucose
('8FDG)
method26 PET studies were carried out on an ECAT II,
between the end of the first week and the end of the first
month of the hospital admission with apparent abstinence.


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Three adjacent brain
levels were scanned consecutively
(respectively 15, 35, 55 mm above and parallel to the orbito-
meatal line) on subjects at rest, eyes closed, ears unplugged
and free from any medication for at least 24 hours, accord-
ing to our usual protocol.25 Briefly, all images were cor-
rected for attenuation using Ge68-Ga68 transmission scans;
18FDG radioactivity blood curve was obtained from cross-
calibrated plasma counting of serial arterial blood samples,
1165


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British Journal of Ophthalmology, 1979, 63, 181-187
Convolution in human rods: an ageing process
JOHN MARSHALL,' JOHN GRINDLE,2 PAUL
L. ANSELL,1 AND
BESSIE BORWEIN3
From the 'Department of Visual Science, Institute of Ophthalmology, London, England; the 2Department of
Clinical Ophthalmology, Institute of Ophthalmology and Moorfields Eye Hospital, London, England; and
the 3Department of Physics, University of Western Ontario, London, Canada
SUMMARY
In a morphological survey of 73 human retinae spanning 9 decades, and including 20
retinae which were obtained from eyes enucleated for malignant melanomas, nodular excrescences
were noted in the outer segments of rods with an incidence which increased with age. These
structures were sectioned in both their vertical and horizontal axes and on electron microscopical
examination were seen to result from the localised convolution of affected outer segments. The
topographic morphology of such convolutions is described and their modes of formation are
discussed.
The process of ageing and its manifestations in the
cells of the human retina has for some time been a
major research interest in our laboratory. These
studies include the electron microscopical examina-
tion of 73 human
retinae obtained from both
enucleations and cadaver eyes. This series contains
specimens from each of 9 decades, the youngest eye
being 19 years and the oldest 90 years. The detailed
morphology of the photoreceptor cells, the pigment
epithelium,
and
Briich's
membrane
have
been
investigated in order to establish control reference
material
for
a
future
study
of
senile macular
degenerations and inherited retinal dystrophies. We
were interested therefore by a recent report pur-
porting to show the fusion of the outer segments of
juxtapositioned rod photoreceptor cells in the retina
of a 47-year-old woman whose eye was enucleated
because of the presence of a choroidal melanoma
(Borwein et al., 1977). In the present paper morpho-
logical evidence shows that this suggested fusion of


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appositioned cells is an age-related process occurring
within the outer segments of individual rods.
Methods
One of the commonest conditions that leads to
enucleation of human eyes is malignant melanoma
of the uveal tract. The retinae of 20 such eyes have
been studied in the present survey, with an age
Address for reprints: Dr John Marshall, Department of
Visual Science, Institute of Ophthalmology, Judd Street,
London WC1H 9QS
range spanning 7 decades. The immediate post-
operative procedures
varied with
the individual
demands of participating centres. In most centres
corneal discs were trephined for subsequent use in
graft procedures. One centre required the dissection
of the globe and the hemisection of the unfixed
tumour so that samples could be processed for tissue
culture as well as histopathology. In some cases
intact
globes were
presented
immediately
after
enucleation, and here transcorneal incisions were
made in the sagittal plain before immersion in
fixative.
All eyes were fixed within minutes of enucleation
by immersion in 100 ml of 0 3 M glutaraldehyde
buffered
in 0-1 M sodium cacodylate containing
10 mg/ml of calcium chloride with a final pH 7-4.
Intact globes were progressively dissected in this
solution, the cornea being removed at the sulcus
sclerae after 5 minutes, the iris after a further 5
minutes, and the lens, ciliary body, and vitreous 20
minutes after the initial immersion.
After a total of 1 hour in fixative all posterior eye
cups were washed
in
0-1 M sodium cacodylate
containing
7-5 %
sucrose,
and
in
this
solution
experimental samples were isolated under a dis-
secting microscope. In all cases the tumour was
isolated
first
and
subsequently
processed
for
conventional histopathology. Where the topography
of the tumour allowed,
5
sets of samples were
isolated for electron microscopical study. These
were the macula and 4 bands of tissue radiating
from the macula to the ora serrata in the cardinal
axes.
All samples were
dissected so
that
their
181


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The Journal of Clinical Investigation   
C L I N I C A L  M E D I C I N E
1
Introduction
Plasmodium vivax causes more than half of all malaria cases in the 
Americas and Southeast Asia (1) and its distinct biology (cf P. fal-
ciparum) presents unique challenges for control and elimination. 
Dormant liver-stage parasites can trigger multiple relapses over 
many months or years (2); asexual blood-stage parasites prefer-
entially accumulate in the spleen to promote chronic infection 
(3); and gametocytes develop rapidly within the bone marrow to 
maximize transmission (4). Total pathogen load is nevertheless 
reduced compared with P. falciparum and severe disease is a much 
less common outcome of infection (5). This may be explained in 
part by P. vivax invading CD71+ reticulocytes (as opposed to mature 
red cells) and sequestering far less effectively than P. falciparum 
(6, 7). But parasite virulence may also be influenced by the host 
response to infection (8). It is well established that the pyrogenic 
threshold is far lower for P. vivax (indicating differential regulation 
of the acute-phase response) and that clinical immunity (leading 
to asymptomatic infection) is acquired much more quickly (9–13). 
Parasite species may therefore regulate the immune response to 
shape the discrete patterns of disease observed in human malaria.
There are large gaps in our understanding of the immune 
response to P. vivax compared with the better-studied P. falciparum 
(14). We know the P. vivax genome is enriched in CpG motifs that 
can bind TLR9 to trigger type I interferon (IFN) production (15, 
16) and that monocytes and neutrophils are highly phagocytic 
(and generate reactive oxygen species) during acute infection (17, 
BACKGROUND. The biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the 
immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field


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isolate of P. vivax and tracked their response through infection and convalescence.
METHODS. Participants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real 
time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and 
cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. 
Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled 
human malaria infection studies.
RESULTS. P. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. 
This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at 
RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation 
were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate 
this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and 
autoinflammatory disease.
CONCLUSION. P. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced 
pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why 
falciparum malaria more frequently causes severe disease.
TRIAL REGISTRATION. ClinicalTrials.gov NCT03797989.
FUNDING. The European Union’s Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.
A systematic analysis of the human immune response 
to Plasmodium vivax
Florian A. Bach,1 Diana Muñoz Sandoval,1,2 Michalina Mazurczyk,3 Yrene Themistocleous,4 Thomas A. Rawlinson,4  
Adam C. Harding,1 Alison Kemp,5 Sarah E. Silk,4,6 Jordan R. Barrett,4,6 Nick J. Edwards,4 Alasdair Ivens,1 Julian C. Rayner,5


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Angela M. Minassian,4,6 Giorgio Napolitani,3 Simon J. Draper,4,6 and Philip J. Spence1
1Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom. 2Insitute of Microbiology, Universidad San Francisco de Quito, Quito, Ecuador. 3MRC Human 
Immunology Unit, Weatherall Institute of Molecular Medicine, and 4The Jenner Institute, University of Oxford, Oxford, United Kingdom. 5Cambridge Institute for Medical Research, University of Cambridge, 
Cambridge, United Kingdom. 6Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Conflict of interest: YT is a contributor to intellectual property (ChAdOx1 nCOV-19 Clini-
cal Data) licensed by Oxford University Innovation to AstraZeneca (no. 18003 DD002).
Copyright: © 2023, Bach et al. This is an open access article published under the 
terms of the Creative Commons Attribution 4.0 International License.
Submitted: June 17, 2021; Accepted: August 22, 2023; Published: October 16, 2023.
Reference information: J Clin Invest. 2023;133(20):e152463.  
https://doi.org/10.1172/JCI152463.


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Journal of Neurology, Neurosurgery, and Psychiatry 1988;51:842-849
The differential involvement of subcortical nuclei in
senile dementia of Alzheimer's type
G K WILCOCK,* M M ESIRI,t D M BOWEN,4
A 0 HUGHES§
From the Department ofCare of the Elderly, Frenchay Hospital,* Bristol, Department ofNeuropathology,
Radcliffe Infirmary, Oxford,t Department ofNeurochemistry, Institute ofNeurology, London,J and Department
ofEpidemiology & Community Medicine, University ofBristol,§ Bristol, UK
SUMMARY
Cell counts have been performed on cholinergic subcortical nuclei, dorsal raphe nucleus,
and locus caeruleus from up to 18 cases of Alzheimer's disease and 10 age-matched control subjects.
In general, the extent of the cell loss in these structures was similar. In the basal nucleus the
anteromedial subdivision was the least, and the posterior subdivision the most affected. A subgroup
of demented subjects with Alzheimer's disease had a relatively preserved basal nucleus, and frontal
lobe (CAT) choline acetyltransferase activities similar to those in control subjects, but significantly
more neuronal loss in the locus caeruleus.
Neuropathological changes in the neocortex of sub-
jects with Alzheimer's disease are known to be accom-
panied by a reduction in certain neurotransmitter
substances or their marker enzymes, and this has
stimulated examination of the subcortical sites associ-
ated with their synthesis. The nucleus basalis of Mey-
nert (NBM) in the substantia innominata (together
with the medial septal nucleus (MSN) and the nucleus
of the diagonal band of Broca (DBB)) is the predom-
inant cholinergic source, and has been shown to be
affected by neuronal loss and other histological fea-
tures of Alzheimer's disease since the early studies of
Pilleri.' 2 Others have also described the presence of
neurofibrillary tangles in the NBM.3-' The neuronal
loss in the basal forebrain in particular has been
confirmed by many studies using either cresyl violet
stained material5 6 8-10 or more specific stains for


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cholinergic marker enzymes such as choline acetyl-
transferase (CAT),7 11 12 and the loss of larger neu-
rons has been reported to be as great as 90% in some
cases. Pearson et al,'3 however, using a monoclonal
antibody staining technique for CAT failed to dem-
onstrate a significant loss of cholinergic cells from the
NBM, but rather a shrinkage of neuronal perikarya.
In a detailed study dividing the NBM into six sub-
populations adapting Mesulam's nomenclature from
the monkey to man,14 Arendt and his colleagues re-
ported an average overall loss of neurons of 57%,
with the most extensive loss occurring in the posterior
Address for reprint requests: Professor G K Wilcock, Department of
Care of the Elderly, Frenchay Hospital, Bristol, BS16 ILE, UK.
Received
14 July
1987 and in revised form
12 January
1988.
Accepted 21 January 1988
part of the nucleus in three of their five cases. How-
ever, all subjects showed an individual pattern of
NBM degeneration.15 They also found that there was
a significant correlation between the degree of cell loss
and the number of neocortical senile plaques.
The locus caeruleus (LC) is the main subcortical
site for the synthesis of noradrenaline and its precur-
sor enzymes. Reduction in the number of pigmented
neurons in this structure in Alzheimer's disease has
been demonstrated in several studies since 1978,16-19
and the extent of the cell loss been shown to correlate
with the severity of the dementia and neurofibrillary
tangle and senile plaque formation,'7 25 although this
has not been found in all studies.20 The central por-
tion of the locus caeruleus, which is considered to
project predominantly to the temporal cortex and
hippocampus, that is, areas of cortex which are usu-
ally severely affected by neurofibrillary tangle and
senile plaque formation, has been reported to show
the most extensive loss of cells.2'
The serotoninergic dorsal raphe nuclei (DRN)
have
been
less
extensively
examined,
although
neurofibrillary tangle formation and neuronal loss


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have also been described in these structures.4 18 22-24
Few studies have compared the changes in different
subcortical structures in each of an age-matched
series of brains from subjects with Alzheimer's disease
and undemented control subjects. Mann and col-
leagues examined the NBM, the LC and the DRN
and the substantia nigra, and reported that the great-
est cell loss occurred in the locus caeruleus with a
strong correlation between cortical plaque and tangle
counts, and nerve cell atrophy and loss in all four
areas.25 However, in this study they used material
842


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Experimental occlusion of the central artery of the retina. IV: Retinal tolerance time to acute ischaemia*


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British Journal of Ophthalmology, 1980, 64, 818-825
Experimental occlusion of the central artery of the
retina. IV: Retinal tolerance time to acute ischaemia*
SOHAN SINGH HAYREH AND THOMAS A. WEINGEIST
From the Department of Ophthalmology, University of Iowa, Iowa City, USA
SUMMARY
Ophthalmoscopic, fluorescein angiographic, electrophysiological, and morphological
studies on 63 eyes of rhesus monkeys with acute transient experimental occlusion of the central
artery of the retina (OCAR) showed that the retina suffered irreparable damage after ischaemia of
105 minutes but recovered well after ischaemia of 97-98 minutes. The tolerance time of the brain
to acute transient ischaemia is many times shorter than that of the retina. The metabolism of
ischaemic neurones (in the retina and brain) is discussed with a view to explaining this difference,
and also the various factors possibly responsible for the retina's longer tolerance of ischaemia, as
compared to the brain.
Occlusion of the central artery of the retina (OCAR)
is a true ophthalmic emergency, when every minute
that elapses increases the chances of death of the
retina. It is therefore absolutely essential to know
how long it takes for acute retinal ischaemia to
produce irreversible damage. Much of the confusion
about this length of time is due to the many con-
flicting claims reported in anecdotal clinical case
studies and in animal experiments, so that it is not
at all surprising that in spite of the considerable
interest which this subject has attracted no definite
conclusion has been reached so far.
Previous studies
CLINICAL CASE REPORTS
Table 1 comprises most of the available reports in
the English literature plus a few from other lan-
guages. Recovery of retinal function is said to take
place
after an ischaemia of anything from
10
minutes to as much as 36 hours. In addition there
are 2 more reports in which slow recovery of vision
after OCAR has been described. Story9 in 1899
described 2 such cases. A 35-year-old man suddenly


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lost vision in the left eye to light perception (LP)
which improved to counting of fingers (CF) and to
*A brief summary of a part of this paper formed a part of
the paper presented at the American Academy of Ophthal-
mology meeting on 7 November 1979 in San Francisco.
Correspondence to Dr S. S. Hayreh, Department of Ophthal-
mology, University of Iowa Hospitals and Clinics, Iowa
City, Iowa 52242, USA.
6/24 after 16 and 24 days respectively, and to 6/9
and 6/6 after 43 and 112 days respectively, with an
ophthalmoscopically normal fundus. And a 39-year-
old woman, who suddenly lost vision in the left
eye, recovered to CF in 7 days and to 6/9 in 32
days. Werner'0 described a 27-year-old syphilitic
woman who, when seen 14 days after a sudden loss
of vision in the left eye, was considered to have
classical ophthalmoscopic findings of OCAR and
doubtful LP. One week later the vision was LP in
the superior nasal quadrant. One week after that
she suddenly lost vision in the right eye with OCAR
and was found to have doubtful LP in the right eye
and CF in the left eye. The visual acuity in the left
eye improved to 6/9 42 days after the occlusion and
in the right eye to 6/12 and 6/9 14 and 20 days after
the occlusion.
EXPERIMENTAL STUDIES
These are summarised in Table 2. There is a good
deal of inconsistency in the results obtained, one
report alleging irreversible retinal damage within
3 minutes, while in others much longer was needed.
The relevance of those findings to clinical OCAR in
man is open to criticism because of the following
limitations in most of these studies.
Some of the animals used in these studies are not
suitable for such an investigation; for example,
rabbits have virtually no retinal circulation and the
retina depends almost entirely for its nutrition on
the choroidal
circulation;
cats have no
central
artery of the retina. The retinal ischaemia in these
experiments was mostly produced by raising the
818


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British Journal of Ophthalmology, 1979, 63, 306-311
Experimental posterior penetrating eye injury in the
rabbit.
I. Method of production and natural history
PHILIP
E. CLEARY
AND STEPHEN
J. RYAN
From the Department of Ophthalmology, University of Southern California, and Estelle Doheny Eye
Foundation, Los Angeles, California, USA
SUMMARY A technique has been developed which produces an experimental posterior penetrating
eye injury that reproducibly results in traction retinal detachment in rabbit eyes. The standard
injury is an incision through the pars plana with vitreous prolapse and incarceration; the wound
is then carefully closed with microsurgical techniques. It appears that blood in the vitreous is an
essential factor in the development of vitreous traction and of traction retinal detachment. The
model, which has been successfully transferred to Rhesus monkey eyes, is considered useful for
further histological, electromicroscopical, electrophysiological, and ultrasound studies of posterior
penetrating injuries of the eye. Our immediate goal is to assess in a controlled experiment whether
pars plana vitrectomy can interrupt the sequence of events leading to traction retinal detachment
after a posterior penetrating injury.
Although the prognosis for penetrating eye injuries
has greatly improved, this
is largely reflected in
injuries which involve only the anterior segment
(Moncrieff and Scherible, 1945; Snell, 1945; Roper-
Hall, 1959; Remky et al., 1967; Watz and Reim,
1973; Eagling, 1975). Unfortunately there has been
little change in the prognosis for injuries to the
posterior segment in the past 15 years (Johnson,
1971; Eagling, 1975), and severe injuries involving
both the anterior and the posterior segments still
result in a blind or excised eye
in most cases
(Johnson,
1971;
Cinotti
and
Maltzman,
1975;
Eagling, 1975). Many of these eyes suffer an expul-
sive choroidal haemorrhage, with disruption of the
intraocular contents and prolapse of the retina, so


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that there is no potential for visual recovery (Eagling,
1975). However, not all eyes losing useful vision are
damaged
beyond
potential
repair;
for
injuries
confined to the posterior segment traction retinal
detachment is the main reason for loss of vision
(Johnson, 1971 ; Eagling, 1975; Faulborn et al., 1977).
The development of vitreous traction and traction
retinal detachment after a penetrating eye injury
has been linked
clinically with the presence of
vitreous haemorrhage and vitreous incarceration in
the
wound
(Roper-Hall,
1959;
Percival,
1972;
Johnson,
1971;
Eagling,
1975; Faulborn
et
al.,
Address for reprints: Mr Philip E. Cleary, FRCS, Ardkeen
Hospital, Waterford, Ireland
1977). Clinical and histopathological observations
suggest that fibrovascular ingrowth from the scleral
wound, vitreous haemorrhage, injury to the lens,
and injury to the ciliary body may all contribute to
a fibroblastic response within the vitreous, which
often
progresses
to
the formation of a
cyclitic
membrane, in which detached retina may be incor-
porated (Hogan and Zimmerman, 1964; Coles and
Haik, 1972; Eagling, 1975).
It has been postulated that the importance of the
vitreous is that it provides a framework or scaffold
for fibrosis from other sources. Removal of this
scaffold is a rationale for vitrectomy in the treat-
ment of complicated
penetrating
injuries which
involve the posterior segment (Coles and Haik,
1972). Furthermore, after a posterior penetrating
injury the blood is typically loculated within the
vitreous (Winthrop et al., 1978), and removal of
this blood by vitrectomy may reduce the stimulus to
inflammation and organisation.
The introduction of pars plana vitrectomy has
offered a new approach to the treatment of compli-
cated posterior penetrating injuries (Machemer and
Norton, 1972; Michels and Ryan, 1975; Peyman
et al., 1975; Benson and Machemer, 1976; Hutton
et al., 1976; Faulborn et al., 1977; Conway and
Michels, 1978). Yet despite the encouraging pre-
liminary results the indications and optimum timing


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Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:1162-1169
Dichotic listening and manual performance in relation
to magnetic resonance imaging after closed head
injury
HARVEY S LEVIN,* WALTER M HIGH, JR,* DAVID H WILLIAMS,*
HOWARD M EISENBERG,* EUGENIO G AMPARO,t FAUSTINO C GUINTO, JR,t
JEFF EWERTt
From the Division ofNeurosurgery* and the Department ofRadiology,t The University of Texas Medical
Branch, Galveston and Department ofPsychology,: University ofHouston, Texas, USA
SUMMARY
In order to investigate post-traumatic hemispheric disconnection effects, dichotic
listening and intermanual tasks were administered to 69 patients who had sustained a closed head
injury of varying severity. The manual tasks consisted of naming objects palpated in either hand,
transfer ofpostures from one hand to the other and writing. Consistent with predictions, the degree of
ear asymmetry in dichotic listening performance was directly related to the severity ofthe head injury
as reflected by the degree of impaired consciousness. Depth and localisation of parenchymal lesion
characterised by magnetic resonance imaging were also related to the degree of ear asymmetry.
Parenchymal lesions situated in sites which could potentially interfere with callosal auditory or
geniculocortical pathways produced a greater disparity in response to left versus right ear inputs as
compared with parenchymal lesions in areas such as the frontal lobes which are purportedly unrelated
to asymmetries in dichotic listening performance. The results provide further evidence for the effects
of multifocal brain lesions involving the white matter on tasks which require intra and/or
interhemispheric integration.
Strich' first published microscopic findings of diffuse
axonal injury (DAI) which she attributed to mechan-
ical disruption (that is, shearing, tearing) of nerve
fibres at the moment of impact in severe closed head
injury (CHI). Focal haemorrhages involving the cor-
pus callosum, the dorsolateral quadrant(s) of the


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rostral brainstem and the white matter of the superior
cerebellar peduncle are frequent pathological findings
in DA`.'-5 Degeneration of the cerebral white matter,
which presumably occurs over periods ofup to several
months, has been implicated in lateral ventricular
enlargement' 256 and long tract signs such as ataxia.7
Consistent with disruption of intra and interhemis-
pheric white matter connections in DAI, clinical
reports have documented neurobehavioural distur-
bances such as ideomotor apraxia using the left hand,
alexia without agraphia and tactile anomia for objects
Correspondence to: Harvey S Levin, PhD, Division of Neurosurgery
D-73, The University of Texas Medical Branch, Galveston, Texas
77550, USA.
Received 11 October 1988 and in revised form 10 March 1989.
Accepted 21 March 1989
palpated by the left hand."'0 Utilising the dichotic
listening technique, Alexander and Warren" recently
reported a survivor of severe CHI who exhibited an
exaggerated right ear advantage (that is, left ear
suppression),
a
finding
which
the
investigators
attributed to a haemorrhagic lesion in the callosal
auditory pathways. Although neuropathologic find-
ings by Oppenheimer'2 indicated the presence of DAI
and corpus callosum lesions in two patients who
sustained relatively mild head injuries and died from
other causes, more recent neuropathological and
antemortem
magnetic
resonance
imaging (MRI)
studies'3 4 have shown that deep white matter lesions
are generally restricted to CHI which produces coma.
This positive relationship between impairment of
consciousness and depth of lesion is also compatible
with
previous
experimental work
in nonhuman
primates by Ommaya and Gennarelli.'5 In view of
previous studies'S
implicating nontraumatic brain
lesions in the auditory interhemispheric connections,
geniculocortical pathways and temporal cortex in
abnormal dichotic listening, it is plausible that the
localisation of brain lesion is related to ear asymmetry
1162


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review
Adipocyte 2:3, 128–134; July/August/September 2013; © 2013 Landes Bioscience
128 
Adipocyte 
volume 2 issue 3
Introduction
The obesity epidemic is a primary health concern in most indus-
trialized countries, as being obese increases the risk of mortality 
due to associated comorbidities. Although both males and females 
are affected, there is a difference among sexes with regards to the 
propensity to develop obesity and the related metabolic compli-
cations.1-4 Substantial differences in the metabolic responses to 
dietary challenges, weight gain, weight loss, and pharmacological 
interventions have been reported between males and females;2,5,6 
however, the mechanisms underlying this dimorphism remain 
largely unknown.
Differences in circulating gonadal steroid levels play an impor-
tant role in many sexually dimorphic features, but they cannot 
account for all of the metabolic dissimilarities observed between 
males and females. Indeed, there are clear differences even before 
the onset of puberty.7,8 Identifying the mechanisms underlying the 
different metabolic responses in males and females will not only 
advance our general understanding of metabolic control, but it is 
fundamental for the development of effective treatments of obe-
sity and its complications in both sexes. Here, we briefly review 
some of the advances in our understanding of sex differences in 
*Correspondence to: Julie A Chowen;  
Email: julieann.chowen@salud.madrid.org
Submitted: 01/31/13; Revised: 02/21/13; Accepted: 02/21/13
http://dx.doi.org/10.4161/adip.24075
Obesity and its associated secondary complications are active 
areas of investigation in search of effective treatments. As 
a result of this intensified research numerous differences 
between males and females at all levels of metabolic control 
have come to the forefront. These differences include not 
only the amount and distribution of adipose tissue, but also 
differences in its metabolic capacity and functions between


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the sexes. Here, we review some of the recent advances in 
our understanding of these dimorphisms and emphasize the 
fact that these differences between males and females must 
be taken into consideration in hopes of obtaining successful 
treatments for both sexes.
Sex differences in adipose tissue
It is not only a question of quantity and distribution
esther Fuente-Martín,1,2,† Pilar Argente-Arizón,1,2,3 Purificación ros,3,4 Jesús Argente,1,2,3 and Julie A Chowen1,2,*
1Department of Pediatric endocrinology; Hospital infantil Universitario Niño Jesús; instituto de investigación La Princesa; Madrid, Spain; 2Centro de investigación Biomédica 
en red de Fisiopatología de la Obesidad y Nutrición (CiBerobn); instituto de Salud Carlos iii; Madrid, Spain; 3Department of Pediatrics; Universidad Autónoma de Madrid; 
Madrid, Spain; 4Department of Pediatrics & Division of Pediatric endocrinology; Hospital Universitario Puerta de Hierro-Majadahonda; Madrid, Spain
†Current affiliation: institute for Diabetes and Obesity; Helmholtz Center Munich; Neuherberg, Germany
Keywords: sexual dimorphism, leptin, steroids, metabolism, morphology
white adipose tissue (WAT) and how this may affect the differen-
tial responses of males and females to some metabolic challenges.
Adipose Distribution
Sex differences in fat distribution can be observed even before 
puberty, although they become much more pronounced after 
pubertal onset.7,8 Females experience a continuous increase in 
both absolute and percent body fat throughout development and 
although males as well display a persistent increase in absolute 
body fat, they have the highest percentage of body fat during 
puberty.9 Thus, the gradual changes in adipose accrual through-
out early development can result in differences between post-
pubertal males and females in the percentage of body fat, with 
a divergent distribution of adipose tissue also becoming clearly 
apparent.9-12 While females predominantly accumulate subcuta-


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neous fat, males amass significantly more visceral fat.10-13 This 
sex difference in visceral adipose diminishes at older ages as 
postmenopausal women have increased visceral fat accrual,14,15 
emphasizing the role of gonadal steroids in this phenomenon. 
Fat distribution is not only influenced by sex, but also by ethnic 
background, as the reported sexually dimorphic adipose distri-
bution is less apparent in some ethnic groups.13,16 Although sex 
steroids are involved in determining adipose distribution, other 
factors are certainly important. Indeed, Chen et al. recently 
reported that the number of X chromosomes affects adipose tis-
sue function in mice.17 This study suggests that genes expressed 
on the X chromosome are specifically implicated in the control of 
adiposity and that dosage or parental imprinting of these genes 
may be involved in the metabolic differences between males and 
females.
The differential location of fat has functional implications as 
adipokine production, development of insulin sensitivity, inflam-
matory responses, mitochondrial function, lipolysis, and free fatty 
acid (FFA) release differs between adipose depots.1,12,18-20 One 
clear example of the importance of adipose distribution vs. total 
body fat is circulating leptin levels. Leptin is a hormone that is pri-
marily produced by adipose tissue,21 with circulating levels being 
positively correlated with total body fat in both human adults 
and children,22,23 as well as in rodents.24 Serum leptin levels are 
sexually dimorphic in post-pubertal humans22,25 and rodents;26,27


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BritishJournal ofOphthalmology, 1991,75,433-435
Welding arc maculopathy and fluphenazine
William J Power, Stephen P Travers, David J Mooney
Abstract
A 45-year-old male patient presented with a
bilateral maculopathy following unprotected
exposure of less than two minutes' duration to
a manual metal arc welding unit. He had been
receiving the drug fluphenazine for the pre-
vious 10 years for treatment ofdepression. We
believe that the drug fluphenazine, which had
accumulated in his retinal pigment epithelium,
may have rendered him particularly suscept-
ible to retinal photic damage.
Research Foundation,
Royal Victoria Eye and
Ear Hospital, Adelaide
Road, Dublin 2, Ireland
W J Power
S P Travers
D J Mooney
Correspondence to:
William J Power, FRCS.
Accepted for publication
13 December 1990
The retina is susceptible to at least three different
forms of light damage - thermal, mechanical,
and photochemical. " Thermal damage is pro-
duced when the retina is exposed to a tempera-
ture rise of 100 to 200C. Photochemical damage
most likely results from longer exposure to bright
sources that produce a considerable amount of
blue or near ultraviolet
light.3 Light levels
required
to
cause
acute
photoretinitis
are
encountered by exposure only to very bright light
sources, such as the sun, welding arcs, arc lamps,
and tungsten halogen lamp filaments. The type
ofretinal damage depends on wavelength, energy
level, duration of exposure, and degree of
pigmentation.4
The radiation emitted from welding units
covers a wide spectrum, from infrared to ultra-
violet and beyond. Excessive exposure to ultra-
violet radiation can result in photophthalmia
('welder's flash') and may, under chronic ex-
posure, result in UV cataract.56 Retinal injuries
resulting from exposure to welding arc radiation
have been reported but are not commonly
seen.7"10 We report here a case of welding arc
maculopathy in a patient who had been taking
the phenothiazine drug fluphenazine.
Case report
A 45-year-old man noticed bilaterally decreased


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visual acuities soon after welding. There was no
accurate record ofthe exact duration ofexposure.
However, the patient's instructor, who was
observing him from a distance, estimated it to be
certainly no longer than two minutes. The
patient had just begun a training course and had
no previous welding experience. He had raised
the protective visor which he was wearing in
order to see more clearly. This was not noticed by
the instructor as the patient was crouched and
had his back towards him. He had been using a
manual metal arc welding unit with a flux coated
rod.
When seen the next day the patient com-
plained
of
bilateral
scotomata
and
meta-
morphopsia. At no time did he complain of
ocular pain. His best corrected visual acuity was
6/18 in the right eye and 6/12 in the left. The
anterior segments were normal. There was no
evidence of a punctate keratopathy when the
corneas were stained with fluorescein. There was
a circular yellow oedematous lesion approxi-
mately 250 Am in diameter present at each fovea
(Figs lA, B). Fluorescein angiography carried
out five days later was normal. In an effort to
demonstrate the capillary-free zone better an
enhanced fluorescein angiogram was prepared.
The angiogram negative was printed in contact
register with an unsharp mask to produce the
finished
result.
This
enhanced
angiogram
demonstrated mild diffuse fluorescence in the
foveal avascular zone (Fig 2). The patient was
followed up on a regular basis for the next six
months. During this period his visual acuities
returned to 6/5 in each eye. The results ofAmsler
grid testing and pattern electroretinograms were
also normal in both eyes. Examination of his
Figure JA
Right eye.
Figure IB
Left eye.
Figure lA, B
Fundus photographs showingyellow oedematous lesions at bothfoveas.
433


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Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases


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NEURAL REGENERATION RESEARCH｜Vol 19｜No. 1｜January 2024｜55
NEURAL REGENERATION RESEARCH
www.nrronline.org
Review
Abstract  
Extracellular vesicles are released by all cell types and contain proteins, microRNAs, mRNAs, and other 
bioactive molecules. Extracellular vesicles play an important role in intercellular communication and in 
the modulation of the immune system and neuroinflammation. The cargo of extracellular vesicles (e.g., 
proteins and microRNAs) is altered in pathological situations. Extracellular vesicles contribute to the 
pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation, 
including cancer, diabetes, hyperammonemia and hepatic encephalopathy, and other neurological 
and neurodegenerative diseases. Extracellular vesicles may cross the blood-brain barrier and transfer 
pathological signals from the periphery to the brain. This contributes to inducing neuroinflammation 
and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in 
neurodegenerative diseases. The mechanisms involved are beginning to be understood. For example, 
increased tumor necrosis factor α in extracellular vesicles from plasma of hyperammonemic rats 
induces neuroinflammation and motor impairment when injected into normal rats. Identifying the 
mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will 
help to develop new treatments and diagnostic tools for their easy and early detection. In contrast, 
extracellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above 
pathologies, by reducing inflammation and neuroinflammation and improving cognitive and motor 
function. These extracellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and 
have advantages as therapeutic tools: they are less immunogenic, may not differentiate to malignant 
cells, cross the blood-brain barrier, and may reach more easily target organs. Extracellular vesicles


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from mesenchymal stem cells have beneficial effects in models of ischemic brain injury, Alzheimer’s 
and Parkinson’s diseases, hyperammonemia, and hepatic encephalopathy. Extracellular vesicles from 
mesenchymal stem cells modulate the immune system, promoting the shift from a pro-inflammatory 
to an anti-inflammatory state. For example, extracellular vesicles from mesenchymal stem cells 
modulate the Th17/Treg balance, promoting the anti-inflammatory Treg. Extracellular vesicles from 
mesenchymal stem cells may also act directly in the brain to modulate microglia activation, promoting 
a shift from a pro-inflammatory to an anti-inflammatory state. This reduces neuroinflammation 
and improves cognitive and motor function. Two main components of extracellular vesicles from 
mesenchymal stem cells which contribute to these beneficial effects are transforming growth factor-β 
and miR-124. Identifying the mechanisms by which extracellular vesicles from mesenchymal stem 
cells induce the beneficial effects and the main molecules (e.g., proteins and mRNAs) involved may 
help to improve their therapeutic utility. The aims of this review are to summarize the knowledge of 
the pathological effects of extracellular vesicles in different pathologies, the therapeutic potential of 
extracellular vesicles from mesenchymal stem cells to recover cognitive and motor function and the 
molecular mechanisms for these beneficial effects on neurological function.
Key Words: extracellular vesicles; inflammation; cognitive function; mesenchymal stem cells; 
neurodegenerative diseases; neuroinflammation; therapy; transforming growth factor-β
Introduction 
Extracellular vesicles (EVs) play a key role in intercellular communication 
(Yáñez-Mó et al., 2015). There is increasing evidence of their contribution to 
the development of different pathologies including cancer and neurological 
and neurodegenerative diseases (Yáñez-Mó et al., 2015; Théry et al., 2018).


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The analysis of the content of extracellular vesicles may become a very useful 
diagnostic tool in different pathologies. Although extracellular vesicles play 
a pathological role in many pathologies, some types of extracellular vesicles, 
i.e. those released by mesenchymal stem cells (MSCs), have therapeutic 
effects which may be beneficial in pathologies associated with sustained 
peripheral inflammation and neuroinflammation including neurological and 
neurodegenerative diseases (Börger et al., 2017; Harrell et al., 2019). We 
will summarize here the role of EVs in some pathologies, the therapeutic 
potential of EVs from MSCs, and some underlying mechanisms, focusing on 
new findings in the field that highlight the therapeutic potential of EVs from 
MSCs to reduce peripheral inflammation and neuroinflammation, restoring 
cognitive function in neurological diseases.
Literature Search Strategy
A computer-based online search of the PubMed database was performed 
to retrieve articles published until January 31, 2023. A combination of the 
following text words (MeSH terms) was used to maximize search specificity 
and sensitivity: “extracellular vesicles”, “mesenchymal stem cells”, “cognitive 
function”, “therapy”, “neurodegenerative diseases”, “inflammation”, 
“neuroinflammation”. The results were further screened by title and abstract, 
and studies focused on the role of EVs in pathology or EVs from MSCs as a 
therapy were reviewed. Studies without full text available were excluded. No 
language or study type restrictions were applied. Clinical trials were searched 
using the database hosted at https://clinicaltrials.gov (date: March 31, 2023). 
Search queries were “extracellular vesicles” and “mesenchymal stem cells”. 
Trials were then filtered by recruitment status, selecting those “completed” or 
“recruiting”.
Role of Extracellular Vesicles in Different 
Pathologies
The International Society of Extracellular Vesicles defines EVs as “particles


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naturally released from the cell that are delimited by a lipid bilayer and 
cannot replicate, i.e. do not contain a functional nucleus” (Théry et al., 2018).
EVs are released by all the cells in the organism and are present in different 
body fluids, such as blood, urine, or cerebrospinal fluid (Yáñez-Mó et al., 
1Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain; 2Neuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
*Correspondence to: Vicente Felipo, PhD, vfelipo@cipf.es.
https://orcid.org/0000-0003-3145-9538 (Vicente Felipo)
Funding: This work was supported in part by the Ministerio de Ciencia e Innovación Spain (PID2020-113388RB-I00 to VF and PID2021-124359OB-I00 to VMM), Consellería Educación 
Generalitat Valenciana (CIPROM/2021/082 to VF), and co-funded with European Regional Development Funds (ERDF) to VF and VMM. 
How to cite this article: Izquierdo-Altarejos P, Moreno-Manzano V, Felipo V (2024) Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative 
diseases. Neural Regen Res 19(1):55-61. 
From the Contents
Introduction
55
Literature Search Strategy
55
Role of Extracellular Vesicles in Different Pathologies 
55
Therapeutic Potential of Mesenchymal Stem Cells
56
Advantages of Mesenchymal Stem Cell-Derived 
Extracellular Vesicles versus Mesenchymal Stem Cells in 
Therapy 
56
Beneficial Effects of Extracellular Vesicles from 
Mesenchymal Stem Cells on Neuroinflammation and 
Neurological and Neurodegenerative Diseases 
57
Mechanisms Underlying the Beneficial Effects of 
Extracellular Vesicles from Mesenchymal Stem Cells: 
Regenerative Properties
57
Mechanisms Underlying the Beneficial Effects of 
Extracellular Vesicles from Mesenchymal Stem Cells: 
Anti-Inflammatory Properties and Effects on the 
Peripheral Immune System 
57
Mechanisms Underlying the Beneficial Effects of 
Extracellular Vesicles from Mesenchymal Stem Cells: 
Direct Effects in the Brain (Modulation of Microglia


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Polarization)
58
Mechanisms Underlying the Beneficial Effects of 
Extracellular Vesicles from Mesenchymal Stem Cells: Role 
of miR-124 and Transforming Growth Factor-β
58
Therapy with Extracellular Vesicles from Mesenchymal 
Stem Cells: Challenges and Future Perspectives
59
Conclusions
59
Pathological and therapeutic effects of extracellular 
vesicles in neurological and neurodegenerative diseases
https://doi.org/10.4103/1673-5374.375301
Date of submission: February 23, 2023 
Date of decision: April 8, 2023 
Date of acceptance: April 20, 2023
Date of web publication: May 31, 2023 
Paula Izquierdo-Altarejos1, Victoria Moreno-Manzano2, Vicente Felipo1, *


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Circulation
Circulation. 2023;147:867–876. DOI: 10.1161/CIRCULATIONAHA.122.061025 
March 14, 2023
Circulation is available at www.ahajournals.org/journal/circ
867
 
Correspondence to: Lael M. Yonker, MD, Massachusetts General Hospital, 55 Fruit St, Jackson 14, Boston, MA 02114. Email Lyonker@mgh.harvard.edu; or David R. Walt, 
PhD, Brigham and Women’s Hospital, 60 Fenwood Rd, Boston, MA 02115. Email dwalt@bwh.harvard.edu
*L.M. Yonker, Z. Swank, and Y.C. Bartsch contributed equally.
†A. Fasano and D.R. Walt contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.061025.
For Sources of Funding and Disclosures, see page 875.
© 2023 American Heart Association, Inc.
ORIGINAL RESEARCH ARTICLE
Circulating Spike Protein Detected in Post–
COVID-19 mRNA Vaccine Myocarditis
Lael M. Yonker
, MD*; Zoe Swank, PhD*; Yannic C. Bartsch, PhD*; Madeleine D. Burns
, MS; Abigail Kane
, MD;  
Brittany P. Boribong, PhD; Jameson P. Davis, BS; Maggie Loiselle, BS; Tanya Novak
, PhD; Yasmeen Senussi
, MBBS;  
Chi-An Cheng
, PhD; Eleanor Burgess, MS; Andrea G. Edlow, MD; Janet Chou, MD; Audrey Dionne
, MD; 
Duraisamy Balaguru
, MD; Manuella Lahoud-Rahme
, MD; Moshe Arditi
, MD; Boris Julg, MD, PhD;  
Adrienne G. Randolph
, MD; Galit Alter, PhD; Alessio Fasano
, MD† ; David R. Walt
, PhD† 
BACKGROUND: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2)–targeted mRNA vaccines have been reported globally, but the underlying 
immunoprofiles of these individuals have not been described in detail.
METHODS: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were 
hospitalized at Massachusetts General for Children or Boston Children’s Hospital for myocarditis, presenting with chest pain 
with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests


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for SARS-CoV-2–specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant 
virome, SARS-CoV-2–specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with 
those from 45 healthy, asymptomatic, age-matched vaccinated control subjects.
RESULTS: Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were 
essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A 
notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, 
were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic 
vaccinated control subjects (unpaired t test; P<0.0001).
CONCLUSIONS: Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine–induced 
immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free 
spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, 
advancing insight into its potential underlying cause.
Key Words: COVID-19 ◼ mRNA ◼ myocarditis ◼ SARS-CoV-2 ◼ vaccine
Editorial, see p 877
W
ithin 9 months of coronavirus disease 2019 
(COVID-19) reaching pandemic proportions, 
novel, lifesaving severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2)–targeted mRNA 
vaccine technologies received emergency regulatory 
approvals and were distributed to many developed 
countries. Following a tiered approach that prioritized 
high-risk individuals, infants ≥6 months of age are now 
eligible for vaccination with SARS-CoV-2 mRNA vac-
cines in select countries. SARS-CoV-2 mRNA vaccines


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Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex ischemia in mice


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636  ｜NEURAL REGENERATION RESEARCH｜Vol 19｜No. 3｜March 2024
NEURAL REGENERATION RESEARCH
www.nrronline.org
Research Article
Visualizing Wallerian degeneration in the corticospinal 
tract after sensorimotor cortex ischemia in mice
Abstract  
Stroke can cause Wallerian degeneration in regions outside of the brain, particularly in the corticospinal tract. To investigate the fate of major glial cells and 
axons within affected areas of the corticospinal tract following stroke, we induced photochemical infarction of the sensorimotor cortex leading to Wallerian 
degeneration along the full extent of the corticospinal tract. We first used a routine, sensitive marker of axonal injury, amyloid precursor protein, to examine 
Wallerian degeneration of the corticospinal tract. An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the 
ischemic cortex, with no positive signal in distal parts of the corticospinal tract, at all time points. To improve visualization of Wallerian degeneration, we 
next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent 
protein-expressing axons. Using this approach, we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke. 
In addition, microglia mobilized and activated early, from day 7 after stroke, but did not maintain a phagocytic state over time. Meanwhile, astrocytes showed 
relatively delayed mobilization and a moderate response to Wallerian degeneration. Moreover, no anterograde degeneration of spinal anterior horn cells was 
observed in response to Wallerian degeneration of the corticospinal tract. In conclusion, our data provide evidence for dynamic, pathogenic spatiotemporal 
changes in major cellular components of the corticospinal tract during Wallerian degeneration.


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Key Words: corticospinal tract; green fluorescent protein; microglia; spinal anterior horn cells; stroke; virus trace; Wallerian degeneration
https://doi.org/10.4103/1673-5374.380903
Date of submission: December 6, 2022 
Date of decision: March 11, 2023 
Date of acceptance: June 6, 2023 
Date of web publication: July 20, 2023 
Introduction 
Stroke remains a leading cause of acquired adult disability and incurs high 
socio-economic costs worldwide (Rochmah et al., 2021; Saini et al., 2021; 
Westendorp et al., 2022). Ischemia in supratentorial motor systems usually 
causes hemiparesis, so recovery of motor function is crucial for stroke 
patients to regain independence (Stinear, 2017). Currently, advanced research 
is aimed at discovering promising strategies to limit neuronal damage in the 
penumbra (Grade and Götz, 2017; Zhou et al., 2018). Unfortunately, almost 
all neuroprotective agents that focus exclusively on cerebral gray matter in 
primary injury locations have failed in clinical trials (Fisher et al., 2009; Luo 
et al., 2020). Indeed, the death of cortical motor neurons causes Wallerian 
degeneration (WD) of neurons along the full length of their projections at sites 
distal from the original injury. The corticospinal tract (CST), which acts as the 
major descending pathway for voluntary motor control, is the most frequently 
affected tract in stroke patients (Yu et al., 2009; Sun et al., 2022; Zhang et al., 
2023). Early WD of the CST correlates with long-term neurological deficits and 
poor motor outcomes after stroke (DeVetten et al., 2010; Puig et al., 2010; 
Sheng et al., 2022). 
WD is defined as progressive anterograde disintegration of axons and 
accompanying demyelination after an injury to the proximal axon or cell 
body (Chen et al., 2017; Cai et al., 2022; Forbrig and Danek, 2022). After 
the initial ischemic injury, distal axons retain morphological stability and 
axonal fast transport for several days, which potentially allows for effective


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pharmacological intervention (Vargas and Barres, 2007). Although significant 
insight has been gained into WD pathogenesis, a full understanding has 
been limited by both technical and animal modeling issues. Previous studies 
have used various antibodies to identify axonal damage during WD (Stone 
et al., 2004; Czeiter et al., 2008). However, whether or not these antibodies, 
particularly those to amyloid precursor protein (APP), can be used to detect 
axonal pathology within distal segments remains unclear (Wakita et al., 
2002; Zuo et al., 2019). In addition, different areas of the cortex exhibit 
different CST projection patterns into the spinal cord (Steward et al., 2021). 
The middle cerebral artery occlusion (MCAO) model used in previous studies 
generally results in widespread, severe cortical infarction, which complicates 
interpretation of the pathophysiologic mechanisms governing stroke-induced 
WD of the CST. Thus, these technical and animal model issues have precluded 
experimental analysis of dynamic WD from initial ischemic injury to ultimate 
disintegration of axons within the CST projecting specific cortical regions. 
To address these issues, we used photochemical infarction of the right 
forelimb representation of the sensorimotor cortex to induce WD along 
the full extent of the CST in an animal model. This model caused selective 
degeneration of fiber tracts that terminate in the cervicothoracic spinal cord, 
without extending to the thoracic levels and below. In addition, we utilized 
an orthograde virus that expresses green fluorescent protein (GFP) to follow 
the fate of the CST. Unlike labeling with antibodies, this approach enables 
visualization of WD through analysis of GFP-expressing axons. The goal of this 
study was to quantitatively definite the time frame during which WD-induced 
axonal degeneration and gliosis occur within the affected area of the CST.


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1Beijing Key Laboratory for Biomaterials and Neural Regeneration, School of Biological Science and Medical Engineering, Beihang University, Beijing, China; 2Department of 
Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
*Correspondence to: Xiaoguang Li, PhD, lxgchina@sina.com or zzgc811@163.com; Zhaoyang Yang, PhD, wack_lily@163.com. 
https://orcid.org/0000-0001-8313-6998 (Zhaoyang Yang); https://orcid.org/0000-0003-4480-3676 (Xiaoguang Li)
Funding: This study was supported by the National Natural Science Foundation of China, Nos. 31730030 (to XL), 81941011 (to XL), 31771053 (to HD), 82271403 (to XL), 82272171 (to 
ZY), 31971279 (to ZY), and 82201542 (to FH); the Natural Science Foundation of Beijing, No. 7222004 (to HD); the Science and Technology Program of Beijing, No. Z181100001818007 
(to ZY).
How to cite this article: Mu J, Hao L, Wang Z, Fu X, Li Y, Hao F, Duan H, Yang Z, Li X (2024) Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex 
ischemia in mice. Neural Regen Res 19(3):636-641. 
Wallerian 
degeneration of 
the corticospinal 
tract after 
stroke causes 
delayed axonal 
degeneration 
and subsequent 
gliosis but does 
not alter spinal 
anterior horn 
cells in mice
From the Contents
Introduction
636
Methods  
637
Results
638
Discussion
640
Jiao Mu1, Liufang Hao2, Zijue Wang2, Xuyang Fu2, Yusen Li2, Fei Hao1, Hongmei Duan2, Zhaoyang Yang2, *, Xiaoguang Li1, 2, *
Graphical Abstract


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Annals of the Rheumatic Diseases, 1980, 39, 529-530
Correspondence
Acute gout during hypouricaemic
therapy: prophylaxis with colchicine
Sir, The efficacy of the uricosuric diuretic agent tienilic
acid in the treatment of both gout and hypertension is
confirmed in 2 papers.1
2 During our inpatient study 3
of the 4 patients suffered attacks of gout, as is often the
case when starting other kinds of hypouricaemic therapy.
It is commonly held that the concomitant use of col-
chicine prevents such attacks, and accordingly we looked
into this in a long-term outpatient study. Twenty patients
were given tienilic acid alone and 10 patients were given
tienilic acid together with colchicine
1 mg b.d. on a non-
selective basis. The patients were followed for between
2 and 12 months, with encouraging results in lowering
both the blood pressure and serum uric acid, but owing
to reports from elsewhere of hepatotoxicity the study
had to be abandoned. Of the patients who received
tienilic acid alone 15 suffered 27 attacks of gout within
2 months of starting therapy, whereas none of the 10
patients who received colchicine in addition suffered
an attack of gout over the same period.
This gives support to the unsubstantiated belief that
colchicine prevents the attacks of gout which are seen
after starting hypouricaemic therapy.
P. HOLLINGWORTH, J. A. REARDON AND J. T. Scorr
Kennedy Institute of Rheumatology, London W6.
Charing Cross Hospital, London W6.


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Annals of the Rheumatic Diseases, 1988; 47, 764-767
Adult onset Still's disease and viral infections
JACQUES M G W WOUTERS,' JOHAN VAN DER VEEN,2
LEVINUS B A VAN DE PUTTE,' AND DIRK-JAN R A M DE ROOIJ3
From the Departments of 'Rheumatology and 2Microbiology, University Hospital Nijmegen, Nijmegen, The
Netherlands; and 3St Maartens Clinic, Nijmegen, The Netherlands
SUMMARY
Several micro-organisms, especially viruses, have been associated with juvenile and
adult onset Still's disease. In the present study a search for probable triggering viral infections in
five consecutive patients with early, active adult onset Still's disease has been made. In one
patient echovirus 7 was identified as a probable triggering agent. Evidence of infection with this
virus was acquired by virus cultures and serological tests. In two patients the illness was probably
initiated by a rubella reinfection. Both had initially high stable monospecific IgG antibody titres
but no IgM antibodies to this virus. In the remaining two cases no particular triggering viral
infection could be designated. Evidence of a viral infection was thus found in three of these five
patients. Adult onset Still's disease may represent a reaction pattern to certain infections.
Key words: echovirus, rubella, cultures, serology.
Juvenile and adult onset Still's disease are related
clinical entities characterised by high spiking fever,
an evanescent maculopapular rash, and arthritis.1 2
Other features frequently found in both conditions
include lymphadenopathy, splenomegaly, pericardi-
tis, pleuritis, neutrophil leucocytosis, and hepatic
abnormalities. Although the cause of these diseases
is unknown, several recent reports have associated
their
development
with
a
variety
of
micro-
organisms, especially viruses.?12
The present study reports on virological studies
performed in five patients with adult onset Still's
disease in an early phase of the disease.
Patients and methods
PATIENTS
During 1983 five patients with early, active adult


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onset Still's disease were seen at two hospitals in the
city
of Nijmegen,
The
Netherlands
(Canisius-
Wilhelmina Hospital, University Hospital St Rad-
boud). All presented with fever of unknown origin
and fulfilled the criteria of Medsger and Christy."3
METHODS
As soon as it was suspected that a patient was
Accepted for publication 26 November 1987.
Correspondence to Professor Levinus B A van de Putte, Depart-
ment of Rheumatology, University Hospital Nijmegen, Geert
Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands.
suffering from adult onset Still's disease virological
studies were started.
Serology
IgG antibody titres to adenovirus, respiratory syn-
cytial
virus,
mumps,
cytomegalovirus,
measles,
herpes simplex, varicella, Coxsackie virus Bi, 2, 3,
4,
5,
and
6,
Coxiella
burneti,
psittacosis, and
Mycoplasma
pneumoniae
were
measured
by
complement fixation tests, IgG antibody titres to
rubella and parainfluenza virus
1, 2, and 3 by
haemagglutination inhibition tests, IgG antibody
titres to Epstein-Barr virus by immunofluorescence
tests, and hepatitis B surface antigen (HBsAg) and
IgG antibodies to HBsAg by means of an enzyme
linked immunosorbent assay (ELISA). IgG anti-
body titres to corona virus and influenza virus A, B,
and C were measured by complement fixation and
haemagglutination inhibition tests. IgM antibodies
to mumps, rubella, and parainfluenza virus 1, 2, and
3 were assayed by haemadsorption immunosorbent
tests and IgM antibodies to Epstein-Baff virus by
immunofluorescence tests.
Virus cultures
All throat swabs and stool specimens were inocu-
lated in Flow 2002 (human lung fibroblasts), HEp2
(human larynx carcinoma), and primary rhesus
monkey kidney cells. Attempts to isolate rubella
virus were made only if the IgG antibody titres to
764


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Lymphocytes bearing Fcy in rheumatoid arthritis. Phenotypic characterisation of mononuclear cells forming Facb in RA


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Annals of the Rheumatic Diseases, 1985, 44, 2-7
Lymphocytes bearing Fcy receptors in rheumatoid
arthritis. II. Phenotypic characterisation of
mononuclear cells forming Facb rosettes in RA
VIVIENNE R WINROW,* LESLEY-JANE EALES,t N D HALL,
N J GOULDING, AND
I M HUNNEYBALLt
From the ARC Research Group, Royal National Hospital for Rheumatic Diseases, Bath, the Pharmacology
Group,
University of Bath, and
#the Boots Company PLC, Nottingham
SUMMARY
We have previously reported an increased proportion of Facb-rosette forming cells in
the peripheral blood of patients with rheumatoid arthritis in comparison with healthy controls.
The present study investigates the surface phenotype of these cells by means of monoclonal
antibodies and a variety of rosetting and lymphocyte fractionation techniques. Facb-R+ cells
were found to lack surface markers characteristic of T and B lymphocytes.
Studies with
monoclonal reagents showed a positive reaction with OKIal, OKM1, and another monocyte-
specific antibody. Facb-R+ cells were recognised by anti-HLA-DR reagents but did not bind the
monoclonal antibody 17.15 that recognises a determinant on HLA-DR antigens expressed by
lymphocytes but not monocytes. These results show that Facb-R' cells share certain surface
characteristics with
monocytes, though they
are
not phagocytic.
These observations
are
consistent with an accessory role for Facb-R+ cells in the immune response.
Key words: Fc receptor, surface marker, monoclonal antibody.
Receptors which bind the Fc portion of IgG (FcyR)
have been demonstrated on the surface of many
peripheral
blood
leucocytes
including
T
lymphocytes,' B cells,2 null cells,?6 monocytes,7
and neutrophils.8 These receptors play significant
roles in chronic inflammation, since they are associ-
ated with phagocytosis
of IgG aggregates8 and
antibody-dependent cellular cytotoxicity9 and have
also been implicated in the regulation of humoral
immunity mediated by specific antibody.102 These
observations have led to the investigation of FcyR


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expression on mononuclear cells from patients with
a variety of autoimmune diseases.
Several authors have reported an increased pro-
portion
of
peripheral
blood
mononuclear
cells
Accepted for publication 16 July 1984.
Current
addresses:
*Bone and Joint Research
Unit, London
Hospital Medical College, London El. tDepartment of Immu-
nology, Wright-Fleming Institute,
St. Mary's Hospital Medical
School, London, W2.
Correspondence to Dr N D Hall, Bath Arthritis Research Centre,
Trim Bridge, Bath BAl 1HD.
(PBMNC) exhibiting FcyR in patients with rheuma-
toid
arthritis
(RA)
compared
with
healthy
controls.'136 These authors did not identify the
subpopulation bearing the FcyR, although Sharpin
and coworkers'7 have recently suggested that this
increased expression is due to an increase in Ty
cells. Other authors have failed to demonstrate any
increase in FcyR expression on rheumatoid mono-
nuclear cells18 or rheumatoid 3rd population (L)
lymphocytes.19 20 In our laboratory mononuclear
cells bearing a receptor capable of binding the Cy2
region of IgG have been detected in peripheral
blood by a novel rosette assay employing calf red
blood cells (CRBC) sensitised with the Facb frag-
ment of rabbit IgG anti-CRBC.2' It has been shown
that Facb-R' cells form an increased proportion of
PBMNC from patients with RA compared with
healthy control subjects and patients with osteoar-
thritis (OA) or ankylosing spondylitis (AS). In this
report a number of techniques have been utilised to
investigate the surface characteristics of the Facb
rosette forming cells in rheumatoid patients.
2


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Annals of the Rheumatic Diseases, 1986; 45, 367-372
Relationships between C3b receptor (CR1) activity of
erythrocytes and positive Coombs' tests
YORITARO
INADA,'
MIKIO
KAMIYAMA,'
TSUNEYOSHI
KANEMITSU,I
WILLIAM S CLARK,' AND YOSHIYUKI ASAI2
From the 'Medical Service, Division of Rheumatology, St Luke's-Roosevelt Hospital Center, The College of
Physicians and Surgeons of Columbia University, New York; and the 2Department of Immunology, Eisai
Co., Ltd, Japan
SUMMARY
Although positive direct Coombs' tests occur in most patients with active systemic
lupus erythematosus (SLE), haemolytic anaemia associated with antibody to erythrocytes (E)
occurs in less than 10%. Our studies show an association between positive direct Coombs' tests
and both the presence of circulating immune complexes and diminished activity of the C3b
receptor (CR1) of E. Data presented in this report suggest that in vivo binding of immune
complexes and complement by the CR1 of E results in positive direct Coombs' tests in the absence
of antibody to E. These observations explain the low frequency of haemolytic anaemia compared
with the high frequency of direct positive Coombs' tests in patients with SLE.
Key words: circulating immune complexes.
Anaemia is common in systemic lupus erythemato-
sus (SLE).
Its features and multiple causes have
been reviewed.' Although positive direct Coombs'
tests
have
been
reported
in
18-65%
of these
patients, haemolytic anaemia occurs in less than
10%.2 A reasonable explanation for this discrepancy
appeared during our studies of the complement
receptor (CR1) function of erythrocytes (E).
Human E possess, on their surfaces, receptors to
the
third complement component.
In
1981
we
reported a new method for measuring circulating
immune complexes (CIC) derived from the immune
adherence
haemagglutination
(IAHA)
phenom-
enon.3 Subsequently we reported
a method
of
measuring CR1 binding activity of E, which in-
volved the inhibition of IAHA.
In the application
of these methods to clinical situations we observed


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that both the presence of CIC and blunting of CR1
activity were
consistently
associated
with
direct
positive Coombs' tests. With one exception in our
studies there was no association of positive Coombs'
tests with haemolytic anaemia.
In this paper we report our observations on the
Accepted for publication 30 September 1985.
Correspondence to Dr Yoritaro Inada, Medical Service, Division
ofRheumatology, St Luke's-Roosevelt Hospital Center, Amsterdam
Avenue at 114th Street, New York, NY 10025, USA.
relation between types of positive direct Coombs'
tests and the presence of CIC and diminished CR1
activity
in
patients with SLE and
related CIC
mediated syndromes.
Materials and methods
CLINICAL MATERIALS
Three hundred and eleven venous blood samples
were obtained from 205 patients. Heparinised blood
for E isolation and untreated blood for serum were
collected. Patient populations were as follows: 164
blood samples from 103 patients with SLE, 46 from
26 patients with rheumatoid arthritis, 33 from 18
patients with vasculitis, nine from six patients with
nephrotic syndromes, eight from six patients with
chronic active hepatitis, six from four patients with
idiopathic pulmonary fibrosis, four each from two
patients with dermatitis herpetiformis and three
with mixed connective tissue disease, two each from
patients with Sjogren's syndrome, sarcoidosis, and
thrombotic thrombocytopenic
purpura,
and one
each from patients with Behqet's syndrome, breast
cancer,
acquired
immune
deficiency
syndrome,
hyperglobulinaemic purpura, meningitis, and mac-
rogammaglobulinaemia. Also there were 25 samples
from patients with unknown diseases who had CIC
or defective CR1 activity of E, or both. Only one
367


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Reaction of rheumatoid factors with IgG3 monoclonal anti-Rh(D) antibodies: more frequent reactivity to a monoclonal antibody of the Gm allotype G3m(5) in rheumatoid patients negative for G3m(5)


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Annals of the Rheumatic Diseases, 1988; 47, 898-905
Reaction of rheumatoid factors with IgG3 monoclonal
anti-Rh(D) antibodies: more frequent reactivity
to a monoclonal antibody of the Gm allotype G3m(5)
in rheumatoid patients negative for G3m(5)
ALISON H PUTTICK,' ELIZABETH A WILLIAMSON,' A H MERRY 2
BELINDA M KUMPEL,3 K M THOMPSON,4 AND VALERIE E JONES'
From the 'Postgraduate Medical School, University of Exeter, Barrack Road, Exeter, Devon; the 2Blood
Group Reference Laboratory, Radcliffe Infirmary, Woodstock Road, Oxford; the 3UK Transplant Service,
Southmead Road, Bristol; and the 4Department of Immunology, Institute ofAnimal Physiology, Babraham,
Cambridge
SUMMARY
Human monoclonal anti-Rh(D) antibodies of known IgG isotype and Gm allotype
were bound to erythrocytes and then used as the target IgG antigens for rheumatoid factors
(RFs) in a direct haemagglutination test. When serum samples from patients with rheumatoid
arthritis (RA) were tested for RF specificity towards these IgG monoclonal anti-D antibodies the
incidence and titre of reactivity towards an IgG3 monoclonal anti-D antibody was considerably
greater than for a polyclonal anti-D antibody of the same Gm allotype, G3m(5). This difference
was not explained by the amount of each anti-D antibody which bound to erythrocytes.
Furthermore, when patients with RA were divided into groups according to their Gm phenotype,
sera from a greater proportion of patients negative for the phenotype G3m(5) reacted to the
G3m(5) monoclonal anti-D antibodies than sera from those patients positive for this allotype.
Analysis of RF reactivities towards two IgG3 and three IgGl monoclonal anti-D antibodies, each
with different Gm allotypic epitopes, indicated, however, that individual serum samples
contained RFs with a spectrum of specificities; some sera appeared to react to a single set of Gm
alleles, whereas others also reacted to isotypic or iso-allotypic epitopes, or both. Our data suggest


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that RFs with specificity for Gm allotypes do not arise in patients who carry that particular
allotype owing to tolerance induced in fetal-neonatal life. Conversely, RFs with apparent
specificity for a Gm allotype formed in patients negative for that allotype may be reacting to a
closely related but different epitope. Final proof requires precise specificities for each RF
formed, and IgG3 monoclonal anti-D antibodies would be useful reagents for this purpose.
Key words: rheumatoid arthritis, autoantibodies, immunoglobulin allotypes.
Rheumatoid factors (RFs) are the characteristic
region of autologous IgG, which includes isotypic
autoantibodies in rheumatoid arthritis (RA). They
and Gm allotypic epitopes, has been under invest-
can be detected early in the disease,' 2 they are
igation for several decades. For example, in 1960
implicated in the chronic pathogenesis of rheumatoid
Harboe showed that RFs to polyclonal IgG3 anti-D
synovitis,3 and their specificity may be related to
antibodies are rare both in patients with RA and in
putative triggers of the disease process.4
normal individuals.5 In 1970 Grubb summarised the
The specificity of RFs for epitopes on the Fc
published work on RF specificity for Gm allotypes,
which also related this RF specificity to the Gm
Accepted
for
publication
13 April 1988.
status of the donor.6 From the few individuals
Accepted for publication 13 April 1988.
Correspondence to Dr Valerie E Jones, Postgraduate Medical
studied, both Grubb and Harboe noted that anti-
School, Barrack Road, Exeter, Devon EX2 5DW, UK.
Gm allotype donors, whether they were rheumatoid
898


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The default mode network is affected in the early stage of simian immunodeficiency virus infection: a longitudinal study


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1542  ｜NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023
NEURAL REGENERATION RESEARCH
www.nrronline.org
Research Article
The default mode network is affected in the early 
stage of simian immunodeficiency virus infection: 
a longitudinal study
Abstract  
Acquired immune deficiency syndrome infection can lead to cognitive dysfunction represented by changes in the default mode network. Most recent studies 
have been cross-sectional and thus have not revealed dynamic changes in the default mode network following acquired immune deficiency syndrome infection 
and antiretroviral therapy. Specifically, when brain imaging data at only one time point are analyzed, determining the duration at which the default mode 
network is the most effective following antiretroviral therapy after the occurrence of acquired immune deficiency syndrome. However, because infection times 
and other factors are often uncertain, longitudinal studies cannot be conducted directly in the clinic. Therefore, in this study, we performed a longitudinal 
study on the dynamic changes in the default mode network over time in a rhesus monkey model of simian immunodeficiency virus infection. We found 
marked changes in default mode network connectivity in 11 pairs of regions of interest at baseline and 10 days and 4 weeks after virus inoculation. Significant 
interactions between treatment and time were observed in the default mode network connectivity of regions of interest pairs area 31/V6.R and area 8/frontal 
eye field (FEF). L, area 8/FEF.L and caudal temporal parietal occipital area (TPOC).R, and area 31/V6.R and TPOC.L. ART administered 4 weeks after infection not 
only interrupted the progress of simian immunodeficiency virus infection but also preserved brain function to a large extent. These findings suggest that the 
default mode network is affected in the early stage of simian immunodeficiency virus infection and that it may serve as a potential biomarker for early changes


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in brain function and an objective indicator for making early clinical intervention decisions.
Key Words: acquired immune deficiency syndrome; analysis of variance; antiretroviral therapy; default mode network; functional magnetic resonance imaging; 
human immunodeficiency virus; longitudinal study; rhesus monkeys; simian immunodeficiency virus; SIV-mac239
https://doi.org/10.4103/1673-5374.360244
Date of submission: March 31, 2022 
Date of decision: July 13, 2022 
Date of acceptance: August 29, 2022 
Date of web publication: November 9, 2022
Introduction 
Human immunodeficiency virus (HIV) infection can lead to brain impairments 
that worsen with the duration of the disease, which greatly affects the quality 
of life of HIV patients, even in the current era of highly active antiretroviral 
therapy (ART) (Nightingale et al., 2014; Watkins and Treisman, 2015; Tang et 
al., 2017a, b). The prolongation of HIV infection leads to the dysfunction of 
multiple brain networks, especially the default mode network (DMN), which 
is the most active network at rest and is closely related to cognitive function 
(Mak et al., 2017; Smith et al., 2018). Several previous cross-sectional studies 
have reported that the dysfunction of the DMN caused by HIV infection is 
associated with cognitive deficits (Ortega et al., 2015; Cohen et al., 2018). 
In earlier studies, HIV infection was shown to result in decreased functional 
connectivity in the DMN in HIV-infected (Thomas et al., 2013) and perinatally-
acquired HIV patients (Herting et al., 2015). Furthermore, it has been shown 
that decreased functional connectivity of the DMN is correlated with poorer 
neurocognitive performance (du Plessis et al., 2017). In addition, another 
study found that abnormal activation of the posterior cingulate cortex in the 
DMN of HIV patients is related to deficits in Hopkins Verbal Learning Test-2 
learning performance (Cohen et al., 2018). Neurocognitive performance and 
functional connectivity of the DMN can be improved by providing patients


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with ART (Zhuang et al., 2017), and more recently, studies have demonstrated 
that changes in the DMN are also closely related to various factors, such as 
aging (Egbert et al., 2019) and HIV self-management interventions (Webel et 
al., 2019).
However, most previous studies used a cross-sectional experimental design, 
and magnetic resonance imaging (MRI) data were acquired at one time point 
only (Cohen et al., 2018; Egbert et al., 2019; Webel et al., 2019). Although 
cross-sectional studies are effective in investigating DMN changes, they are 
unable to reveal dynamic changes in the DMN following acquired immune 
deficiency syndrome (AIDS) infection or ART over the disease or treatment 
1Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, China; 2Key Laboratory of Big Data-Based 
Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People’s Republic of China, Beijing, China; 3Key Laboratory of Molecular Imaging, 
Institute of Automation, Chinese Academy of Sciences, Beijing, China; 4Beijing Youan Hospital, Capital Medical University, Beijing, China; 5Renji Hospital, Shanghai Jiao Tong University 
School of Medicine, Shanghai, China; 6Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China 
*Correspondence to: Hong-Jun Li, MD, lihongjun00113@ccmu.edu.cn; Jie Tian, PhD, tianj@buaa.edu.cn; Hui Zhang, PhD, hui.zhang@buaa.edu.cn.
https://orcid.org/0000-0003-2883-4931 (Hui Zhang); https://orcid.org/0000-0003-0498-0432 (Jie Tian); https://orcid.org/0000-0001-5887-5684 (Hong-Jun Li)
#These authors contributed equally to this work.
Funding: This study was supported by the National Natural Science Foundation of China, Nos. 82271963 (to HJL), 81771806 (to HJL), 61936013 (to HJL), 82001914 (to ZCT), 81871511 (to 
HZ); National Key R&D Program of China, No. 2021YFA1301603 (to ZCT); and the Natural Science Foundation of Beijing, No. 7212051 (to HJL).


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How to cite this article: Tang ZC, Liu JJ, Ding XT, Liu D, Qiao HW, Huang XJ, Zhang H, Tian J, Li HJ (2023) The default mode network is affected in the early stage of simian 
immunodeficiency virus infection: a longitudinal study. Neural Regen Res 18(7):1542-1547. 
Graphical Abstract
Longitudinal default mode network (DMN) changes due to simian immunodeficiency virus infection
From the Contents
Introduction
1542
Methods
1543
Results
1544
Discussion
1545
Zhen-Chao Tang1, 2, 3, #, Jiao-Jiao Liu4, #, Xue-Tong Ding1, 2, 3, #, Dan Liu5, Hong-Wei Qiao6, Xiao-Jie Huang4, Hui Zhang1, 2, 3, *, 
Jie Tian1, 2, 3, *, Hong-Jun Li4, *


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Neuro-Oncology
25(4), 617–627, 2023 | https://doi.org/10.1093/neuonc/noac236 | Advance Access date 11 October 2022
617
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Cellular immunotherapy for medulloblastoma
  
Michael Y. Schakelaar†, Matthijs Monnikhof†, Sandra Crnko, Emma W. Pijnappel, Jan Meeldijk, 
Toine ten Broeke, and Niels Bovenschen
Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands (M.Y.S., M.M., S.C., 
E.W.P., J.M., T.B., N.B.); Center for Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, 
The Netherlands (J.M., N.B.); Bachelor Research Hub, Education Center, University Medical Centre Utrecht, 3584 CX 
Utrecht, The Netherlands (S.C., E.W.P., J.M., T.B., N.B.)
Corresponding Author: Niels Bovenschen, PhD, Department of pathology, University Medical Center Utrecht, Utrecht, The Netherlands 
(n.bovenschen@umcutrecht.nl).
†These authors contributed equally to this work.
Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children, making up ~20% of all primary 
pediatric brain tumors. Current therapies consist of maximal surgical resection and aggressive radio- and chemo-
therapy. A third of the treated patients cannot be cured and survivors are often left with devastating long-term side 
effects. Novel efficient and targeted treatment is desperately needed for this patient population. Cellular immu-
notherapy aims to enhance and utilize immune cells to target tumors, and has been proven successful in various 
cancers. However, for MB, the knowledge and possibilities of cellular immunotherapy are limited. In this review, 
we provide a comprehensive overview of the current status of cellular immunotherapy for MB, from fundamental 
in vitro research to in vivo models and (ongoing) clinical trials. In addition, we compare our findings to cellular im-


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munotherapy in glioma, an MB-like intracranial tumor. Finally, future possibilities for MB are discussed to improve 
efficacy and safety.
Keywords 
cellular immunotherapy | cytotoxic lymphocytes | medulloblastoma
The incidence of central nervous system (CNS) tumors 
is most frequent in pediatric patients (0–21  years of age). 
Medulloblastoma (MB), a World Health Organization (WHO) 
grade IV classified malignancy, is the most prevalent1 and re-
sponsible for over 60% of all intracranial embryonal tumors 
in the USA diagnosed between 2011 and 2015.2 The peak in-
cidence is between 6 and 8 years of age.1 In childhood, ap-
proximately 1 in 200 000 individuals is diagnosed with MB,2 
whereas the incidence in adulthood is much lower (1 in 
2 000 000).3 MB originates from the progenitor cell popula-
tions in the cerebellum during early life and has been linked to 
specific genetic aberrations. Based on these aberrations, four 
MB subgroups have been described; Wingless (WNT), Sonic 
Hedgehog (SHH), Group 3 (G3), and Group 4 (G4).4,5 Although 
morphologically all classified as MB, these subgroups are dif-
ferent in cell-of-origin, driver aberration, and prognosis thus 
should be treated as biologically distinct entities (Figure 1).
In most WNT-MB patients, an activating mutation in the 
gene encoding β-catenin results in a constitutively active WNT 
signaling that contributes to enhanced cell growth and pro-
liferation.6 Patients often have a favorable prognosis mainly 
attributed to an altered vasculature in the brain and higher 
permeability of blood brain barrier (BBB), making it more 
susceptible to systemic chemotherapies.1 SHH-MB is genet-
ically best characterized with most mutations found within 
the SHH pathway. This subgroup is more heterogenetic com-
pared to WNT-MB and is divided in four additional subgroups 
(SSHα, SSHβ, SSHγ, and SSHδ).7 Depending on the subtype of 
SSH-MB, adult patients can be treated by inhibiting proteins 
upstream of SSH. However, children cannot use these inhibi-


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tors because of potential skeletal abnormalities resulting in a 
far worse prognosis.1 Additionally, TP53-mutant tumors dras-
tically decrease survival in both children and adults.8 For sub-
groups 3 and 4, less than a third of cases can be dedicated 
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License 
(https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 
medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com


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Annals ofthe Rheumatic Diseases 1995; 54: 443-450
REVIEW
Skeletal evidence of osteoarthritis:
a palaeopathological perspective
Robert D Jurmain, Lynn Kilgore
Osteoarthritis
(OA),
or
degenerative
joint
disease, is the most common form of joint
pathology, and
it has an extensive history.
Indeed, it has been observed in a variety of
fossil animals, and has been reported in the
fossil remains of dinosaurs.'
Among
preindustrial human
groups,
as
documented by skeletal remains, osteoarthritic
changes are quite frequently the most common
pathological lesion seen. Such degenerative
changes have been described for archaeological
samples varying widely in time and location.2"
In many cases,"'5 frequencies of involvement
have also been calculated and presented.
Skeletal evidence from archaeological sites
thus has potential to expand considerably the
range of epidemiological data concerning OA.
Human populations long since extinct can be
sampled.
Current epidemiological
data
are
limited
almost
entirely
to
clinical
samples
drawn from urban contexts, mostly from North
America
and
Europe.
Earlier
populations,
ranging from arctic hunters, to early Romano-
British agriculturists, to Mediaeval Nubians
(and, obviously, many others) may have led
lifestyles very different from those character-
istic of contemporary groups. Accordingly,
skeletal analysis provides a 'window' into a
vastly broader sample of human groups than
afforded solely by clinical samples. If varying
levels of mechanical loading are important in
the aetiology of OA, as suggested by the 'stress
hypothesis','6
earlier
populations
could be
expected to exhibit definitive patterns of joint
involvement. Such patterns should be reflected
in differential involvement both within and
among joints; moreover, patterns of bilateral
asymmetries, sex based variation, and perhaps,
most crucially, clearly demarcated frequencies
of involvement among prehistoric populations
should be manifest.
Available materials
In recognition of the fact the osteoarthritic


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process begins in articular cartilage, analysis of
the 'hard' tissues can provide another window
not commonly available to the clinician. With
joint surfaces free of overlying tissue, subtle
degenerative changes involving bone are easily
seen. Presumably slight arthritic involvement
includes small marginal lipping (osteophytes)
or small erosive changes to the joint surface
itself. In modern contexts, such minor bone
involvement is not usually recognised as it does
not
present
radiographically;
occasionally,
following surgical replacement, a few macer-
ated specimens have become
available,'7 18
thereby giving researchers a rare glimpse of
underlying bony tissue.
In addition, materials derived at postmortem
are a most useful supplement and help bridge
the gulf between clinical data and fully macer-
ated remains. Several detailed studies have, in
fact,
investigated the frequency of OA
in
postmortem collections.'9-21 Moreover, in a few
cases large numbers of macerated specimens
have carefully been obtained from dissecting
room
samples
and have been
curated
as
permanent collections (most notably, the Todd
Collection
at
the
Cleveland
Museum
of
Natural History and the Terry Collection at the
US National Museum of Natural History).
These collections have proven a rich source of
information,
as
the
skeletons
are
virtually
intact,
sex
and
age
(approximated)
were
recorded at the time of dissection, and for
many individuals cause of death (and some
clinical history) is also noted. Building upon
this rich data source, skeletal biologists2 9 20
have used dissecting room skeletal collections
to refine their descriptions of osseous degener-
ative lesions, and to make epidemiological
comparisons with other groups.
For
archaeologically
derived
specimens
there are tens of thousands of examples of
remodelled
joint
surfaces.
Moreover, when
skeletal materials are well preserved, numerous
regions can be systematically observed,
in-
cluding the large peripheral joints, the vertebral
column
(body
surfaces
in
addition
to


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to
apophyseal articulations), and the numerous
small articulations of the hands and feet. In
this way,
a pattern
of involvement within
individuals and, more generally, within popu-
lations can be established.
Finally, in addition to a palaeoepidemiology
of degenerative arthritis in human groups, such
comparative perspectives can be expanded to
include non-human animals. Recent work with
non-human primates,22 23 especially the study
of joint involvement in great apes,2426 has
opened the potential
for an even broader
perspective concerning the aetiology of osteo-
arthritis. By studying animals with differing
postural/locomotory
adaptations and
corre-
lating these factors with the pattern of degener-
ative lesions, we should be able to gain a fuller
understanding of some
of the mechanical
factors influencing the aetiology of OA.
Department of
Anthropology,
San Jose State
University,
San Jose,
CA 95192, USA
R D Jurmain
Department of
Anthropology,
Colorado State
University,
Fort Collins,
CO, USA
L Kilgore
Correspondence to:
R D Jurmain.
Accepted for publication
13 October 1994
443


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Annals of the Rheumatic Diseases 1995; 54: 757-778
Third International Symposium on
the Immunotherapy ofthe Rheumatic Diseases
10-14 May 1995, Cyprus
Introduction and overview
When the First International Symposium on the Immuno-
therapy of the Rheumatic Diseases was held in London in
February 1991, immunotherapy was an exciting but largely
theoretical concept. That meeting, focusing exclusively on
immune cells and mediators as therapeutic targets, was
almost entirely restricted to in vitro and animal studies, as
only a few small open studies had been performed in
humans in vivo. Just four years later, the situation has
evolved beyond all recognition. Whilst in vitro and animal
experiments are still vital, an increasing variety of treat-
ments have been tested in vivo in humans in double blind
placebo controlled trials. In addition, the purview of the
Symposium is now much broader as the mesenchyme,
including synoviocytes, proteolytic enzymes, and angio-
genesis, is now an active target for antirheumatic drug
development.
Inevitably,
there have
also been some
failures over the past four years. Some initially promising
treatments,
such
as major histocompatibility complex
(MHC) blocking peptides and lymphocyte depleting anti-
bodies, appear to have fallen by the wayside and, even
more disappointingly perhaps, we are no further forward
in
identifying
the
putative
autoantigens
involved
in
triggering or perpetuating the disease. However, as can be
seen from the ensuing review and abstracts, gains have far
outweighed losses, setting the scene for a fascinating
conference.
Somewhat paradoxically for a meeting on the Immuno-
therapy of the Rheumatic Diseases, the conference started
with a Keynote Address by Dr L Adorini (Milan) on
the non-obese diabetic (NOD) mouse as a model for
developing and testing immunotherapy in human diabetes.
There was method in the apparent madness. Diabetes in
the NOD mouse represents one of the best spontaneously
developing animal models available, as it has a similar


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pathology, analogous genetic susceptibility and identical
putative
autoantigens
as
obtain
in human
diabetes.
Examination of how data from this model can be applied
to the human disease may help us to interpret information
from the rather less satisfactory animal models available for
the rheumatic diseases.
The Symposium proper began with an overview of the
pathogenesis ofrheumatoid arthritis (RA) (Dr G H Kingsley),
followed by five presentations on various topical aspects.
Dr Panayi put forward the hypothesis that RA is an organ
specific
autoimmune
disease
in
which
the
immune
response
is directed to the chondrocyte. As immune
responses to two putative cartilage autoantigens, collagen
type II and cartilage proteoglycan, have proved difficult to
find, the group has developed a chondrocyte expression
library and is screening it with RA serum to identify
chondrocyte specific proteins which may have a role in RA.
The identification of such candidate antigens would allow
therapeutic approaches using antigen specific tolerance
similar to those for diabetes discussed in the Keynote
Address.
Dr
Natvig's
group
has
demonstrated
that
rheumatoid factor in healthy individuals is subject to a
controlling mechanism which limits affinity maturation.
He suggested that the apparent loss of such control in
RA may be of pathogenetic significance; the question of
what role rheumatoid factor has in synovitis remains
unanswered. Turning to T cells, Dr Amento has found, in
several autoimmune animal models, that administration of
TCR peptides from disease perpetuating T
cells can
suppress disease by upregulating counter regulatory T
cells; however, as the question ofwhether there is restricted
T cell receptor (TCR) usage in RA remains unresolved,
the potential of this type of treatment in humans is as yet
unknown. The collagen induced arthritis developed by
Dr Bontrop and colleagues in rhesus monkeys is probably
the
best
characterised
primate
inflammatory
arthritis
model, and should allow the testing of pathogenetic and


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therapeutic hypotheses in much the same way as the NOD
mouse model does in diabetes. In the last presentation on
immunopathogenesis, Dr David reviewed the
role of
human MHC class II genes in mediating susceptibility to
arthritis, using a new model system. In this model, human
MHC class II genes from RA susceptible or resistant
haplotypes were introduced into mice from which the
endogenous class II genes had been 'deleted', so that their
only functional class II molecules were those coded by the
human
genes. The
effect of these manipulations on
arthritis
susceptibility
could then be examined
in
a
controlled fashion which may help to explain the role of
MHC class II in determining disease susceptibility in
humans.
The
next
major
theme
of the
meeting
was
the
immunologist's holy grail, the induction of tolerance.
Immunosuppressive approaches to the treatment of auto-
immune disease have two major drawbacks-the need for
long term treatment to prevent return of disease, and the
risk of infection or tumour as a result of a generalised
loss of immune function. In contrast, the reinduction of
tolerance to the putative rheumatoid autoantigen(s) has
the potential to provide a permanent and highly selective
treatment. Three different approaches to induction of
tolerance were discussed at the meeting. In session II,
Drs Hafler, Wraith and Sieper reviewed tolerance induced
by
nasal
or
oral
antigen
administration.
Whilst
this
technique has progressed the furthest in clinical terms
(indeed, the results of two double blind placebo controlled
clinical trials of oral collagen in RA were presented, one
positive and one negative), the mechanisms underlying
oral and nasal tolerance remain far from clear. Dr Cohen
and Dr Sette discussed ways of interfering with the specific
T cell receptors (TCR) involved in the 'autoimmune'
MHC-antigen-TCR complex. Though potentially very
757


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Association of glucose-6-phosphate dehydrogenase deficiency with diabetes mellitus in ethnic of Singapore


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Journal of Medical Genetics, 1979, 16, 431-434
Association of glucose-6-phosphate dehydrogenase
deficiency with diabetes mellitus in ethnic groups of
Singapore
N. SAHA
From the Department ofPhysiology, Faculty of Medicine, University of Singapore, Singapore
SUMMARY
Six hundred and nine male patients suffering from maturity onset diabetes mellitus,
comprising 422 Chinese, 66 Malays, and 121 Indians, were investigated to determine the incidence
of G6PD deficiency, ABO blood groups, and haemoglobin types, and these were compared with
normal healthy controls. A positive association with a higher incidence of G6PD deficiency in
diabetics was observed in Chinese and Indian patients. There was no significant difference in the
frequencies of ABO blood groups and haemoglobin types between the patients and the controls in
any of the ethnic groups studied.
The genetic association of diabetes mellitus has been
studied in the past mainly by the relative incidence of
blood groups and serum proteins (Craig and Wang,
1955;
McConnell
et
al.,
1956;
Andersen
and
Lauritzen, 1960; Macafee, 1964; Berg et al., 1967;
Klebe and Nielsen, 1972; Lamba et al., 1974), but
the results, far from being in agreement, are rather
conflicting. From an epidemiological study into the
incidence
of cancer
and
diabetes
mellitus
and
glucose-6-phosphate dehydrogenase (G6PD)
defi-
ciency in different populations of the world, Kessler
(1970) suggested a negative association of G6PD
deficiency in cancer and a positive relationship in
diabetes
mellitus.
Naik
and
Anderson
(1971)
observed a negative association of G6PD deficiency
in cancer in American Negro patients, but only in
the case of females. In an earlier study on a pooled
sample of smaller size we failed to observe any
association of G6PD deficiency and ABO blood
groups in diabetes mellitus (Saha, 1971). The three
ethnic groups in Singapore (Chinese, Malays, and
Indians), who have different incidences of the disease,
with a higher incidence among Indians compared
with the other two (Cheah et
al.,
1972,


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1972,
1975),
provided an excellent opportunity to study the
possible association ofG6PD deficiency, ABO blood
groups, and haemoglobin types in diabetes mellitus.
We present in this report the incidence of G6PD
deficiency, ABO blood groups, and haemoglobin
types in maturity onset diabetes mellitus compared
with healthy controls in the three ethnic groups of
Singapore.
Received for publicaiion 16 February 1979
Materials and methods
PATIENTS
Six hundred and nine male patients, comprising 422
Chinese, 66 Malays, and 121 Indians, attending the
Diabetic Clinic at the Tan Tock Seng Hospital,
Singapore, were investigated for the distribution of
G6PD deficiency, ABO blood groups, and haemo-
globin
types.
These
were
consecutive
cases
of
maturity onset diabetes mellitus as confirmed by
standard glucose tolerance tests after oral glucose.
Five diabetic patients with G6PD deficiency at the
first test were followed up and tested for blood
glucose levels and G6PD deficiency on three or four
subsequent visits while undergoing treatment.
CONTROLS
For comparison,
controls
were taken from
(a)
patients proved to be normal and (b) series in
published reports.
(a) Seven hundred and forty seven male subjects
comprising 523 Chinese, 87 Malays, and 137
Indians attending the same diabetic clinic
formed the control series. These were con-
secutive cases confirmed as non-diabetic by
standard glucose tolerance tests. They were
investigated for the distribution of G6PD
deficiency, ABO blood groups, and haemo-
globin types.
(b) Published
data. ABO
blood
groups
were
compared with the series of Chan (1962), cases
ofG6PD deficiency with the series of Saha and
Banerjee (1971a, b), and for comparison with
431


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Journal of Medical Genetics, 1979, 16, 330-337
Medical genetics in China
W. F. BODMER1 AND C. A. CLARKE2
From the Genetics Laboratory, Department of Biochemistry, University of Oxford,
Oxford OX] 3QU2; and the Royal College ofPhysicians Medical Services Study Group, King's Fund
Centre, London NWJ 7NF2
In July 1978 a Royal Society delegation visited the
People's Republic of China for about three weeks to
discuss medicobiological matters with the Chinese
Academy of Sciences, in particular the reason for the
high incidence of cancer of the oesophagus in one
county in the north and ofnasopharyngeal carcinoma
in the south. Dr Michael Stoker was the leader (the
Chinese are insistent on this protocol) and the other
scientific members were Professor Walter Bodmer,
Sir Cyril Clarke, Sir Richard Doll, and Professor
Avrion Mitchison. We were accompanied by Miss
Elizabeth Wright, Director of the Great Britain-
China Centre. She spoke excellent Chinese and
reported on the translation of our lectures and other
discussions.
This
varied
greatly
but was
never
manipulated.
The authors of this paper thought that readers of
the Journal might be interested to hear about our
impressions of genetics in the Republic, genetics
being interpreted in the liberal Lederberg sense of
'anything interesting.'
Medical statistics
We did not come across any organisation such as our
own OPCS (Office of Population Censuses and
Surveys) and
it seems probable
that
the most
reliable data are those relating to cancer, particu-
larly in the high incidence areas; these are collected
by the Oncology Institutes.
In each commune (essentially a group of villages
with,
on
average,
between
50 000 and
100 000
people)
individual
registration
is
required
for
rationing
purposes.
It
is
therefore
possible
to
obtain basic information about the
size of the
population. This is then looked at in more detail for
one of the 10 to 20 communes which make up each
county, and by summing the total populations from
each commune, a rough estimate of the population


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structure of the whole county can be made by
extrapolation. The provinces, which are large regions,
Received for publication 7 February 1979
are divided for administrative purposes into counties
corresponding roughly to those in the UK.
As regards malignancy, data obtained from the
Peking Institute of Oncology showed that cancer
mortality had been determined by means of a retro-
spective
study
of death
certificates
in
selected
provinces over the 3-year period 1972, 1973, and
1974, and is now being determined for the whole
country by a similar study in 1975. Information
obtained in discussion suggested that a positive
diagnosis
of cancer on
a death
certificate was
reasonably reliable. In Kiangsu Province (containing
Shanghai and Nanking, and not ahighincidencearea)
we were shown a detailed map of the cancer mortality
in each commune and how the diagnosis had been
arrived at. This was by microscopy in 16 % of cases,
by hospital investigation including x-ray in 65%,
by clinical examination in 15%, and by history or
barefoot doctor alone in 4%. Similar information is
available from the high cancer incidence areas.
Data on congenital malformations seemed to be
based only on personal experience and individual
hospital records. For example, in discussing anence-
phaly, spina bifida, and hydrocephalus in Peking,
we were told that there was an extraordinarily high
incidence: up to 1 % of births in Peking itself, and
up to 3 % further north, but much lower in Shanghai.
This seems highly improbable and it may be that
there was some confusion and that the Chinese
were talking about total malformations. In Taiwan,
the
incidence
of anencephaly
is
'intermediate',
around 1 17/1000 births (Emanuel et al., 1972).
Visits to Genetics Institutes
ACADEMY INSTITUTE OF GENETICS, PEKING
The Institute was started in 1951, at first doing mainly
plant genetics, but in 1959 animal work was started
as well. There are now 250 research workers (the
distribution
between
scientists,
technicians,
and


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and
others is not clear) in five departments. One of these
dealt with human and animal genetics, and we paid it
two visits. The first time, we heard a great deal about
330


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Journal of Medical Genetics, 1979, 16, 351-357
Genetic polymorphisms in diabetics and non-diabetics
D. R. R. WILLIAMS AND R. A. CARTWRIGHT
From the MRC Dunn Clinical Nutrition Centre, Addenbrookes Hospital, Trumpington Street,
Cambridge CB2 1 QE; and the Yorkshire Regional Cancer Organisation, Cookridge Hospital,
Leeds LS16 6QB
SUMMARY
Phenotype distributions of some genetic polymorphisms are reported in a sample of
721 diabetics and 515 non-diabetic, non-blood donor controls. Reference is also made, in the case
of the ABO and Rhesus systems, to previously published results for blood donors resident in the
Durham area. Non-insulin-taking diabetics show an increased frequency of blood group A1 (and
A1 + A2) when compared with controls. This difference is particularly marked in male diabetics.
When diabetics are compared with age matched controls, the difference is confined to the older cases.
It is proposed that this effect is predominantly the result of a deficiency of group A1 in controls
rather than the result of increased susceptibility to the disease among A1 people. No association with
any of the Rhesus phenotypes is shown. In non-diabetics, the results suggest an enhanced survival
value for the rr genotype.
No significant associations are seen when the MNSs, Kell, Lewis, Duffy, haptoglobin, red cell
acid phosphatase, phosphoglucomutase, adenylate kinase, and adenosine deaminase distributions
in these groups of subjects are compared.
The ABO blood groups of diabetics have been
extensively studied since McConnell's suggestion, in
1955, of an increased frequency of blood group A in
these patients. Despite considerable effort, however,
this approach has contributed little to knowledge of
the hereditary factors involved in the predisposition
to diabetes, and there has been some measure of
disagreement among the authors concerned. Other
red cell polymorphisms and serum protein systems
have been less well studied in diabetics and few clear
conclusions have been drawn.


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The present study was undertaken to investigate
the distribution of some of these polymorphisms in
diabetics and in non-diabetic controls. The results
for the esterase-D polymorphism in these subjects
have
been
published
elsewhere
(Williams
and
Cartwright,
1978),
as have those for the histo-
compatibility antigens (Williams, 1977).
Two features distinguish this particular study.
Firstly, the sample of diabetics consists of a large
proportion
of
the
out-patients
attending
one
particular hospital, and the phenotype frequencies in
these patients are analysed
in terms of current
treatment,
current
age,
and
sex.
Secondly,
the
controls are drawn from the same geographical area
as the diabetics, are age matched with them for
Received for publication 29 December 1978
analysis, and are not a sample of blood donors,
though previously published data from donors are
included for comparison.
Materials and methods
DIABETIC SUBJECTS
Patients were chosen from those attending out-
patient
clinics
at
Dryburn
Hospital,
Durham.
Venous blood samples were taken from 721 of the
diabetics attending between November 1974 and
June 1976. This represents about 75% of the total
attendance during
this time. Sampling was not
random since patients attending more frequently had
a greater chance of selection. The series collected was
slightly younger in mean age and consisted of a
higher proportion of insulin-taking patients and a
lower proportion of diet-treated patients than the
complete
out-patient
population,
though
these
differences were not significant (Williams, 1977).
CONTROL SUBJECTS
These were selected from three sources: (a) age and
sex matched neighbours of some of the diabetics
(72 subjects); (b) patients attending the orthopaedic
department of Dryburn hospital for treatment of
traumatic conditions, mainly fractures and head
351


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Non-progressive cerebellar ataxia, aplasia of pupillary of iris, and mental subnormality (Gillespie's syndrome) affecting 3 members of non-consanguineous family in 2 generations


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Journal of Medical Genetics, 1979, 16, 373-378
Non-progressive cerebellar ataxia, aplasia of
pupillary zone of iris, and mental subnormality
(Gillespie's syndrome) affecting 3 members of a
non-consanguineous family in 2 generations
M. d'A. CRAWFURD,1 R. B. HARCOURT, AND P. A. SHAW2
From the Department of Genetics, University ofLeeds'; and the Ophthalmic Department, Leeds
General Infirmary,2 Leeds
SUMMARY
A family is reported in which a brother and sister both showed non-progressive cere-
bellar ataxia, aplasia of the pupillary zone of the iris, and mild mental subnormality. These clinical
findings were similar to those in two previous case reports. Despite the birth of an affected son to the
affected sister, this family is considered to confirm autosomal recessive inheritance of this syndrome.
The paternity of the mother's husband is supported by blood groups and biochemical markers and
it is presumed that the husband is a heterozygote, even though no consanguinity could be detected.
The hereditary ataxias are an ill-defined group of
disorders of which the best known is Friedreich's
ataxia. Many other syndromes have been described,
some of which are clearly defined entities, but others
are of uncertain clinical, pathological, and genetic
status. The clear delineation
of further
specific
disorders is helpful in the classification of this group
and is of practical use in genetic counselling.
Gillespie (1965) first reported the combination of
partial aniridia, cerebellar ataxia, and mental sub-
normality affecting a brother and sister. Sarsfield
(1971) described a sporadic case of a boy similarly
'Present address: Division of Inherited Metabolic Diseases,
MRC Clinical Research Centre, Watford Road, Harrow,
Middlesex HAI 3UJ.
2Present
address:
Consultant Ophthalmic Surgeon,
City
General Hospital, Stoke-on-Trent, Staffs.
Received for publication 29 December 1978.
T
1r1
2r'
3r7
affected. We report here a further family of a young
man, his elder sister, and her son, all with the same


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association of abnormalities (Fig. 1).
Case reports
CASE
1 (III.8)
This Caucasian female, the first of three sibs, was
born at term in 1955. She was delivered at home after
a prolonged labour of about 36 hours and weighed
3300 g. In the first few months of life she suffered
unexplained episodes of vomiting and had difficulty
with feeding. The parents also noticed a tremor of
the hands and feet from early infancy and she was
late in passing most of her milestones. She first sat
at 15 months, stood at 20 months, and first spoke at
2 years; there was also some delay in walking and
she was backward in her social behaviour. At the
1976
Fig. 1
Pedigree offamily.
Genetic family L1013
373


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X;15 translocation in retarded girl: X inactivation pattern and localise the hexosaminidase A and other loci


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Journal of Medical Genetics, 1979, 16, 254-262
X;15 translocation in a retarded girl: X inactivation
pattern and attempt to localise the hexosaminidase A
and other loci
RENEE BERNSTEIN, BRONWEN DAWSON, RUDI KOHL, AND
TREFOR JENKINS
From the Department ofHuman Genetics, School ofPathology, The South African Institute for Medical
Research and University ofthe Witwatersrand, Johannesburg; and the Department ofPaediatrics,
State Hospital, Windhoek, SWA/Namibia
SUMMARY
Cytogenetic studies on a retarded girl showed a complex X; 15 translocation, karyotype
45,X,- 1 5,+t(X;1 5). The translocation X chromosome was non-randomly partially inactivated, the
inactivation being mainly confined to the X segment and in some cells only to the X long arm. Gene
marker studies failed to show anomalous segregation of the hexosaminidase A gene or any other gene
markers tested.
Nearly 50 patients with an X autosome translocation
have been reported and attempts made to correlate
the phenotypic expression with the type and site of
translocation, as well as with the X inactivation
pattern (Cohen et al., 1972; Summitt et al., 1974;
Therman and Patau, 1974; Gilgenkrantz et al., 1975;
Bartsch-Sandhoff et al., 1976; Hagemeijer et al.,
1977). A further 18 X;autosome translocations are
listed by Borgaonkar and Dolling (1977). Every
autosome except chromosomes 10 and 20 has been
implicated and in at least 5 cases the autosome has
been identified as chromosome 15 (Engel et al., 1971;
Lucas and Smithies, 1973; Sujansky et al., 1973;
Laurent, 1971, quoted by Gilgenkrantz et al., 1975;
Bartsch-Sandhoffet al.,1976).
The X inactivation pattern of sufficient numbers of
such cases has now been studied to establish that
balanced X;autosome translocations usually show
non-random inactivation of the normal X chromo-
some,
while
in
unbalanced
translocations,
the
derivative abnormal X
is usually completely or
partially
inactivated,
with
resultant
diversity
of
phenotypic expression. For a valid correlation to be
made between the phenotype and the karyotype in


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these patients, it is important to determine whether
X inactivation has spread from the X segment to the
attached autosome. Such an exercise was often
difficult
with
autoradiographic
techniques,
but
incorporation of 5-BrdU during DNA synthesis
(Dutrillaux et al., 1973) has provided a simple and
Received for publication 11 October 1978
accurate means ofstudying the replication patterns of
chromosomal DNA,
including
the
inactivation
patterns ofthe X chromosome.
We report the investigation of a markedly retarded
girl, who was found to have a complex translocation
of chromosomes X and
15
(45,X,-X,-15,+t
(X;15)) in the majority of her peripheral blood
metaphases, and a minor mosaic 45,X (Turner)
cell-line. The translocation X chromosome
was
found to be non-randomly partially inactivated.
Serogenetic studies were performed on the child and
her parents in an attempt to localise genes on
chromosomes X and 15.
Case report
A
4-year-old
girl
was
brought
to
hospital
in
Windhoek, Namibia/South West Africa from a
remote country area for investigation of marked
mental and physical retardation. She was the fourth
born of 5 children, and was delivered normally after
an uneventful pregnancy. Both parents and the 3
older sibs, all boys, are phenotypically normal, as was
the youngest sib, a girl, who died recently of 'con-
gested
lungs'.
There
is
no
known
history
of
abnormality in either parent's family. The mother is
of (black) Tswana origin, while the father has mixed
Tswana/Caucasoid ancestry.
The birthweight is not known, but the child was
said to be weak and had difficulty in sucking. The
mother thought the child was normal until 3 months
of age, but development was then noted to be slow
254


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Congenital haemolytic anaemia resulting from glucose phosphate isomerase deficiency: genetics, clinical picture, and prenatal diagnosis


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Journal of Medical Genetics, 1979, 16, 189-196
Congenital haemolytic anaemia resulting from glucose
phosphate isomerase deficiency: genetics, clinical
picture, and prenatal diagnosis
A. G. L. WHITELAW,
P. A. ROGERS, D. A. HOPKINSON, H. GORDON,
P. M. EMERSON,
J. H. DARLEY, C. REID, AND M. d'A. CRAWFURD
From the Departments ofPaediatrics, Obstetrics, and Haematology, Northwick Park Hospital; the
Division of Inherited Metabolic Disease, Clinical Research Centre, Northwick Park Hospital;
the MRC Human Biochemical Genetics Unit, The Galton Laboratory, University College London; and
the Department ofHaematology, Radcliffe Infirmary, Oxford.
SUMMARY
Glucose phosphate isomerase (GPI) deficiency with severe haemolysis and hydrops
fetalis was found in the first child of unrelated, healthy Caucasian parents. The child died at 3 hours.
Both parents were found to have 50 % of normal red cell GPI activity and qualitative tests on their
red cells and white cells showed that each was heterozygous for a different GPI variant allele associa-
ted with enzyme deficiency. Tests on the placenta showed that the propositus was a 'compound'
heterozygote.
Examination of amniotic cells obtained by amniocentesis on the mother at 28 weeks in her second
pregnancy led to the prenatal diagnosis of GPI deficiency. This second child, a 'compound' hetero-
zygote at the GPI locus indistinguishable from the first, was successfully treated by immediate
exchange transfusion and subsequent blood transfusions.
Glucose phosphate isomerase (EC: 5.3.1.9) (GPI) is
a dimeric enzyme which catalyses the interconversion
of fructose-6-phosphate and glucose-6-phosphate. It
is determined by an autosomal locus which has been
assigned to chromosome 19 (McMorris et al., 1973).
Several electrophoretic variants have been identified
in population studies on normal healthy subjects
in addition to the common phenotype GPI 1 (Detter
et al., 1968; Shinoda, 1970; Tariverdian et al., 1970;
Welch, 1971; Omoto and Blake, 1972). The variant


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alleles are mostly rare with the exception of GPI3
which
reaches
polymorphic
frequency
in
some
Indian populations (Blake et al., 1971).
Some electrophoretic variants are associated with
deficient activity of GPI and may manifest with non-
spherocytic
haemolytic
anaemia.
The
affected
subjects may be homozygous for the variant allele
causing GPI deficiency, for example, GPI Espeln,
also known as phenotype GPI 9 (Arnold et al., 1973).
In other cases, patients have been shown to be
heterozygous for two different variant alleles both
associated with GPI deficiency, for example, GPI
Seattle, also known as phenotype GPI 9-10 (Baughan
et al., 1968; Detter et al., 1968). In some other cases,
Received for publication 30 August 1978
the product of the variant allele is indistinguishable
electrophoretically from normal, and indeed some-
times the alleles appear to be 'silent'.
The various reports of GPI deficiency associated
with haemolytic anaemia were reviewed by Paglia
and Valentine (1974). Several new cases have been
identified since then; for example, GPI Utrecht
(van Biervleit, 1975), GPI Nordhorn (Schroter et al.,
1974), and GPI Barcelona (Kahn et al., 1977), and
the genetic and molecular
basis
for haemolysis
because
of GPI
deficiency
has
been
reviewed
recently (Kahn et
al.,
1976,
1977; Schrbter and
Tillmann, 1977). Most of the cases are relatively
mild, but there is a report of a family from Kentucky
in which 3 of 4 affected children in a family of 8
died, one at the age of 11 days (Hutton and Chilcote,
1974).
A family is described here in which 2 sibs have
had severe congenital non-spherocytic haemolytic
anaemia because of deficient activity of GPI. The
first child died at 3 hours with hydrops fetalis. The
second child was diagnosed antenatally by amnio-
centesis at 28 weeks' gestation, and was successfully
treated by exchange transfusion following delivery at
35 weeks and subsequent blood transfusions. Each
189


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Review Article
J. med. Genet. (i964), I, 50.
Sex Chromatin*
URSULA MITTWOCH
From Galton Laboratory, University College, London
The term 'sex chromatin', in present-day usage,
denotes a body in the nuclei of cells, which indicates
the sex of the organism from which the cell origi-
nated.
The sex chromatin body is present in the
nucleus
only
during interphase and
disappears
during mitosis.
The term 'sex-chromatin' had
previously been used in a different sense by Wilson
(1925) to describe the (hypothetical) part of the
sex chromosomes that acted as a sex differentiator
in development.
Although the subject of sex chromatin has be-
come a part of human genetics only within the last
decade or so,
it has attracted very considerable
interest and today provides one of the most active
growing points. One reason for this is practical.
It
has been estimated that about 2 or 3 persons per
i,ooo suffer from an abnormality of their sexual
development (Overzier, i963), and it appears that
the incidence may be even higher at birth (see p.
70). The sex chromatin test provides a simple and
often indispensable aid in the diagnosis of such
patients.
Moreover, the technique has made it
possible to screen large populations and thus obtain
estimates regarding the incidence of these abnor-
malities. On a more theoretical level, the origin of
the sex chromatin and its relation to the sex chromo-
somes has given rise to speculations, which are
further stimulating experimental work, as to the
way in which the X chromosome functions, both in
sex determination and in general.
Some Landmarks in the Development of the
Sex Chromatin Concept
The discovery of sex chromatin
is generally
placed in I949, when Barr and Bertram, in London,
Ontario,
described
a
morphological
distinction
between neurones of male and female cats.
The
sex difference consisted of a small body which was
present in the nuclei of nerve cells from female cats
but was absent in those of males (Fig.
i).
The
*Received February 13, I964


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body, which stained with nuclear dyes, was inti-
mately associated with the nucleolus and was at
first called a 'nucleolar satellite'. This term became
inappropriate when
Barr (I95I) found
that in
neuroglial cells of the cat the sex differentiating body
lies against the inner side of the nuclear membrane.
Henceforth, the term 'sex chromatin' was employed.
The finding of the sex chromatin in the cat was an
unexpected result of experimental neurocytology.
Barr and Bertram (1949) wrote: 'It appears not to
be generally known that the sex of a somatic cell as
highly differentiated as a neurone may be detected
with no more elaborate equipment than a compound
microscope following staining of the tissue with the
routine Nissl method'.
Sections of brain, spinal
cord, or sympathetic ganglia could now be readily
attributed to the correct sex of the animal from
which they originated.
A few years before the appearance of the paper by
Barr and Bertram, S. G. Smith (I944, I945a, b), in
Ottawa, Ontario, found that in cells of the larvae
of the spruce budworm, Choristoneura (Archips)
fumiferana (Clem.), a darkly staining body was
present in the nuclei of the female and was absent
from the male (Fig. 2). This body could be used for
sexing larvae prior
to the development of the
gonads, and it was suggested that this method might
be applied to other organisms, including mammals.
These findings are of importance not only because
they provide the first indication that a nuclear body
present in interphase can be used as an indicator of
sex, but also because the spruce budworm is a
member of the Lepidoptera, and in this order the
female is the heterogametic sex. A female spruce
budworm has only one X chromosome, and Smith
postulated that the single X remained condensed
(heteropycnotic) in interphase nuclei, in contrast
to the two X chromosomes of the male, which be-
came invisible. Thus, the situation appears to be
precisely the opposite from that found in mammals.
Sex chromatin in heterogametic females will be


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J. med. Genet. (I964).
i, 88.
Discordance in Monozygotic Twins: One Diabetic, the
Other an Idiot with Neurological Abnormalities*
NEVILLE PARKERt
From the Medical Research Council Psychiatric Genetics Unit, Maudsley Hospital, Londont
While our knowledge of aetiology remains in-
complete, the reporting of examples of discordant
monozygotic twins continues to be of value.
Cases
where the difference has been present from birth
also serve to remind us of a fact, commonly over-
looked, that in exceptional circumstances the intra-
uterine environment may be significantly different
for monozygotic twins.
The few case reports available are of consider-
able interest but often of limited value.
In the
earlier papers zygosity could not be established to
the satisfaction of workers today, and in almost
every study the particular prenatal factor could
not be determined.
The pair to be described, though looking iden-
tical for the first few months of life, were distinctly
different in health, and with time this difference
became more exaggerated.
Now, at I9 years, one
is a bed-ridden idiot with small head and spastic
diplegia, subject to frequent grand mal seizures,
while his twin, a farm labourer of dull normal in-
telligence,
suffers from diabetes.
Neither twin
shows any features of the other's condition.
Case Report
The proband (Twin A) was included in an unselected
series of twins attending the Maudsley Hospital Child-
ren's Department.
He was referred in 1957 for an
opinion as to whether he was epileptic. The twins were
conceived 5 years after the mother's only other preg-
nancy, which resulted in a healthy female child, and
were born in the summer of I944; the mother was then
aged 30 and the father 3I.
The only incident during
the nine-month pregnancy was a fall at 8 weeks which
resulted in a broken finger, but no per vaginam loss.
The mother can recall no minor illnesses while she
was carrying the twins; there were no signs of toxaemia
nor any suggestion of threatened abortion.
The only


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The only
radiological examination was two weeks before the
confinement to confirm the multiple pregnancy, and
she was taking no drugs.
After a labour lasting 8 to io hours Twin A presented
as a vertex and was born without difficulty, weighing
6 lb. 9 oz. (2976 g.).
Ten minutes later Twin B pre-
sented as a breech and was also delivered without any
trouble; he weighed 4 lb. 6 oz. (I984 g.).
The first-
bom was a healthy baby, but the second was 'slightly
shocked' and jaundiced, and was placed in an oxygen
cot; the mother did not see him until IO days later.
The only information available about the afterbirth is
from the midwife's record, which refers to, 'binovular
placenta and membranes complete'.
The twins were both on bottles when they were taken
home from hospital at 3 weeks of age, and their sub-
sequent progress was recorded by the health visitor.
Twin B was a lazy placid baby, and great difficulty was
experienced in getting him to suck; it was realized from
the outset that something was wrong, and after getting
opinions from several doctors the parents took him to
the Hospital for Sick Children, Great Ormond Street,
when he was 14 months old.
The consultant there
considered he was microcephalic, obviously retarded,
and possibly with impaired vision, and recommended
re-examination after a lapse of twelve months.
Before
this time, however, his management had become such
a problem that he was admitted to hospital; he was
then 21 months old. He was diagnosed as a 'microce-
phalic idiot with spastic paralysis of the lower limbs'
and transferred to a colony for mental defectives four
years later; and there he has remained. On admission
to the colony he was a 'helpless incontinent bedridden
microcephalic idiot' who had no awareness of what
was going on around him, and his mental age was
assessed at about 3 months.
The only change in his condition has been in the
character of his frequent epileptic seizures; at first these
were petit mal, but since the age of I5 years tonic and
grand mal seizures have predominated


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Due to his
complete inability to co-operate, he is still fed on a
liquid diet, and is taking phenobarbitone and primi-
done mysoline.
His only illnesses have been mild
attacks of measles at 9 months, chicken-pox at 21 months,
and otitis media at the age of 8 years. At no time have
reducing substances been found in his urine, and a
glucose tolerance test is within normal limits. Examina-
88
* Received August 27, 1963.
t This work was done during the author's tenure of a Nuffield
Dominion Travelling Fellowship.
$ Present address: Depts. of Genetics and Psychiatry, University
of Queensland, Brisbane, Queensland, Australia.


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7. med. Genet. (I964).
I, 107.
Blood Groups in the Philippines*t
G. R. FRASER,+ E. R. GIBLETT, E. STRANSKY, and A. G. MOTULSKY
From the Department of Medicine and Genetics, University of Washington, Seattle; King Country Central Blood Bank,
Seattle, and the Department of Pediatrics, Philippine General Hospital, Manila, Philippines
During I960 blood samples were obtained from
413 adult Philippinos living in Manila but origi-
nating from
all parts of the island (Motulsky,
Stransky, and Fraser,
I964).
The main object
of this study was to determine the incidence of
abnormal haemoglobins and G6PD deficiency but
the opportunity was
also taken to
characterize
the blood and serum group frequencies of this
population.
Blood Groups
ABO System.
Blood groups following ABO
system are set out in Table I.
TABLE I
ABO
Numbers
Frequency
System
0
183
o0454
A
I04
0-258
B
92
0-228
AB
24
o-o6o
403
The gene frequencies were determined by the
method of Race and Sanger (I962): A = OI7;
B = OI5; 0 = o 58.
The value of x' for one degree of freedom, based
on the differences between the observed and ex-
pected numbers of AB, is 0-39, showing an ex-
tremely good fit.
These gene frequencies are in good agreement
with the very large sample of Atienza
(1955):
A = o i68; B = o i6o; 0 = o-672.
* Received February 6, I964.
t This study was supported by U.S. Public Health Service Grants
H 309I and H 5780.
t Present address: Department of Ophthalmology.
Royal College
of Surgeons, Lincoln's Inn Fields, London, W.C.2.
MNSs System.
(Table II).
and anti-s sera were used.
Anti-M, anti-N,
TABLE II
Genotypes
Number
Number
Observed
Expected
MMSS
3
4-3
MMSs, MMss
II9
129-4
MNSS
7
5.2
MNss, MNSs
213
1917
NNSS
I
'-5
NNSs, NNss
60
70-9
The chromosome frequencies were
calculated
according to the methods of Mourant (I954) as:
MS = O0103; Ms = 0473; NS =o-o62; Ns =
0362.
The fit is not very good, reflecting the hetero-
geneous origin of the sample.
The X2 value for
one degree of freedom for the MN frequencies
alone is 5-5 and for the above table, including Ss,


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is 6i for two degrees of freedom (o 05 > p > 0 OI
in both cases).
These frequencies are somewhat
similar to those for Chinese (Miller, Rosenfield,
and Vogel, I95I).
Rhesus System.
Anti-D, anti-C, anti-E, and
anti-c sera were used and tests were done with
anti-Du on all those persons negative with anti-D
(Table III).
Gene frequencies were estimated by a suitable
modification of the methods of Mourant (1954):
R1 + Rul (CDe + CDue) = o08Io; R, (cDE)=
0-092; R2 (CDE) = o-o65; r (cde) = o0033.
These figures agree reasonably well with those
of Simmons and Graydon (1945).
These authors,
however, did not use anti-c and were therefore
unable to identify the R, chromosome.
The frequency of Ru1 or CDue may be estimated
as i/i8 of the frequency of R, + Ru1 (= 0o045),
since one case with the genotype CDue/cde and 17
with CDe/cde were found.
This would give a
frequency of R, of o0765.
I07


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Review Article
J. med. Genet. (I964).
I, II8.
Profound Childhood Deafness*
G. R. FRASER
From the Godfrey Robinson Memorial Unit, Department of Ophthalmology, Royal College of Surgeons, London W.C.2
'It will be a great step forward whn the physician takes part in the work for defec-
tives who have hitherto been entrusted wholly to teachers in schools.... The prob-
lems of deafness are deeper and more complex, if not more important, than those of
blindness. Deafness is a much worse misfortune.
For it means loss of the most vital
stimulus-the sound of the voice-that brings language, sets thought astir and keeps
us in the intellectual company of man.'
From The Deaf Child,
by J. Kerr Love, Simpkin and Co., London, I9Ii.
Definition and Introduction
The term profound childhood deafness is used
in preference to the old-established one of deaf-
mutism, since it is now clear that, contrary to the
accepted dogma current from antiquity to recent
times, mutism is not due to a pathological lesion
of the speech apparatus associated with failure to
hear, but to a lack of suitable training which can
often be remedied.
Profound childhood deafness
is a socio-educational entity and may be defined as
deafness with an early enough onset and of suffi-
cient degree to necessitate the use of special or
supplementary methods for the learning of speech.
This definition excludes the very common deaf-
ness of adult life often inherited in a dominant
manner, whether conductive (otosclerosis) or per-
ceptive.
Many rare genetical syndromes are also
excluded of which deafness of a less severe nature
and/or of late onset is a component part.
These
include such recessive syndromes as perceptive
deafness,
atypical
retinitis
pigmentosa,
chronic
polyneuritis and ataxia (Refsum, Salomonsen, and
Skatvedt,
1949),
and
perceptive
deafness
with
optic atrophy and diabetes (Shaw and Duncan,
I958), with diabetes mellitus, retinal degeneration,
and
obesity
(Alstrom,
Hallgren,
Nilsson,
and
Asander,
I959) with congenital
facial paralysis
(Thomas,
1898;


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1898;
Cadwalader,
I922), and many
others; in addition, the dominant syndromes of
perceptive deafness with nephritis (Alport, 1927),
with auditory neurofibromata (Gardner and Frazier,
I930), and with ectodermal dysplasia (Helweg-
* Received July 20, x964.
Larsen and Ludvigsen, I946; Robinson, Miller,
and Bensimon, I962) and others, and of conductive
deafness with osteogenesis imperfecta (van der
Hoeve and de Kleijn, I9I7).
Occasionally pro-
found childhood deafness will occur in association
with one of these conditions; conversely, persons
will occasionally suffer from only mild losses of
hearing in association with syndromes more usually
associated with profound childhood deafness. No
biological classification can be expected to follow
very closely lines of demarcation defined on the
basis of socio-educational criteria.
There is even
no absolute correlation between educational seg-
regation and degree of hearing loss.
Thus severe
hearing loss in infancy is sometimes compatible
with normal education, and special schooling may
occasionally be necessary with a relatively mild
deafness.
Other,
as yet ill-understood, factors
may condition the extent of the child's adaptation
to the hearing loss.
Many other difficulties stand in the way of an
unambiguous biological classification of profound
childhood deafness.
Thus an unequivocal dif-
ferentiation between congenital and postnatal onset
is often impossible, since the diagnosis of deafness
may only be made when speech fails to develop
normally in the first two years of life or even later.
Furthermore,
congenital and postnatal
deafness
cannot be equated simply with genetical and ac-
quired forms.
Congenital deafness may be due to
maternal rubella, and, owing to diagnostic diffi-
culties in infancy, evidence is lacking as to whether
genetical
childhood
deafness
is
in
fact usually
congenital
or
rapidly progressive
in
early
life.
II8


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J. med. Genet. (I965).
2, 2I.
Blood and Serum Groups in Taiwan*
G. R. FRASERt, E. R. GIBLETT, TING-CHIEN LEE, and A. G. MOTULSKY
From the Departments of Medicine and Genetics, University of Washington, the King County Central Blood Bank,
Seattle, Washington, and the Department of Pediatrics, National Taiwan College of Medicine, Taipeh, Taiwan
During I960 blood samples were collected in
Taiwan from 300 male adolescents and adults in
the capital town of Taipeh and in the small com-
munities of Chi-Chi (centre of Island) and Chung-
Li (N.W.)
(Motulsky, Lee, and
Fraser,
I964).
The donors from Taipeh originated in all parts
of Taiwan.
The main object of the study was to
investigate the distribution of abnormal haemo-
globins and G6PD deficiency but the opportunity
was also taken of characterizing blood and serum
groups of this population.
An attempt was made
to restrict this study to the main group of Formosan
Chinese who had imnigrated from Fukien pro-
vince on the mainland in the I7th century.
Blood Groups
The blood groups are set out in Table I.
TABLE I
ABO
Taipeh
Chi-Chi
Chung-Li
Total
0
46
6i
44
15I
A
28
20
31
79
B
I9
I5
i6
50
AB
5
4
II
20
98
100
102
300
The gene frequencies (Table II) were calculated
by the method described by Race and
Sanger
(I962) and a X2 value for one degree of freedom
was derived, based on the difference between the
observed and expected numbers of AB individuals.
TABLE II
GENE FREQUENCIES
Taipeh
o-I8
O-I3
o-69
0-03
Chi-Chi
0091
O079
I-*Is
Chung-Li
0-21
O-II
o-68
4.45
A G test was performed to test heterogeneity
between the samples by the method of Woolf
(I957). A value of 8-42 was obtained which is not
significant at the 5 % level if we assume that this
value follows the distribution of X2 on four degrees
of freedom.
It is legitimate, therefore, to pool the sample and
calculate gene frequencies for the whole group.
The same method was employed and gave the
following gene frequencies: A = o1I7; B = o-II;
0 = 072 (x2 = 5.37).
These figures do not agree very well with pub-


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lished data for Formosa (Mourant, Koped, and
Domaniewska-Sobczak
I958)
in
that
the
fre-
quency of B in most previous samples has been
higher.
MNSs Groups.
Anti-M, anti-N, and anti-s
sera were used, but there were no negative re-
actors with the last.
Only the frequencies of the
alleles M and N can, therefore, be considered
(Table III).
TABLE III
Taipeh
Chi-Chi
Chung-Li
Total
MM
25
32
32
89
MN
5I
52
52
155
NN
22
I5
I8
55
The gene frequencies are given in Table IV.
TABLE IV
GENE FREQUENCIES
M
04585
3o-587
0-569
04557
N
0-48:5
0 413
0-431
O 443
Xi
0-17
o-67
O-I6
1I84
The G test for heterogeneity was again per-
formed and gave a value of X% of 2 I6. The values
were, therefore, combined for a pooled estimate
of M and N frequencies.
21
Received February 6, I964.
v This study was supported by U.S. Public Health Service Grants
H 309I and H 5780.
t Present address: Department of Ophthalnology, Royal College of
Surgeons, Lincoln's Inn Fields, London W.C.2.


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J. med. Genet. (I965).
2, 93.
Congenital Hereditary Lymphoedema*
JOHN R. ESTERLY
From Division of Medical Genetics, Department of Medicine and Department of Pathology, Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.
Occasionally
primary
lymphoedema
is
both
congenital and familial. The first reports by Nonne
(I89I) and Milroy (I892) were of families in which
the oedema was present at birth and was described
as non-tender chronic swelling of the lower ex-
tremities, not influencing the general health of the
subjects or their longevity.
This is distinguished
from the familial form of lymphoedema praecox
(Letessier, I865; Meige, I898, I899) characterized
by an abrupt onset, most often at puberty, and
frequently associated with signs and symptoms of
acute inflammation. The congenital form of familial
lymphoedema is usually called Milroy's disease and
the form with later onset, Meige's disease.
The oedema of the affected individuals in the
family described in this report is typical of the
condition described by Milroy and is of genetic
interest for several reasons, including the presence
of an apparent
'skipped'
generation.
Linkage
studies were practical in view of the size of the
kindred and the number of affected persons.
Received January 4, I965.
* This study was supported in part by U.S.P.H. Research Grant
No. H-3313
Family History
There were i5 affected individuals in three generations
of this family including, by history, a stillbirth.
In
addition, the family tree for three preceding generations
was known with a total of 245 members (Fig. i). There
was no history of consanguinity nor any suspicion of
affected persons outside the progeny of I.2 (Fig. 2).
There was no evidence of concomitant lymphoedema
praecox.
The proposita (II.5) was a 35-year-old white woman
of excellent general health and strength, with bilateral
swelling of the legs and feet, which had been present
since birth.
There was no history of any pain or in-
flammation
associated
with
the oedema, though
it


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it
progressed in severity during the first decade of life.
On several occasions significant but incomplete reduc-
tion in the swelling had accompanied prolonged bed-
rest.
The physical examination was within normal
limits save for the gross enlargement of her lower
extremities.
The massive oedema extended above the
knees and pitted with ease (Fig. 3). The overlying skin
had no trophic changes and was impressively warm to
touch.
There was a constant tachycardia (90-iOO a
minute).
Radiographs and laboratory tests were not
remarkable;
in particular, serum proteins and renal
function were normal.
The mother of the proposita, the probable mutant
*
AFFECTED
O
NORMAL
o
STILLBIRTHS
ot PROPOSITA
FIG. I. Pedigree chart.
93
-MG1


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J. med. Genet. (I965).
2, I22.
Smallpox Vaccination: ABO and Rhesus Blood Groups
GEOFFREY J. BOURKE, NOEL CLARKE,* and EDWARD H. THORNTONt
From the Departments of Social Medicine, Pathology, and Statistics, Trinity College, Dublin, Eire
The hypothesis has been advanced (Pettenkofer
and Bickerich, I96o) that vaccinia virus and, by
implication, variola virus contain antigenic proper-
ties similar to human blood group A substance.
Vogel, Pettenkofer, and Helmbold (I960) assert
that possession by
variola
virus of a material
serologically resembling human blood group A
substance may have been responsible, in
part,
for determining the present-day global distribution
of the human ABO blood groups.
Pettenkofer,
Stoss, Helmbold, and Vogel (I962) claim that,
in smallpox infection, persons with blood groups
B or 0, in whom anti-A normally occurs, have an
immunological advantage over persons of blood
groups A and, presumably, AB who lack this
antibody.
In support of their work these authors
report that of I03 Germans with severe post-
vaccination reactions (more than go % encephalitis)
a
significantly
higher
proportion
belonged
to
blood groups A and AB; moreover, in India and
Pakistan, among 358 subjects with severe smallpox
scars a similar excess of blood groups A and AB
was demonstrated.
If the above hypothesis is correct, and recent
experimental work (Harris, Harrison, and Rondle,
I963) suggests that it is not, one would expect,
among a group of individuals vaccinated against
smallpox that: (i) persons of blood groups B or 0,
who
possess anti-A substance, would be more
likely to
resist the procedure, and present an
unsuccessful vaccination, than groups A or AB;
(ii) persons of blood groups A or AB, who do not
possess anti-A in their serum, would have a more
severe clinical response, and might be expected to
produce a larger lesion following successful vac-
cination, and to have a greater
scar area from
previous vaccination than persons of blood groups
B or 0.
The present study is concerned with the distri-


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bution of the ABO and Rhesus blood groups
among a number of university students vaccinated
against smallpox.
The materials and methods,
reading of results, and observations on clinical
reaction have already been outlined (Bourke and
Clarke, I963, 1964).
Results
The results relate tO 78I persons of the 994
included in the original study, on whom ABO
and
Rhesus
blood
group
determinations
were
made by a tube technique.
These 78I subjects
have been found to be fully representative of the
original group, for all pertinent data.
Of these
78I
subjects,
6I2
had
successful
vaccinations
(Tables I and III), and of these 6I2, 565 completed
questionnaires
relating to
their symptomatology
and to the severity of clinical reaction (Tables IV
and V).
It will be seen from Table I that there is no
significant
difference between any of the ABO
and Rhesus blood groups in the proportion falling
into the successful and unsuccessful categories.
Moreover, when groups A and AB are combined
and compared with groups B and 0 taken together,
the
x2
value
is
reduced
(X2 = o038o,
n = I)
o7o > p > o.50).
Since the outcome of vaccina-
tion may be affected by country of origin and the
time since the previous vaccination, it was necessary
to standardize for these factors; such corrections
were found not to alter the original, negative,
conclusion.
Table II shows that the scar area varies little
between the ABO groups, and that there are no
significant
differences
between
the
mean
scar
area of the Rhesus positive and negative groups.
Similarly, in Table III the mean lesion size shows
little change from one blood group to another.
Corrections for period since last vaccination for
both scar area and lesion size do not alter the
findings.
Table IV demonstrates that in three instances
statistically significant associations between blood
I22
Received July 30, 1964.
* Present address: Department of Pathology, University College,
Dublin.
t Present address: Middle East Technical University, Ankara.


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J. med. Genet. (I965).
2, 227.
Family Studies and Aetiology of Club Foot
RUTH WYNNE-DAVIES
From the Medical Research Council, Research Group on Genetic Problems in Orthopaedic Disease, Department of
Orthopaedic Surgery, University of Edinburgh
Congenital club foot and talipes are used to
describe various abnormalities of the foot in the
newborn child.
The most serious of these
is
talipes
equinovarus
in
which
there
is
plantar
flexion of the ankle and inversion of the foot.
This deformity is difficult to treat, having a marked
tendency to recur, and causes a real disability.
About
half
the
cases
are
bilaterally
affected.
Patients frequently attend hospital for the
first
Io-i5 years of life. A long-term follow up of the
results of treatment of patients with talipes equino-
varus
has
been
reported
elsewhere
(Wynne-
Davies, I964a).
The family findings in a series of
patients with talipes equinovarus, mild (postural)
talipes equinovarus, talipes
calcaneo-valgus, and
metatarsus varus have been reported in summary
form (Wynne-Davies, I964b).
In this paper the
family data, especially that on talipes equinovarus,
are presented and discussed in more detail.
Cases
secondary
to
spina
bifida,
cerebral
palsy,
and
arthrogryposis are not included.
Subjects and Method
The present study is based on patients attending
the Princess Elizabeth Orthopaedic Hospital, Exeter,
who were born in I940-6I.
This Orthopaedic Hospital serves the greater part
of the largely rural county of Devon (excluding the
Plymouth area), and there is available a stable popula-
tion, making the tracing of families
relatively easy.
The orthopaedic service is based on the hospital at
Exeter, and out-patient
clinics are held at intervals
of one, two, or four weeks throughout the county-at
Exeter, Torquay, Newton Abbot, Okehampton, Barn-
staple,
Bideford,
Honiton, and
Tiverton.
Patients
attending currently for treatment during I96I were
seen at one of their routine visits to a clinic.
Former
patients were first approached by letter and were then


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seen at the outlying clinic which they had previously
attended. A family history was taken from the individual,
or where more appropriate, a parent, and nearly all
affected relatives were personally examined.
(Details
of families with an affected first-degree
relative are
Received February 22, I965.
given in Appendix A.) In the only two instances where
an affected first-degree relative was not seen personally,
there was reliable medical evidence of the deformity
(Index patients 30 and io8).
Relatives stated to be
normal were not specially examined, though in fact
many were seen, as they attended with the patient.
In the case of talipes equinovarus, with the standard
of school and other medical services easily available
in this country, it is most unlikely that such a severe
deformity would pass unnoticed or ignored, and the
ascertainment of affected relatives will be nearly com-
plete. In the case of postural talipes equinovarus, talipes
calcaneo-valgus, and metatarsus varus, relatives were
not examined since these deformities almost invariably
disappear and retrospective diagnosis is not possible.
Only those cases confirmed by medical evidence have
been classed as affected, but obviously many
cases
never reach hospital, and the ascertainment of affected
relatives will be incomplete.
For talipes equinovarus, I63 case sheets were available
for patients born from I940 to I96I.
Of these, I44
were traced of whom I33 were seen personally and
ii replied to questionnaires.
Of the remaining
I9,
13 were not traced, 2 were foster children, and 4 refused
to co-operate.
Index patients with the three other
common forms of talipes were those born between
I948 and I96I; 31 patients were traced with postural
equinovarus, 74 with talipes calcaneo-valgus, and 72
with metatarsus varus.
Results
Incidence.
Since
the
Princess
Elizabeth
Orthopaedic
Hospital
is
the
only
orthopaedic
hospital in the area and both private and National
Health
Service
patients
have
been
included,
ascertainment of cases needing hospital treatment


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will be nearly complete.
Comparing the numbers
of patients with the Registrar General's figures
for all live births in the area over the same period,
the incidences of the different forms of the mal-
formation
were:
talipes
equinovarus-i -24
per
iooo live births (males
i 62 per IooO, females
o-8o);
postural
talipes
equinovarus-o 5o
per
IooO live births (males 0-24 per Ioo, females
o-78); talipes calcaneo-valgus
-o9 per IooO live
births (males o-o7 per IooO, females o-33); meta-
227


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J. med. Genet. (I965).
2, 233.
Epidermolysis Bullosa
B. C. CLARE DAVISON
From Medical Research Council, Population Genetics Research Unit, Old Road, Headington, Oxford
The term epidermolysis bullosa is applied to
a group of conditions where vesicles occur most
commonly on the skin but sometimes on mucous
membranes.
The
content of these vesicles
is
serous but may become turbid or haemorrhagic,
and secondary infection sometimes occurs.
Apart
from a type that may follow administration of
sulphonamides (Bloom, I953),
all forms appear
to be genetically determined at single gene loci.
Further,
all cases appear to be determined by
autosomal mutations, with the exception of the
patients in one family where epidermolysis bullosa
appears as part of a widespread syndrome deter-
mined by a sex-linked gene.
This family first
described by Mendes da Costa and Van der Valk
(I908) has subsequently been reported by various
authors over a number of years under varying
titles: perhaps the most generally used
at the
present
time
being
dystrophia
bullosa,
typus
maculatus (Woerdeman, I958).
Determination
by
autosomal
dominant
and
recessive genes has long been known and, as is
usual in other traits where this phenomenon is
found, the recessive forms are on the whole more
severe in their effects.
However, in epidermolysis
bullosa there appears to be considerable overlapping
in severity of forms determined in the two ways.
The most distinctive clinical finding is whether
or not
scarring follows
the
healing of lesions
(Pearson,
I962;
Schnyder, Jung, and
Salamon,
I964).
This division corresponds to 'dystrophic'
and 'simplex' (non-dystrophic) forms.
It has been
demonstrated by Johnson and Test (1946) that in
the simplex type the blisters form in the epidermis
or are subcorneal, while Touraine (I942) showed
that in the dystrophic form the blister formation
was subepidermal.
Parent Investigation
Ascertainment of Cases in the Oxford Area.
In I962 all general practitioners in the Oxford
Received February IO, I965.
-MG2
Regional
Hospital
Board


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Board
area
were
asked
to
notify cases of epidermolysis bullosa.
First noti-
fication of I2 cases was from this source.
In
addition the six consultant dermatologists in the
area notified all cases seen by them and subse-
quently they reported new cases as seen. Twenty-
two index patients first became known through
dermatologists.
Four individuals could not be traced and in
two notified patients the diagnosis was not con-
firmed, so that in all 28 families were ascertained
through index cases.
It was realized that ascertain-
ment was incomplete and it was decided not to
make more determined
efforts
as
it was
soon
obvious that all severely affected cases were known
to dermatologists while many subjects with milder
types
simply regarded
themselves
as prone
to
blistering and never attended a doctor.
In the
following
discussions
of
clinical
aspects,
an
additional
family
seen
in Northern
Ireland
is
considered, so that in all 29 families were seen.
In all these families at least one member had
been seen by a dermatologist.
In i0, only one
member was affected. In the I9 families with more
than one affected the pedigree suggested dominant
gene inheritance in 17 and recessive gene inheritance
in two.
Clinico-genetic
Grouping of Cases.
The
most clear-cut division of cases where more than
one case occurred is on the basis of mode of inherit-
ance.
As
already
noted,
the
primary
clinical
separation is on the basis of severity-scarring or
dystrophic and non-scarring or simplex.
It seems
likely that the recessive form is always dystrophic,
never simplex, and that the dominant form is more
commonly
milder
or
simpJex.
The
dominant
simplex form appears to have two variants, one
where only the feet are affected (Cockayne, 1938),
and one where the blisters are widespread though
most commonly occurring on the extremities. The
family cases therefore
fall into three (or four)
groups-dominant simplex (dominant Cockayne),
dominant
dystrophic,
and
recessive
dystrophic.
-33


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J. med. Genet. (I966).
3, IO.
ABO and Rhesus Blood Group Distribution among
Patients Attending Venereal Diseases Clinics
C. B. S. SCHOFIELD
From the Department of Venereology, clo Ruchill Hospital, Glasgow
In one of the earliest papers on blood groups in
-disease
Alexander
(192I),
while
investigating
malignancy in Dundee, used as controls 50 cases of
'active syphilis', together with a like number of
normal subjects and of patients with tuberculosis.
He did not find any significant differences, and
the frequencies of the 'active syphilis' group and
the normals were almost
identical.
Apart from
Poehlmann (I934), who investigated 300 patients
with positive Wassermann reactions and found them
to have the same ABO blood group distribution as
among the general Munich population, there would
not appear to be any published investigations into
the
distribution
of
blood
groups
in
venereal
diseases, and this investigation was planned to find
out if there were any differences in the commoner
conditions for which patients attend a venereal
diseases clinic.
Present Investigation
Information as to the ABO and Rhesus blood groups
of patients
attending
the
clinics
at Newcastle and
Tynemouth between July I956
and
October
1958,
together
with
clinical manifestations and
sex, were
recorded on punch-cards for later analysis.
Controls for the ABO blood groups for the Newcastle
upon Tyne Hospital Region already
exist.
Roberts
(I953), using material supplied by the Regional Blood
Transfusion Service, analysed a total of 54,579 record
,cards of blood donors for ABO groups. The frequencies
he found are as follows: 0, 49-484%; A, 38-627%; B,
9-I26%; AB, 2-763%, and these figures have been used
in
this
investigation,
but unfortunately there
is no
similar control for the Rhesus (D) distribution in this
area.
Results
2,575 sera were tested, I,63I (63%) from men
Received September 29, I965.
and 944 (37%) from women. Approximately 55%
of the patients were suffering from syphilis, I4-5%
from
gonorrhoea,
I3-5%
from
non-gonococcal


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urethritis, while the remainder (about I7%) were
without evidence of venereal disease (NVD). The
frequency distributions of the blood groups and
their incidence relative to one another for these
main classifications are set out in Table I.
Although there are some differences in blood
group distribution, these differences are without
statistical significance.
The vast majority of all
female patients and those men with syphilis were
native to Tyneside, while a number of men with
gonorrhoea
and
non-gonococcal
urethritis
were
peripatetic.
In view of the possibility that the syphilis group
was not homogeneous, it was broken down into the
anatomical diagnoses.
There was no significant difference in the ABO
distribution among patients with contagious syphi-
lis, neuro-syphilis, or benign tertiary syphilis, or of
any of the clinical entities within these groups, but
when patients with cardiovascular
syphilis were
divided arbitrarily into those with aortic valvular
damage (aortic incompetence) and those without
(aortitis and aneurysms of the aorta), as shown in
Table II, it was found that the excess of male
patients with blood group A and suffering from
aortitis and/or aneurysms of the aorta had significant
statistical difference when compared with (a) the
controls, (b) with women having the same com-
plaint, and (c) with men and women suffering from
aortic incompetence.
While there was a wide range in the incidence of
Rhesus positives, the differences were not significant
in any entity.
Discussion
The ABO frequencies of men and women, though
not parallel, do not differ significantly from the
IOI


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J. med. Genet. (I966).
3, 203.
The Use of the Surname as a Genetic Marker in Wales
DAVID J. B. ASHLEY and H. DUNCAN DAVIES
From Morriston Hospital, Swansea
To some extent the population of the Principality
of Wales, especially the industrial areas of South
East
Wales,
is
heterogeneous,
comprising
the
Welsh, descended from the long-standing inhabi-
tants of this part of the world and the immigrants
who have arrived mostly within the past hundred
or so years. The two populations live in the same
physical environment and, in the industrial social
milieu, tend to work side by side in the factories and
mills, though it is possible that the traditional craft
of coal-mining claims a higher proportion of Welsh-
men than do some of the newer industries.
It would be interesting and useful if these two
populations could be identified by some easy marker
so that the proportions of Welsh and non-Welsh
could be assessed in relation to their illnesses,
immunities, and other possibly genetically deter-
mined traits.
The typical Welshman tends to be
short in stature, long-headed, black-haired, and
pale-faced, and many of us can readily call to mind
such an individual. Unfortunately, however, many
men
of English
descent
have
similar
physical
characteristics and many Welshmen are burly of
figure and ruddy of complexion.
Physical assess-
ment is a notoriously unreliable method of assigning
individual people into broad categories if a large
block of 'middlemen' is not to be avoided, and it is
extremely difficult, vide the problems of the colour
bar,
to define exact parameters which may be
applied in such a context.
The second character
of the Welshman,
not commonly
acquired by
immigrants, is the use of the Welsh language.
It
may fairly be suggested that one who speaks Welsh
is a Welshman, the occasional exception serving
only to underline the general truth of the assertion.
In the present series only 9 of 231 people born
outside Wales were Welsh speaking. Command of
the Welsh language is, however, rarely recorded as
a


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a
descriptive item in hospital
case notes, with
which
we
are
principally
concerned,
and
the
character becomes useless for retrospective investi-
gation and hardly more
useful
for
prospective
Received September 14, I965.
investigations involving more than a small number
of people.
In very large-scale inquiries involving
the whole of the country, the proportion of Welsh-
speaking people in different areas may prove useful
where whole counties can be taken as the units of
investigation.
For
example,
in
the
County
of
Carmarthen more than 70% of the men over the
age of 45 claim to be Welsh-speaking, whereas in
the County of Brecknock 36% do so and in Mon-
mouth only 5.5% speak this tongue.
The final, easily determined, character, and the
one on which this investigation is based, is the
surname. The surname can, in males, be regarded
as a character inherited in the holandric manner.
A man hands on his surname to his sons, as he does
his Y chromosome, and they in turn pass it on to
their sons. The number of surnames in use among
Welshmen is small, and each is characteristically
derived from a Christian name: Davies, Evans,
Thomas, Williams, Owens, Roberts, and Phillips,
by the simple use of the genitive case, and others,
Price, Pritchard, Pugh, and Parry, for example, by
elision of the Welsh prefix Ap 'the son of'.
In
contrast English surnames most often derive from
place names, as does Ashley; from occupations,
Smith, Weaver, Miller; or from nicknames, Arm-
strong, White, Black, and Small. The characteristic
Welsh surnames have been used (Legon, i963) in
an observation on the frequency of gastric carcinoma
in the Welsh and non-Welsh inhabitants of North
Wales. The present investigation is an attempt to
validate the use of this parameter as a marker by
which the two components of a heterogeneous
population may to some extent be separated.
Methods and Procedures
A questionnaire was circulated among a miscellaneous
group of the male inhabitants of Swansea and the
surrounding districts. Each man was asked to give his


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name, address, and age, his mother's maiden name, the
place of birth of himself and his two parents, and
whether or not he and his parents were Welsh-speaking.
In all 558 completed forms were analysed.
In most
cases all the information requested was available; in a
203


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J. med. Genet. (I966).
3, 2I7.
A Pair ofTwins, One ofwhom has Chronic Granulocytic
Leukaemia
LESLEY DOUGAN*, IAN D. SCOTT, and H. J. WOODLIFF
From the Cancer Council of Western Australia, the Department of Genetics, University of Western Australia, and the
Department of Haematology, Royal Perth Hospital, Western Australia
The finding that one of our patients with chronic
granulocytic leukaemia had an apparently identical
twin brother led us to undertake genetic studies to
establish
zygosity, and
to study
carefully
their
history
for any
possible leukaemogenic
factors.
Bone-marrow cells of the affected twin contained
the Ph' chromosome whereas those of his brother
did not (Woodliff and Dougan, I965).
Material and Methods
Blood was collected from the twins, one sib, and their
parents by venepuncture (Fig.).
Blood groups were determined by standard methods at
the Human
Genetics
Unit,
University
of Wesstern
Australia.
The
antisera used were
anti-A, en l-A,
anti-B, anti-AB, anti-C, anti-c, anti-D, ar,.;-E. anti-e,
anti-Cw, aniti-Ew, anti-ET, anti-V, anti-M,anti-N., anti-S,
anti-s,
anti-Mia, anti-Vw, anti-Mg, anti-PL, anti-K,
anti-k, anti-Kpb, anti-Kpa, anti-Lea, anti-Leb, anti_Fyb,
anti-Lub, anti-Xga, anti-Vel, anti-Wra., anti-Dia, anti-jsa,
anti-Jka, anti-Jkb, and anti-Fya. The Gm and Inv types
were done by courtesy of Dr. Arthur G. Steinberg.
Transferrin and haptoglobin types were determined by
vertical starch gel electrophoresis by the method of
Smithies (I959). Serum alkaline phosphatase types were
examined by a modification of the method of Arfors,
Beckman, and Lundin (I963), as previously described
(I. D.
Scott and M. K.
Scott,
I966, unpublished
observations).
The parents, the twins, and the younger sister were
carefully interviewed concerning their family history,
and a standard questionnaire was completed for the
twins.
Results
Genetic Study.
The detailed findings of the
blood group-Ing investigation and the examination
of the serum genetic markers are given in Table I.


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In addition, all subjects were found to be Cw(-),
EW(_), V(-)., Mg(-)I VW(-)3 Vel(-)., Di(a-),
Wr(a-), and Js(a-).
Results of the Gm typing
showed that I.2 was homozygous for the factors
Received April I8, I966.
Gm3'
D13
1, and that the subjects I.I, II.3, II.4, and
II.5 were heterozygous Gm'/Gm 3 5,13,14
All sub-
jects were of the Inv phenotype Inv(i -).
The
nomenclature is that proposed by a committee of
W.H.O. (I965).
From the results of the Gm typing and the
findings set out in Table I, the probability that this
pair of twins was monozygotic was calculated as
suggested by Dr.
C. W. Cotterman (Race and
Sanger, I962), and is as shown in Table II.
It was calculated that the probability that the
twins were monozygotic was 0o995.
Personal and Family Histories
The twins E.F. and F.F. were bom at King Edward
Memorial
Hospital
for Women,
Subiaco,
Western
Australia, on March 30, 1928; the parents were Roman
Catholics who had recently migrated to Australia from
Italy.
This was the mother's third pregnancy and it
continued to term.
She had no recollection of any
antenatal X-ray examinations.
F. was bom first as a
vertex presentation and E. within the next few minutes
by the breech.
Their early development was quite
normal and the first IO years were spent in an inner
suburb of metropolitan Perth. In I938, when the twins
I
b.lU
1
2
b. 1921
b.l1922
d. 1922
2
1901
b. 1901
3
4
b.1928
b.1928
5
b.1931
0
male studied
/$ifemcle studied
male with Ph+ chronic
female not studied
G
granulocytic leukoemia
e
FiG. Pedigree chart.
217


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Review Article
Journal of Medical Genetics (1973).
10, 50.
Fetal and Embryonic Haemoglobins
P. A. LORKIN
MRC Abnormal Haemoglobin Unit, University Department of Biochemistry, Cambridge
Haemoglobin has been the subject of intensive
research for many years and is one of the most
thoroughly understood of all protein molecules.
The amino-acid sequences of haemoglobins from
many species of animals have been determined
(tabulated by Dayhoff, 1969) and the molecular
structures of horse and human haemoglobins have
been determined in great detail by x-ray crystallo-
graphy (Perutz et al, 1968a and b; Perutz 1969).
A
mechanism of action of haemoglobin has been pro-
posed
(Perutz,
1970a and
b and
1972).
The
haemoglobins of higher organisms share a common
tetrameric structure built up of two pairs of unlike
chains; the a chains containing
141 amino-acid
residues and the non-a chains containing generally
145 or 146 amino acids.
In man, five types of
non-a chains have been recognized, /3, y, 8, E. and 4,
corresponding to different stages of ontogenesis.
The globin chains of haemoglobin and ofmyoglobin
have a similar overall tertiary structure composed of
segments of a helix interspersed with non-helical
regions forming a compact structure of great com-
plexity.
Amino-acid residues whose side chains
are of a polar nature, ie, those which bear an electric
charge or a strong dipole movement are located at
the outer surface of the molecule in contact with the
aqueous
surroundings,
whereas
the
non-polar
hydrocarbon side chains are, in general, located
within the interior of the molecule.
The haem
groups are accommodated within deep cavities or
pockets lined with non-polar side chains and are
anchored in position by links between the haem iron
and the imidazole side chains of histidines.
The
non-aqueous environment of the haem promotes
reversible binding of oxygen and protects the iron
from oxidation to the ferric form characteristic of
methaemoglobin which is incapable of reversible
oxygen binding.


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The four chains of the tetramer fit together to
Received 27 November 1972.
form a nearly spherical molecule with extensive
areas of contact between unlike chains; the two
main types of contact are denoted alp, and alg2
The
tetramer
exhibits
cooperative
behaviour
or
haem-haem interaction.
As each haem combines
with oxygen the affinity of successive haems in-
creases.
The oxygen affinity curve of the tetramer
is sigmoidal and may be represented approximately
by the Hill equation:*
=
kpo2n
y +kpo2n
Oxygen affinity data are usually presented
in
terms of P102, the partial pressure of oxygen re-
quired to attain half saturation with oxygen, and of
n, the exponent of the Hill equation.
These para-
meters respectively give measures of the oxygen
affinity and of the degree of haem-haem interaction.
For normal haemoglobin n
is approximately
3.
Myoglobin, isolated chains, and tetramers composed
of one type of chain such as Hb H (4) show no
haem-haem interaction, their oxygen dissociation
curves are hyperbolic and the n value is 1.
The haemoglobin tetramer has a lower oxygen
affinity, more appropriate of its physiological func-
tion, than single chains.
The cooperative behaviour
of the tetramer renders it more efficient in releasing
oxygen in response to relatively small changes in
oxygen
tension.
The
tetramer
exhibits
other
physiologically advantageous properties; the oxygen
affinity varies withpH (Bohr effect) in such a manner
as to facilitate the release of oxygen in the tissues.
Haemoglobin binds CO2 at the N terminus of the
/
chains (Kilmartin and Rossi-Bernardi, 1969) and
assists its transport from the tissues to the lungs.
Furthermore
its
oxygen
affinity
is
reduced
in
the presence of organic phosphates
particularly
2,3
diphosphoglycerate
(2,3 DPG) and
inositol
* Hill equation: y =fraction of haemoglobin in oxy form, P02
partial pressure of oxygen, k and n are constants.
50


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CD30 co-stimulation drives differentiation of Mycobacterium tuberculosis protective T cells during infection


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ARTICLE
CD30 co-stimulation drives differentiation of
protective T cells during Mycobacterium tuberculosis
infection
Taylor W. Foreman1, Christine E. Nelson1, Michelle A. Sallin1, Keith D. Kauffman1, Shunsuke Sakai1, Francisco Otaizo-Carrasquero2,
Timothy G. Myers2, and Daniel L. Barber1
Control of Mycobacterium tuberculosis (Mtb) infection requires generation of T cells that migrate to granulomas, complex
immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in
pulmonary granulomas, bronchoalveolar lavage, and blood of Mtb-infected rhesus macaques to identify granuloma-enriched
T cell genes. TNFRSF8/CD30 was among the top genes upregulated in both CD4 and CD8 T cells from granulomas. In mice,
CD30 expression on CD4 T cells is required for survival of Mtb infection, and there is no major role for CD30 in protection by
other cell types. Transcriptomic comparison of WT and CD30−/− CD4 T cells from the lungs of Mtb-infected mixed bone
marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and the expression of multiple effector
molecules. These results demonstrate that the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is
critical for protective T cell responses against Mtb infection.
Introduction
Mycobacterium tuberculosis (Mtb) is a leading cause of global
mortality due to infectious disease. The current vaccine for
Mtb infection, Bacillus Calmette-Gu´erin (BCG), is adminis-
tered neonatally and provides protection against severe
forms of tuberculosis (TB) in children, but it does not pro-
vide sufficient protection in adolescents and adults to dras-
tically reduce the global burden TB. Over the past few years,
clinical vaccine trials using BCG re-vaccination or an ad-
juvanted fusion protein have demonstrated ∼40–50% pro-
tection (Nemes et al., 2018; Van Der Meeren et al., 2018), and
several vaccine studies in non-human primates (NHPs) have


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afforded extraordinary levels of protection, showing that a
highly effective vaccination for TB is achievable (Darrah
et al., 2020; Dijkman et al., 2019; Hansen et al., 2018;
Kaushal et al., 2015; Sharpe et al., 2016; White et al., 2015). A
better understanding of the mechanisms of host protection
against Mtb infection would improve our ability to develop
novel vaccination as well as host-directed therapeutic
strategies for TB.
Control of Mtb infection requires the generation of T cells
that can traffic to pulmonary granulomas, but little is known
about the basic biology of granuloma T cells (i.e., the mecha-
nisms regulating the generation, differentiation, homing, and
effector functions of protective granuloma T cells). CD4 T cell
responses to mycobacterial infections in humans, NHPs, and
mice are primarily comprised of IFNγ-producing effector cells.
However, there are differences in the quality of CD4 T cell dif-
ferentiation observed in response to mycobacterial infection in
C57Bl/6 mice compared to macaques and humans. In mice, Mtb-
specific CD4 T cells develop into highly polarized Th1 cells, with
some cells even differentiating into terminally differentiated
Th1 effector cells. In contrast, these terminally differentiated
cells are not observed in NHPs or humans (Kauffman et al.,
2018b). Instead, in primate hosts, Mtb-specific T cells mostly
differentiate into atypical IFNγ-producing cells referred to as
Th1* cells that are characterized by a mixture of Th1 and Th17-
like features (Acosta-Rodriguez et al., 2007; Burel et al., 2018;
Lindestam Arlehamn et al., 2013; Singhania et al., 2021). Another
.............................................................................................................................................................................
1T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;


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2Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Correspondence to Daniel L. Barber: barberd@niaid.nih.gov
T.W. Foreman’s current affiliation is Discovery, Early Oncology R&D, AstraZeneca, Gaithersburg, MD, USA. M.A. Sallin’s current affiliation is Maryland Department of
Health, Linthicum Heights, MD, USA.
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. This article is distributed under the
terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After
six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://
creativecommons.org/licenses/by-nc-sa/4.0/).
Rockefeller University Press
https://doi.org/10.1084/jem.20222090
1 of 14
J. Exp. Med. 2023 Vol. 220 No. 8
e20222090


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Review Article
Journal of Medical Genetics (1974).
11, 80.
Immunoglobulins
JOHN BRADLEY
Sub-Department of Immunology, University of Liverpool Medical School
An immunoglobulin is a protein which is com-
posed of a characteristic unit of four polypeptide
chains: a pair of identical 'light' chains with a mole-
cular weight of 22,000, consisting of - 214 amino-
acid residues which do not contribute at all to class
specificity but are common to all the immuno-
globulins, and a pair of identical 'heavy' chains,
molecular weight 50,000-70,000.
The heavy poly-
peptide chains of the immunoglobulin classes and
subclasses vary in amino-acid composition and se-
quence and it is these variations that give each class
or subclass its specificity.
These chains are linked
by disulphide bridges.
Among the classes and
subclasses of immunoglobulins, members with anti-
body activity have been identified.
The approxi-
mate molecular weights of immunoglobulins range
from 160,000 for IgG to 900,000 for the IgM mole-
cule which consists of five monomeric IgM units
linked by disulphide bonds to form the IgM mole-
cule.
However, monomeric IgM (7S IgM) does
exist in the serum of normal individuals as well as in
a number of disease states.
In man, five distinct
classes have so far been identified according to their
general properties and the class of their heavy
chains; these are IgG, IgA, IgM, IgD, and IgE.
Immunoglobulin Classes
Immunoglobulin G is the major immunoglobu-
lin component of serum and of the body extravascu-
lar
spaces.
Members
of
this
immunoglobulin
group
neutralize
bacterial
toxins,
enhance
the
phagocytosis of micro-organisms, and may pro-
duce cell lysis by activation of the complement se-
quence.
Analysis of IgG myeloma proteins have
revealed the presence of four subclasses, IgG1,
IgG2, IgG3, and IgG4.
These subclasses (Table I)
vary in amino-acid composition and the number of
disulphide bridges present.
They also vary in their
Received 30 July 1973.
80
TABLE I
IgG SUBCLASSES
Disulphide Complement
Cross
Macrophages
Total


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Total
Bridges
Fixation
Placenta
Binding
IgG
IgG,
2
+ + +
+ +
+ + +
65-70°,,
IgG2
4
+
-
+
20-23%,
IgG3
5
+ + + +
+ +
+ + +
8%,'
IgG4
2
++
±
4%
ability to activate complement, to fix to macro-
phages, and to cross the placenta.
Immunoglobulin A appears selectively in sero-
mucous secretion tears, nasal secretions, saliva, and
gastrointestinal secretions.
In these secretions it is
present as a dimer with an additional secretory com-
ponent synthesized by the local secretory epithelium.
IgA is also present in the serum but mainly as the
basic 7S monomer.
The s!cretory IgA present in
colostrum, although not absorbed from the gastro-
intestinal tract of the newborn, probably helps to
control the intestinal flora.
Serious neonatal in-
fections are less frequent in babies whose milk intake
is from the breast in the first few days of life (Win-
berg and Wessner, 1971).
Although IgA does not
appear to
activate the
classical complement se-
quence, there is evidence that aggregated IgA can
do so via the 'alternate pathway' by acting on C3
proactivator to generate C3a.
The two subclasses
of IgA are differentiated immunochemically and
called IgAj and IgA2.
Structurally these sub-
classes are quite different; IgA2 lacks the interchain
disulphide bonds linking the heavy and light chains
which
are
characteristic
of
all
other immuno-
globulins.
Because of this, the subclasses can be
differentiated by electrophoresis in starch or acryla-
mide gel by suitable conditions (8M urea, pH3)
which dissociates the heavy and light chains of IgA2.
Normally human serum consists of approximately


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Journal of Medical Genetics (1974).
11, 117.
Evidence for mutation being the source of the
abnormal gene for plasma cholinesterase
R. T. EVANS and P. J. MAGILL
Biochemistry Department, Southmead Hospital, Bristol
Summary.
Results of cholinesterase, dibucaine and fluoride numbers, and
scoline hydrolysis rates are presented in a family found to have normal, silent and
abnormal genes for plasma cholinesterase.
Five sibs, confirmed by red cell group-
ing and tissue typing, have been shown to possess a cholinesterase pattern which
cannot be explained on the basis of accepted theories of inheritance.
In view of
this it is suggested that, in this family, a mutation has occurred from a normal or
silent gene to an abnormal gene.
Soon after the introduction of succinyl dicholine
(Scoline, Suxamethonium) as a short acting muscle
relaxant in 1949 it was recognized that the brief
period of action was due to its rapid breakdown by
plasma cholinesterase (acetyl choline acyl hydrolase
E.C. 3.1.1.8) (Bovet-Nitti, 1949).
Subsequently it
was discovered that some patients are peculiarly
sensitive to the drug, muscle relaxation lasting for
several hours rather than the normal 2-3 minutes
(Evans et al, 1952).
Lehmann and Ryan (1956)
showed that this sensitivity could often be attribu-
ted to the inheritance of two co-dominant genes for
an abnormal enzyme, which was later demonstrated
to be unable to hydrolyse scoline at pharmacological
concentrations (Davies, Marton, and Kalow, 1960).
The observations of Kalow and Genest (1957)
that this protein could be differentiated from the
normal on the basis of a simple biochemical test
represented a considerable advance in the labora-
tory
detection
of
sensitive
individuals.
These
workers showed that the abnormal enzyme was
resistant to inhibition by the local anaesthetic agent
dibucaine and devised the concept of the dibucaine
number (DN), which was defined as the percentage
inhibition ofthe enzyme by 10- 5M dibucaine.
The
DN is 80 ± 4 for normal enzyme, but only 20 ± 4 for


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enzyme from persons homozygous for the abnormal
gene.
An intermediate group of subjects were ob-
served to have dibucaine numbers of 60±5 and
these were shown to be heterozygotes.
These ob-
servations have since been confirmed (Johnson and
Received 19 November 1973.
Whitehead, 1965; Fishtal, Evans, and Chapman,
1972).
Other selective inhibitors are now well recog-
nized, the most important of which is fluoride, and a
gene has been described which is responsible for the
production of enzyme specifically resistant to fluo-
ride inhibition (Harris and Whittaker, 1961).
In 1962, profound Scoline sensitivity was re-
ported in a patient having no detectable plasma
cholinesterase
activity
(Liddell,
Lehmann,
and
Silk, 1962).
Several other cases have since ap-
peared in the literature (Doenicke
et al,
1963;
Szeinberg et al, 1966; Heyworth and Firth, 1967).
These patients are believed to be homozygous for
the so-called 'silent gene' but evidence is at present
equivocal as to whether there is a complete failure of
enzyme synthesis, or whether enzyme is present, but
in an inactive form (Goedde, Gehring, and Hof-
mann, 1965; Hodgkin et al, 1965).
The incidence
of this condition is low, approximately 1 in 300,000
in Caucasians, but it has been observed to be very
high in some isolated Eskimo communities where it
is present in an estimated 1-5% of the population
(Gutsche, Scott, and Wright, 1967).
Four allelic genes determining plasma cholines-
terase are now recognized:
Eu-the normal or usual gene.
Ea-the abnormal, dibucaine-resistant gene.
Ef-the fluoride resistant gene.
Es-the silent gene.
All the expected
genotypes corresponding to
117


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Journal of Medical Genetics (1974).
11, 190.
Observations on human amniotic fluid cell strains
in serial culture
GRANT R. SUTHERLAND, RHONA BAULD, and A. DOUGLAS BAIN
Department of Pathology, Royal Hospital for Sick Children and University of Edinburgh, Edinburgh EH9 ILF
Summary.
Observations made on 31 amniotic fluid cell strains serially cul-
tured until senescent are recorded.
The cell strains had an average life in culture of
13-9 passages (range 3-29).
The source of the amniotic fluid from which the cul-
tures were initiated did not influence the behaviour of the cell strains.
The be-
haviour ofthe cell strains was unrelated to the growth characteristics ofthe primary
cultures from which they were derived.
Cell strains derived from serial samples of
amniotic fluid from three women were compared and their characteristics were no
more related to each other than to the group as a whole.
The cell types found in
amniotic fluid cultures are described.
The karyology of 12 of the cell strains was
monitored and no significant changes from normal diploidy were seen.
Possible
reasons for the highly variable and unpredictable behaviour of amniotic fluid cell
strains are discussed.
Cultured amniotic fluid cells are now in wide-
spread use for the antenatal diagnosis of chromo-
some disorders and inborn errors of metabolism
(Emery,
1970; Sutherland,
1972; Emery, 1973;
Milunsky, 1973).
An accurate knowledge of the
behaviour of normal cultured amniotic fluid cell
strains is therefore essential for their use in genetic
studies.
However,
little
appears
to be known
about the characteristics of these cells in tissue cul-
ture.
It has been stated (Melancon, Lee, and
Nadler, 1971) that there are at least two morpho-
logically distinguishable cell types in amniotic fluid
cell cultures-an epithelial type which cannot be
subcultured more than two to five times and a
fibroblast-like cell which can be cultured for more
than 30 passages.
On the other hand, Littlefield
(1971) has said that '. . . 6 to 8 weeks of rapid cul-


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ture can approach the limit of the growth potential
of amniotic fluid cells.. .'.
This report records
observations made during the long-term culture of
31 amniotic fluid cell strains.
Materials and Methods
Amniotic
fluids
were obtained from hysterotomy
specimens
(HS), by
amniocentesis
on Rhesus
iso-
immunized women (RhS) and by artificial rupture of
Received 5 November 1973.
membranes (ARM) for the induction of labour.
The
primary cultures were set up as previously described
(Sutherland and Bain, 1972) and subcultured according
to the method of Butterworth et al (1973).
The cell
strains were maintained in 250-ml glass vessels with a
growth surface area of 40 cm2 and regularly subcul-
tured on reaching confluency, using a 1:2 subculture
ratio.
Throughout this study, all cell strains were cul-
tured in Ham's F10 tissue culture medium supple-
mented with 30% fetal calf serum and with the anti-
biotics kanamycin, or penicillin and streptomycin in
combination.
The methods used for cytogenetic studies
on primary cultures have been described (Sutherland,
Grace, and Bain, 1973b).
Once cell strains became
established, chromosome preparations were made using
standard methods.
Cell strains were stored in 10%
dimethyl sulphoxide in culture medium in the vapour
phase of a liquid nitrogen unit.
Results
The 31 cell strains were derived from amniotic
fluid samples taken from 25 women, ie, one woman
contributed four samples, another three, and another
two at different stages of pregnancy.
The gesta-
tional ages, means of collection, and chromosomal
sexes of the amniotic fluids are shown in Table I.
All had normal karyotypes with the exception of two
samples from one pregnancy which had a karyotype
46,XY,t(1 ;12)(p21 ;q21).
190


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Translocation, t(4q 3q+), in three generations resulting in partial trisomy of the long of chromosome 4 in the fourth generation


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Journal of Medical Genetics (1974).
11, 201.
Translocation, t(4q -;13q+), in three generations
resulting in partial trisomy of the long arm
of chromosome 4 in the fourth generation
HELMUT G. SCHROTT,* SUMIKO SAKAGUCHI,t UTA FRANCKE,t
LUIGI LUZZATTI,t and PHILIP J. FIALKOW**
Summary.
The karyotype of a child with severe mental retardation, micro-
cephaly,
minor
facial
anomalies, and urinary
tract
outflow obstruction
was
found to be 46,XY,13q+mat.
Trypsin-Giemsa banding studies showed an in-
herited translocation, t(4q-;13q+), in several asymptomatic members of the
family including the propositus' mother. This indicates that the propositus had
partial trisomy for the distal one-third of the long arm of chromosome 4.
Review
ofthe literature suggests that urinary tract and genital anomalies may be a consistent
feature of this partial trisomy.
Chromosomal translocations are found in approxi-
mately 0-140/% (1/700) of all newborn babies (Sergo-
vich et al, 1969, Walzer, Breau, and Gerald, 1969;
Lubs and Ruddle,
1970;
Ratcliffe
et
al,
1970;
Turner and Wald, 1970). Of these, one-third are
reciprocal translocations resulting from the mutual
exchange of chromosome segments between two
non-homologous chromosomes.
Individuals bear-
ing both products of the exchange ('balanced translo-
cation carriers') are generally normal phenotypically
because they have lost little or no genetic material.
However,
such
translocation
heterozygotes may
transmit to their offspring only one of the two
translocation chromosomes, and this results in a
child with chromosomal deficiency or duplication.
It is the consequent congenital anomalies that bring
the family to the attention of a physician.
We
report here a family in which a balanced transloca-
Received 20 August 1973.
* Department of Internal Medicine, University of Iowa, University
Hospitals, Iowa City, Iowa 52240, USA.
t Department of Pediatrics, Stanford University School of Medi-
cine, Stanford, California 94305, USA.
t Department of Pediatrics, School of Medicine, University of


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California at San Diego, La Jolla, California 92037, USA.
** Departments of Medicine (Division of Medical Genetics) and
Genetics, University of Washington, Seattle, Washington 98195,
USA.
tion, presumably reciprocal, was transmitted through
three generations and was then unmasked in the
fourth generation by the birth of a child with
multiple congenital defects.
The child had partial
trisomy of the distal long arm of chromosome 4.
Case Report
The propositus was admitted to Stanford University
Hospital at 3 months of age because of multiple con-
genital defects and failure to thrive.
He was the second
child of unrelated parents, a 25-year-old mother and 26-
year-old father.
A 4-year-old brother was normal and
there was no history of previous spontaneous abortions.
Delivery allegedly occurred 1 month early; birth weight
was 1986 g.
Shortly after birth, the patient was noted to
urinate
only
by
dribbling.
Intravenous
pyelogram
showed absence of renal function on the left and moder-
ate hydronephrosis and hydroureter on the right side.
Voiding cystourethrogram showed a small, thickened
bladder with bilateral ureteral reflux.
The obstruction
was relieved by a suprapubic cystostomy.
Follow-up
pyelogram showed a normally functioning right kidney
and a hydronephrotic left kidney.
At 2 months of age,
the patient had aspiration pneumonia.
Weight was
2560 g, length was 48-7 cm, and head circumference was
32-6 cm.
He had a good cry, although muscle tone was
poor.
The head was normal in shape and the anterior
fontanelle was closed.
The nose was prominent and the
201


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hUVi41y74
Journal of Medical Genetics (1974).
11, 221.
Congenital limb anomalies: frequency and
aetiological factors
Data from the Edinburgh Register of the Newborn (196448)
E. J. ROGALA, R. WYNNE-DAVIES, A. LITTLEJOHN, and J. GORMLEY
Department of Orthopaedic Surgery, University of Edinburgh
Summary.
This paper reports a detailed follow up of 156 patients with struc-
tural upper and lower limb anomalies, obtained from the Edinburgh Register ofthe
Newborn (a registration of 52,029 consecutive births between 1964 and 1968).
At
the time ofthis survey the patients were between 4 and 9 years of age.
The Register had noted probably 96% of all children born with limb defects in
Edinburgh between 1964 and 1968.
It was found that the diagnosis was completely
accurate in only 26% of cases, and partially so in a further 42%.
The frequency of each anomaly has been noted, subdivided into isolated ano-
malies; those that occurred with other limb anomalies, and those that formed part
of a syndrome.
Syndactyly of toes, post-axial polydactyly of the fingers, polysyn-
dactyly, and brachydactyly were found to have a genetic basis.
All 'absence' de-
fects, pre-axial polydactyly, and multiple limb deformities appeared to be sporadic.
Amongst the sporadic group, the main aetiological factors noted were an excess of
maternal toxaemia of pregnancy and of illegitimate children, when compared with
the Register Control Data.
Little is known about the frequency of the indi-
vidual structural deformities of the limbs.
Some
surveys mention 'skeletal anomalies' without fur-
ther definition, and in others delineation of the indi-
vidual anomalies is difficult because of variation in
terminology and the general, purely descriptive
terms so often used (Carter, 1963; Stevenson et al,
1966;
Butler and Alberman,
1969).
A
further
source of error is that most surveys have included
only hospital (not domiciliary) births and thus many
of the less severe anomalies will have been omitted.
McIntosh
et
al
(1954),
Marden,
Smith,
and


