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Clinical and genetic variations in the syndrome of adult GM2 gangliodosis resulting from hexosaminidase a deficiency.

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Clinical and Genetic Variations
in the Syndrome of Adult GM2
Ganghosidosis Resulting from
Hexosaminidase A Deficiency
2. Argov, MD," and R. Navon, PhD?
Six patients from three families developed adult GM2 gangliosidosis resulting from severe P-hexosaminidase A
deficiency. The clinical picture varied between and within families and included spinocerebellar, various motor
neuron, and cerebellar connection syndromes. Psychosis appeared in each family. Involvement of three generations was
recorded in one family. The phenotype of adult GM2 gangliosidosis is variable and cannot form a basis for genetic
classification. Detailed hexosaminidase determinations in eight patients from five families revealed all patients to have
minor quantities of hexosaminidase A (about 15% of normal), with marked increase in hexosaminidase I isotyme.
Argov Z , Navon R Clinical and genetic variations in the syndrome of adult GMI gangliosidosis resulting
from hexosaminidase A deficiency. Ann Neurol 16:14-20, 1984
Hexosaminidase (Hex) A is a lysosomal enzyme that
catalyzes the degradation of GM2 gangliosides. Total
absence of this enzyme results in accumulation of GM2
gangliosides in neurons, leading to the infantile
neurological disorder Tay-Sachs disease (TSD). This
disorder is thought to be inherited in an autosomal
recessive manner and is much more frequent among
Ashkenazi Jews than in other ethnic groups [14}. Severe deficiency of Hex A results in the juvenile form of
GM2 gangliosidosis, similar to TSD but less malignant
although it usually leads to death in the second decade.
The juvenile form has no ethnic predilection [141. In
1973 Navon and colleagues 1131 found severe
deficiency of Hex A in four adult sibs, two of whom
had children who died of TSD. The clinical characteristics of these four sibs were recently reported [lo}.
Since the first report of Rapin and co-workers El61, on
neurological manifestations in adult GM2 gangliosidosis, fifteen cases (including our original four) have
been described in detail [ 5 , 10, 11, 181 and eight more
have been briefly reported [4, 6, 81. The descriptions
in these reports might suggest that adults with severe
Hex A deficiency have either an atypical Friedreich's
ataxia or lower motor neuron-like syndromes and that
the clinical picture is quite uniform within families [ 3 } .
We present new clinical, genetic, and biochemical
data about five patients from nvo families we have
lately described C 111, plus observations concerning
three new patients of three different families. Our
studies in these cases suggest:
From the *Department of Neurology, Hadassah University Hospital,
Jerusalem, 91 120, and the ?Department of Human Genetics,
Sackler School of Medicine, Tel Aviv University and the Chaim
Sheba Medical Center, Tel Hashomer 52621, Israel
Received Oct 12, 1983. Accepted for publication Dec 4, 1983.
14
1. The neurological syndromes of adult GM2 gangliosidosis are more variable than previously thought.
2. Because diverse clinical pictures exist within the
same family, the phenotype cannot form a basis for
genotypic classification.
3. The disorder is transmitted as an autosomal recessive trait and probably has the same ethnic distribution as TSD.
4. Recurrent psychosis is an integral part of adult GM2
gangliosidosis.
5. In all patients studied, Hex A activity is not absent
but severely reduced (15% of normal). There is no
correlation between Hex A levels and the clinical
picture.
6. Hex I isozyme is markedly increased in fibroblasts
of patients.
Case Reports
Clinical features of all patients are summarized in Table 1;
pedigrees are presented in Figure 1.
Family I
CASE 11-1. A 27-year-oldbank clerk came to our neuromuscular clinic complaining of progressive leg weakness. In the
last 5 years she had experienced increasing difficulty in climb-
Address reprint requests to Dr Argov.
Table 1 . Summary of Clinical Features
Symptoms
Patient
Designation
Age
(yr)
Time of Onset
Cerebellar
LMN
Pyramidal
Psychosis Other
25
Second decade
19yr
+++
++
++
++
+++
67
38
Third decade
First decade
+
+++
11-3
Family 3
29
Second decade
Family 1
11-1
11-2
Family 2
1-1
II-1
29
11-3
29
Patient A
40
Seconddecade
First decade
Patient B
44
(?)Fourth decade
LMN
=
lower motor neuron;
+
to
++ ++
+++ +++
>
++
++
+++
++
Family 2
2
I
+++
I
...
...
Action tremor
Dementia; ocular
movement disorder
...
+ + + indicates presence and severity of features: +
Family 1
I.
++
+++
++
+++ +++
+++ ++
Severity
...
Dementia; involuntary movements
...
= mild;
++
+
+++
+
+ + +(dead)
++
++
+++
+t
= moderate;
+++
=
severe.
Family 3
2
Q
T
\
3
I,
I
?
T " P
II.
Hex A Levels
Fetus
@
F
M
8 F
J Normal
Intermediate
Severe Deficiency
Qoead
,--.
:
Not Examined
L...,
Fig 1. Pedigrees and Hex A leveh in the three familaes.
ing stairs and in rising from a sitting position on the floor. She
had had frequent falls when walking on high heels. She did
not complain of difficulties in hand function or in speech.
Sensory as well as sphincter symptoms were lacking. On examination she was found to be bright and alert, with no apparent mental problems. Cranial nerve, cerebellar, and sensory system findings were normal. Abnormal signs were
confined to her legs, where moderate weakness of quadriceps
and hip flexors and mild weakness of peroneal muscles were
found. The affected muscles were mildly atrophied, but no
fasciculations were observed. Normal tendon reflexes were
elicited, with no abnormal pyramidal signs.
Electromyography (EMG) of both quadriceps revealed no
spontaneous activity at test. Recruitmer pattern wa reduced, with only a few abnormally large motor unit potentials
appearing on maximal effort. Nerve conduction velocities
were normal. Muscle biopsy (right vastus lateralis) showed
many small atrophic, angulated fibers. Adenosine triphosphatase stains revealed fiber type grouping. Creatine kinase
levels were normal. The findings were interpreted as indicating a chronic lower motor neuron disorder.
CASE 11-2.
A 25-year-old man has been followed by several
psychiatric institutions because of recurrent psychotic episodes. At age 19 he was asymptomatic and had started his
university studies when his father died. During the subsequent month he became increasingly agitated, and psychosis
with thoughts of grandeur and paranoid fears appeared,
necessitating hospitalization. Since then he has had at least
Argov and Navon: GM2 Gangliosidosis
15
four major psychotic events. Between attacks he is withdrawn, aggressive, and unproductive; he never returned to
his studies or performed constructive work. Several psychiatrists have diagnosed him as probably having hebephrenic
schizophrenia. At age 20 a neurologist found severe cogwheel rigidity, hypomimia, and dystonic postures of the feet.
Marked hyperreflexia with no abnormal pyramidal signs was
also noted. Results of examination of his cranial nerves and
cerebellar functions were normal. Antipsychotic drug dosage
was reduced, and the extrapyramidal signs disappeared.
The patient reported experiencing progressive difficulty in
walking since the age of 18. Two years before we saw him,
frequent falls began. His family noticed that his speech
tended to be explosive and less comprehensible.
After we found his sister to be Hex A deficient, he was
evaluated during a quiet period in his mental disturbances.
He was receiving thioridazine, 100 mg a day.
O n examination he was cooperative and appeared of normal to high intelligence. His speech was dysarthric and explosive, and we observed titubation of the head as well as ataxia
of gait and dysmetria of the hands. There was no weakness of
the arms, but in the legs, quadriceps, hamstrings, and to a
lesser degree the peroneal muscles were weak. Apart from a
normal knee reflex, all tendon reflexes were abnormally hyperactive, with Babinski’s signs present bilaterally. Cranial
nerves were intact, and no sensory abnormalities were
elicited. EMG showed severe reduction of recruitment on
maximal effort with only a few prolonged high-amplitude
potentials. Nerve conduction was normal. Sural nerve biopsy
showed no abnormality on histological and electron microscopic evaluation. Rectal biopsy showed numerous membranous cytoplasmic bodies, typically found in neurons in TSD
{2}, in myenteric neurons and axons.
Family 2
CASE 11-3. The propositus, a 29-year-old technician, was
screened for TSD carrier status when his wife was in the
second month of her first pregnancy. He had suffered from a
form of neuromuscular disorder since adolescence.
His motor development and performance were normal until his mid-teens. He always had a strange running pattern,
however, and did not d o well in physical education classes.
He graduated from a special technical school with a degree in
mechanics and joined the army at age 18. Although he began
to complain of increasing gait difficulties, he was drafted without special medical limitations. During his obligatory service
he experienced frequent falls because his legs “gave out.” His
ability to climb stairs was reduced, and he had to drag himself, using the banister. When walking on level ground he
became fatigued but could walk for long distances. He did
not complain of weakness in the arms but thought they were
tremulous. From the time he was 22, progressive muscie
wasting of the lower limbs appeared, with twitching in proximal muscles. He had no speech, swallowing, coordination, or
sensory problems.
He was incorrectly diagnosed by several physicians as having “muscular dystrophy,” but when in the T S D screening he
was found to have very low Hex A levels, he was reevaluated.
He was still working in his profession.
O n examination he showed no overt mental disturbances.
The only abnormality o n cranial nerve resting was atrophy of
16 Annals of Neurology Vol 16 No 1 July 1984
both masseters. There was diffuse muscle atrophy including
neck, arm, and leg muscles. Especially weak were the shoulder and hip girdle muscles; distal muscles were less affected.
Myokymia and fasciculations were present in the shoulder
and chest muscles. Tendon reflexes were hyperactive in the
arms but unobtainable in the legs. Bilateral extensor plantar
responses were elicited. He had unstable steppage gait without cerebellar ataxia. Mild distal action tremor was observed,
but otherwise no extrapyramidal or abnormal sensory signs
were found.
Nerve conduction was normal. On EMG, spontaneous activity was recorded bilaterally from quadriceps and triceps
muscles, but noc from distal muscles (tibialis anterior, gastrocnemius, and first dorsal interosseous). In all muscles, recruitment pattern was markedly reduced, with few similar large
motor unit potentials appearing on maximal effort. Muscle
biopsy confirmed the neurogenic nature of the muscle disorder. Rectal biopsy showed many intracytoplasmic inclusions
in axons of the myenteric plexus that were similar to membranous cytoplasmic bodies.
The patient’s wife was found to have intermediate levels of
Hex A activity, as seen in TSD carriers. Amniocentesis was
performed, and cells in culture were devoid of Hex A activity. The family decided to terminate the pregnancy. The fetal
brain did not contain membranous cytoplasmic bodies or
other similar intracellular inclusions at 18 weeks of gestational time (R. Navon and U. Sandback, personal communication, 1983).
The patient reported his sister to be afflicted with degenerative brain disease and to be hospitalized in a chronic
care nursing institution, and his mother to suffer from “shaking hands.” Both were examined.
CASE 1-1. A 68-year-old housewife had first noticed tremor
of her hands, more on the left, after delivery of her first child
at age 30. Over the years the tremor worsened but no other
symptoms appeared. The patient had no gait difficulties or
muscle weakness. H e r only disability was related to the
tremor: she could not write, sew, eat soup, or serve tea, and
needed help in dressing.
Examinatiotl revealed mild resting tremor of both hands
and the head, markedly increased on action, developing a
flapping character of high amplitude. The legs were unaffected. Coordination could not be tested accurately, but no
gross impairments were seen in finger-to-nose testing. Tonus
was slightly reduced in all four limbs. There were no muscle
atrophy or weakness, pyramidal signs, extrapyramidal features, or sensory impairments. The findings were thought to
be similar to those observed in disorders of the dentatorubral
connections. The patient refused further tests other than Hex
A level determination.
CASE 11-1. The patient had been symptom free until about
age 9. At that time she complained of gait instability and her
speech became dysarthric. At first she avoided only physical
education classes but later became withdrawn.
She was first evaluated at age 16. General physical examination findings were normal. She was dysarthric, with ataxia
of all limbs. Muscle tone was normal, and no muscle atrophy
was reported, although she had difficulty in climbing stairs.
Tendon reflexes were all present, and bilateral signs of py-
ramidal dysfunction were elicited in the legs and arms. The
only abnormality on cranial nerve examination was a limitation in upward gaze. There were no abnormalities in sensory
functions. Skull roentgenograms, electroencephalogram
(EEG), serum and cerebrospinal fluid biochemical findings,
and blood count results were normal. Psychological tests revealed “average intelligence with marked anxiety, childish
behavioral responses, and problems in accepting her physical
disabilities.”
Her speech difficulties increased. Muscle wasting in her
lower limbs developed, and she stopped bicycle riding and
developed knee contractures. At age 20 she experienced an
acute psychotic episode and was hospitalized in catatonic
stupor. Examination showed diffuse muscle atrophy, especially in her lower limbs. Tendon reflexes were hyperactive,
with bilateral Babinski’s signs. She was dysarthric and had
swallowing difficulties. Action tremor, dysmetria, and dysdiadochokinesia were found. She was unable to initiate upgaze. She slowly recovered from her psychosis and was discharged to a sheltered workshop while receiving a continuous
dosage of chlorpromazine (100 mg a day). During the next 3
years her gait difficulties increased, and she became unable to
walk unaided outside her home. Dyskinetic movements of
her tongue and lips appeared, and swallowing became further
impaired, until she had to be fed by a nasogastric tube.
At age 23 she was hospitalized, and dysarthria, tremor,
ataxia, hyperreflexia, and Babinski’s signs were recorded,
along with involuntary movements. Muscle atrophy was
marked, with steppage gait resulting from bilateral foot drop.
Upward gaze was almost absent, but other cranial nerve,
fundi, and sensory test findings were normal. EEG was normal, and EMG of legs showed fibrillation potentials and a
reduced recruitment pattern compatible with a lower motor
neuron disorder. Intelligence was low average, with an overall score of 78. She was thought to have an atypical Friedreich’s ataxia associated with an unrelated psychiatric condition, perhaps schizophrenia. She continued to receive
antipsychotic drugs. H e r condition gradually worsened, with
recurrent prolonged psychotic episodes and incomplete interim recovery. H e r mental functions progressively deteriorated, and involuntary movements of her arms appeared. She
was hospitalized in a nursing institution where she was seen
by us, at the age of 38, after her brother was found to have
low Hex A levels.
She was profoundly demented and lacked verbal or any
other communication. She had extreme muscle wasting,
weighing not more than 25 kg. She had no tendon reflexes,
but extensor plantar responses were easily elicited. Continuous choreoathetotic movements affected all limbs and
stopped only during sleep. She died a few months later. Permission for postmortem examination was not given.
All other members of this family were tested for Hex A
levels but were neurologically intact.
Family 3
CASE 11-3.
A 33-year-old man had been born with a funnel
chest requiring surgery at age 6. His motor and mental development was normal. During his late teens he became withdrawn and inhibited in interpersonal relations. At 2 1, after he
completed army duty, he attempted an intersexual relationship, which failed, and was hospitalized then and subse-
quently in a psychotic state. A diagnosis of hebephrenic
schizophrenia was suggested by several psychiatrists.
At age 21, he first complained of leg weakness, which
progressed over the years. He had no formal investigations
for a neuromuscular disorder until he was referred to us for
muscle biopsy at age 33. General examination revealed only
bilateral pes cavus. He was cooperative and pleasant, with no
impairment of orientation, mode of thinking, or affect. He
was taking 100 mg of chlorpromazine daily. The only abnormality in cranial nerves was tongue and lip dyskinesias, with a
nasal quality to his speech. He had difficulty in performing
repetitive changing movements and had ataxia of gait. Muscle
tone was reduced, and proximal leg muscles (mainly quadriceps and iliopsoas), peroneals, and some shoulder girdle
muscles were weak. Tendon reflexes were hyperactive, with
bilateral extensor responses. No fasciculations, sensory impairment, or abnormal movements were found.
Results of laboratory investigations, including EEG, computed tomographic scan, and cerebrospinal fluid examination,
were normal. EMG revealed spontaneous activity (fibrillation
potentials and positive sharp waves) in distal muscles, with
the appearance of many short polyphasic units on weak recruitment. The findings were consistent with a neurogenic
disorder with secondary myopathic changes. Muscle biopsy
confirmed this diagnosis. Evaluation of mental status revealed
an average IQ but difficulties in task performance and low
initiative. Rectal biopsy confirmed the presence of structures
resembling membranous cytoplasmic bodies in myenteric axons.
The patient’s elder brother had developed psychosis in his
early twenties. He had been hospitalized twice in a psychiatric hospital and died during his second hospitalization, about
15 years prior. Neurological examination findings and EEG
were reportedly normal. He was diagnosed as a probable
schizophrenic. Postmortem examination did not include electron microscopic study of the nervous system. In retrospect,
the family and nurses that cared for both brothers were convinced that they had a similar disorder.
The father has had Parkinson’s disease since age 45. At age
66 he was in an advanced stage, with dementia. He did not
have severe deficiency of Hex A (see Fig 1).
Referral Cases
We were consulted on two additional patients from different
families who were not clinically evaluated by us. Patient A, a
40-year-old woman, had experienced motor and speech
difficulties since age 7, and psychosis since age 17, progressing recently to an advanced stage with dementia. Patient B, a
44-year-old woman, had experienced clinical onset of spinocerebellar disorder with depressive psychosis early in her
thirties.
Materials and Methods
Total and heat-stable Hex activities were determined in
serum, peripheral leukocytes, and cultured skin fibroblasts.
The activity was determined with the fluorogenic substrate
4 - methylumbellifery - 2 - aceto- 2 - deoxy - p - D -glucopyranoside
(Koch-Light, Colnbrook, England), as previously described
IS).
Skin fibroblasts were cultured from skin biopsy specimens
taken from the patients with adult GM2 gangliosidosis, from
Argov and Navon: GM2 Gangliosidosis
17
Table 2. Hexosaminidase A Levels in Patients Studied”
~
Patient
Designation
Family 1
11-1
11-2
Family 2
1-1
11-1
11-3
Family 3
11-3
Patient A
Patient B
Normal range
TSD carriers
TSD patients
Serum
Leukocytes
0
6
8
7
Fibroblasts
5
0
I
3
2
7
Fraction Number
0
1
6
7
11
10
Fig 2. Dielhylaminoethyl cellulose chromatography of hexosaminidasefrom skin fibroblasts. (A)Patient with adult GM2
gangliosidosis. (B) Normal individual. Awows indicate start of
gradient.
9
0
0
48-64
32-46
0-13
12
10
5
58-69
37-54
0-13
5
( Irnl
10
1
50-68
20-27
...
“Percentages of total hexosaminidase, determined by heat inactivation method. TSD = Tay-Sachs disease.
patients with infantile TSD, and from normal controls. The
cells were cultured with Eagle’s modified essential medium
(Gibco, Cat. No. 430-2 100)containing 105%fetal calf serum.
Hex from skin fibroblasts from the adult patients, from
patients with TSD, and from normal controls was separated
by ion-exchange chromatography into its isotymes 191. Supernatant from the fibroblast extract from each of three flasks
(75 cm2 of confluent cultures) was used for each separation.
The supernatants were dialyzed overnight against 10 mM
sodium phosphate buffer, pH 6.0, and applied to microcolumns, 0.5 x 7.0 cm dielhylaminoethyl (DEAE) cellulose
(type 52), equilibrated with 10 mM sodium phosphate buffer.
The column was eluted with 20 ml of buffer followed by 30
ml of a linear 0 to 0.3 M sodium chloride gradient in 10 mM
phosphate buffer. Fractions of 1ml were collected. Total and
heat-stable @-Hexactivities were determined in each fraction.
Results
All those affected with adult GM, gangliosidosis had a
marked deficiency of Hex A in serum, leukocytes, and
skin fibroblasts, as determined by the routine heat inactivation method {l5] (Table 2). As can be seen from
the table, Hex A values in the adult patients were indistinguishable from those found in patients with TSD.
Parents of adult patients had intermediate Hex A levels
in their leukocytes, in the range of obligate heterozygotes for TSD, except one (family 2, patient I-l), an
adult patient with GM2 gangliosidosis, who had a
marked Hex A deficiency, Residual Hex A activity of
15% (range, 13 to 2296%)
was detected by ion-exchange
chromatography in skin fibroblasts from all the adult
patients. In samples from all adult patients, extreme
high activity of an intermediate peak, Hex I, was eluted
shortly after the NaCl gradient was applied (0.02 to
0.05 M NaC1) (Fig 2A). This activity constituted about
18 Annals of Neurology Vol 16 No 1 July 1984
75% of the total (range, 67 to 81%; average, 74%) in
patient fibroblasts, compared with a very small proportion ( 3 to 16%; average, 11%) in normal fibroblasts
(Fig 2B). In TSD fibroblasts Hex I activity was even
more pronounced (80 to 98%). The isozymes B, I (11
12), and A found in the adult patients had the same
heat stability and electrophoretic properties as normal
Hex isozymes (under identical chromatographic conditions Hex I was sometimes eluted in one peak and
sometimes in two).
+
Discussion
Adult GM2 gangliosidosis resulting from Hex A
deficiency, a rare disorder, has been recognized only in
the last decade. To date, including this report, about
thirty cases have been described, not all with full clinical details 14-6, 8, 11, 16, 181. All but one patient {S}
were Ashkenazi Jews, and twelve patients were diagnosed in Israel.
Precise determination of age at onset is difficult, because the disorder is slowly progressive, but four of our
present six patients developed symptoms in their second decade, as did some of the other reported patients.
One of our patients showed clinical signs in her first
decade and was more severely affected. This was also
the experience in our original family {lo}. Thus, an
early presentation may indicate a worse prognosis.
There have been other reports of patients who became
symptomatic in their first decade {4, 181, and the question may arise as to whether they have a “protracted
juvenile form” of Hex A deficiency, with longer survival. The demarcation between the juvenile and adult
disorders is not clear, but the ethnic predilection and
the fact that other family members develop symptoms
much later indicate that adult GM2 gangliosidosis probably is a separate entity. Clinical onset may be delayed
until the twenties or thirties (patient 1-1 of family 2,
and another patient in our original report) { 101. When
evaluating those with Hex A deficiency, delayed onset
in apparently healthy persons should be considered,
this possibility calling into question some of the early
reports of “healthy” subjects with Hex A deficiency
who were not followed 171.
Most previously reported patients evidenced a combined cerebellar and pyramidal syndrome masquerading as Friedreich‘s ataxia 1181. Few had motor system
disorder 15, 67. Of our patients, only one had a spinocerebellar disorder similar to what Rapin and colleagues 1161 described. Two had a predominantly
motor neuron disease, one with amyotrophic lateral
sclerosis-like syndrome (muscle atrophy, fasciculations, and pyramidal signs), the other with lower motor
neuron involvement of the legs without fasciculations,
suggesting a spinal muscular atrophy-like disorder.
When detailed clinical muscle testing, electrophysiological studies, and muscle biopsies were performed,
however, there was evidence of lower motor neuron
disease in all but one patient (patient 1-1, family 2).
Thus, motor neuron involvement may be more frequent in Hex A deficiency than previously thought and
should be investigated appropriately.
Psychosis appeared in one case in each of our
families, in our two consultative cases, and in patients
previously reported in the literature 110, 16, 18). In
our patients recurrent psychotic attacks of a variable
nature, starting in early adulthood and with some progressive personality disintegration, led to the diagnosis
of hebephrenic schizophrenia (usually by several psychiatrists). Of the twenty-two patients reported or
studied by us, at least eight had psychosis (about 40%),
a number too high to be a chance occurrence. Psychosis apparently is integral to adult GM2 gangliosidosis
syndrome and is part of a more severe and incapacitating syndrome (see Table 1).
An unusual finding was the dentatorubral tremor
localized to the arms in patient 1-1 of family 2. If we
add to this finding the extrapyramidal features we observed in two cases and the dementia in two, we are led
to conclude that various areas of the brain can be
afflicted and that the distribution is not fixed. The variability and severity of the disorder are not related to
the age at evaluation. Patient 11-1 of family 2, who died
at age 38, had been bedridden and demented since her
early twenties; her 30-year-old brother is still working,
and their mother, at age 67, is our least affected patient. The same lack of correlation between severity
and age is apparent when one compares sibs in our
original family [lo] and the first family reported in this
study.
In early reports on families with several affected sibs
(including our original family), all members evidenced
a rather uniform clinical syndrome. There was, however, marked disparity among families, leading some
investigators to suggest that the phenotypic presentation could serve as a basis for genotypic classification
13, 51. In two of the families we report here, we have
encountered marked intrafamilial variations. In family 1
a brother with spinocerebellar disorder and psychosis
and his elder sister, with lower motor neuron involvement confined to her legs, showed intrageneration variation. Family 2 (a mother with cerebellar connection
disorder, a daughter with diffuse disease, and a son
with an amyotrophic lateral sclerosis-like syndrome)
showed variability between and within generations.
The attempt of Johnson [3] to “assign” a different gene
to each clinical syndrome cannot account for such intrafamilial variability. It can be argued that the interfamilial and intrafamilial phenotypic variability results
from variable expression of the genotype.
The adult GM2 gangliosidosis disorder affects the
Hex A isozyme, presumably in the (Y subunit gene.
Hex A isozyme is a heteropolymer composed of subunits (Y and p, encoded on different chromosomes
1171. The most common mutation in the 01 subunit
gene is the TSD allele, which in its homozygous state
causes total absence of Hex A isozyme [14, 171. In
contrast, adult a subunit mutation causes a severe, but
not complete, deficiency of Hex A. All affected patients examined by us had a marked deficiency of Hex
A activity in their serum, leukocytes, and skin fibroblasts. The deficiency was demonstrated with the heat
inactivation method, the method most commonly used
to detect Hex A activity. The values obtained were
indistinguishable from those of patients with TSD. Evidence of residual Hex A activity in the newly described
affected individuals is provided by ion-exchange
chromatography, with findings similar to those in our
first family and in other reports 18, 12, 181. Residual
Hex A activity in affected patients can also be demonstrated by other methods (1, 8, 181.
The extremely high activity level of an intermediate
peak of Hex eluted at 0.05 M NaCl was observed in all
our adult patients. This striking increase in the heatstable Hex I isozyme is related to the low Hex A
isozyme level. It is clear that the residual Hex A activity of 15% found by ion-exchange chromatography in
the adult patients is masked in the heat inactivation
assay by the high level of heat-stable Hex I activity,
especially because Hex A activity is defined as the percentage of the heat-labile isozyme from total Hex activity. Therefore, heat inactivation test results for adult
patients (with residual Hex A activity) are indistinguishable from those of patients with TSD (with no
Hex A activity). The high Hex I activity level in adult
GM2 gangliosidosis is also a typical finding in TSD 191.
This high activity level is probably the result of severe
deficiency in a subunits, with relatively high excess of p
subunits. The Hex I may represent a polymer of p
subunits in these two disorders. The effect of such a
mutation would be a relative deficiency of (Y subunits
and, therefore, an excess of p subunits. The latter
might combine to form the Hex I isozyme, explaining
the high Hex I activity level found in the adult patients.
Argov and Navon: GM2 Gangliosidosis
19
In adult GM2 gangliosidosis both sexes are affected,
and parents of affected individuals we and others have
studied show reduced Hex A activity in the same range
as TSD carriers. Thus, it can be concluded that the
disorder is transmitted as an autosomal recessive trait.
In our family 2, however, the union of an affected
mother with a heterozygote father resulted in a
pseudodominant pattern of inheritance, providing the
first report of a family with transmission from one generation to the next. Such transmission can occur in
societies with high carrier frequency, in which persons
with late onset are not identified before marriage and
have no genetic counseling. The clinical heterogeneity
raises the question of whether different mutations exist, leading to partial Hex A deficiency in different
families. Furthermore, some affected patients may be
homozygotes for a single mutation, whereas others
may be compound heterotygotes, carrying two abnormal alleles on homologous chromosomes (the TSD allele and another rare allele). A compound heterozygote condition was shown in only one family in which
both adult GM2 gangliosidosis and TSD occurred [10,
131. The genotypes of our other families and those
reported by other investigators are less clear, but, as
mentioned, nearly all family members are Ashkenazi
Jews, among whom TSD carriers are very frequent.
Our other patients may all be compound heterozygotes, but why this unusual genetic state results in different clinical syndromes is not clear. The proper classification of adults with Hex A deficiency must await
elucidation of the basic biochemical defects responsible
for this disorder. The frequency of adult GM2 gangliosidosis among Ashkenazi Jews cannot yet be determined, although attempts have been made, partly because of a lack of awareness on the part of physicians of
this recently recognized disorder. Because we cannot
differentiate biochemically between TSD carriers and
carriers of adult GM2 gangliosidosis, the carrier rate for
the adult disease cannot be established. Some of those
believed to be TSD carriers may in fact be adult GM2
gangliosidosis carriers.
These genetic factors produced poignant considerations when the pregnant wife of our patient 11-3 of
family 2 came for counseling and was found to be a
carrier. Cultured amniotic fluid cells were severely deficient in Hex A activity. It could not be determined
whether the fetus had TSD or adult GM2 gangliosidosis, and whether the adult syndrome would be
mild or severe. Electron microscopic studies of
neurons from the fetal brain showed no evidence of
lysosomal storage, which we typically find at that gestational age in fetuses with TSD. Thus, we feel that this
20 Annals of Neurology
Vol 16 No 1 July 1984
fetus had adult type disease, representing the third generation of this family so affected.
The authors thank R. Koppel and R. Fuchs for laboratory assistance.
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