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Chronic hexosaminidase A and B deficiency.

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Chronic HexosaminidaseA and B Deficiency
William D. G o l d i e , MD, D a v i d H o l t z m a n , P h D , MD, and K u n i h i k o Suzuki, MD
The leukocytes and fibroblasts f r o m a mildly retarded 10-year-old g i r l who had a slowly progressive motor
dysfunction showed absence of hexosaminidase A a n d B activities. Leukocytes f r o m her asymptomatic mother and
sister contained half the normal levels of both enzymes. T h i s child is the second patient reported w i t h a chronic form
of hexosaminidase A and B deficiency, an enzyme deficiency previously described only i n infants w i t h rapidly
progressive psychomotor deterioration (Sandhoff’s disease).
Goldie W D , Holtzman D, Suzuki K: Chronic hexosaminidase A and B deficiency.
Ann Neurol2:156-158, 1977
A b s e n c e of hexosaminidase A a n d B has been associated with progressive p s y c h o m o t o r deterioration
characterized b y onset i n infancy and a rapid course
culminating i n d e a t h i n t h e first f e w years [4, 61.
A b n o r m a l accumulations of t h e GM, ganglioside a n d
globoside h a v e b e e n found i n t h e brain a n d viscera of
t h e s e children. We a r e r e p o r t i n g a mildly retarded
preadolescent non-Jewish girl with a slowly progressive motor dysfunction and absence of hexosaminidase A and B activity i n leukocytes and fibroblasts.
The patient is the 10-year-old daughter of nonconsanguineous Iranian mother and Lebanese father. H e r birth weight
was 2.85 kg. Gestation, labor, and delivery were normal.
Early development was reported to have been normal. She
sat at age 7 months, walked at 11 months, spoke in short
phrases by 18 months, and was toilet trained at 2 years. At 5
years she attended kindergarten, but was noted to be clumsy
and weak and had poorly articulated speech compared to
her classmates.
She was first seen by the Stanford Pediatric Neurology
Service at age 6 years for abnormal posturingof the left arm.
At that time her developmental assessment was normal.
Speech was mildly dysarchric but fluent. Vision was normal,
and funduscopic examination showed no abnormalities. She
had a mild left hemiparesis with increased tone and a coarse
tremor of the left arm. T h e deep tendon reflexes were
diffusely hyperactive. Snout and grasp reflexes were present, but the plantar toe responses were flexor. She complained of distal dysesthesias, but no specific sensory deficits
were found.
At age 9, her general level of functioning was that of a
6-year-old. Dysarrhria with fluent speech was noted. Visual
acuity was normal with minimal strabismus and normal
funduscopy. Saccadic eye movements were hypometric, but
there was no nystagmus. T h e left hemiparesis was present
with diffusely hyperactive deep tendon reflexes, bilateral
palmomental and snout reflexes, and extensor plantar toe
responses. There was dystonic posturing in all extremities,
with a positional tremor present in the arms. Finger-to-nose
testing showed bilateral dysmetria. There was diffuse distal
muscle wasting and prominent fasciculadons of the tongue.
The sensory examination was entirely normal.
Normal laboratory studies at age 7 years included blood
counts and morphology, electrolytes, liver enzymes, thyroid
studies, serum copper, ceruloplasmin, and urine amino acids
and heavy metals. EKG, EEG, and roentgenograms of the
chest, skull, and spine were normal. Nerve conduction
velocities were normal, but electromyography showed denervatiori potentials and fasciculations consistent with loss
of anterior horn cells. T h e cerebrospinal fluid prorein was
38 mg per 100 ml with a normal protein electrophoresis
pattern and n o pleocytosis. Light and electron microscopical
evaluations of a skin biopsy revealed no abnormalities.
Neuropsychological testing using the WISC, Raven progressive matrices, and Peabody Picture Vocabulary Tests
showed an I Q of 7 0 with very little scatter.
Biochemical Studies
Peripheral leukocytes were prepared by the dextran differential sedimentation procedure essentially according to
Snyder and Brady [?I. T h e final leukocyte pellets were
suspended in distilled water, 1 ml per 10 ml of original
blood, alternately frozen and thawed three times, and briefly
sonicated in a water bath ultrasonicator. Plasma specimens
were obtained from portions of the same blood samples
used for leukocyte isolation. The anticoagulant used was
sodium heparin.
Initially skin fibroblasts were grown at the Stanford Medical Center. A portion was transferred to the Bronx, where it
was then maintained under the standard culture conditions
of the laboratory. The cells were harvested by brief trypsinization, and the final cell pellets were prepared for enzymatic
assays as described for leukocytes.
Protein content of the enzyme sources was determined by
the method of Lowry et a1 [2] with bovine serum albumin as
the standard.
Enzyme assays were carried out according to our routine
From the Departments of Neurology and Pediatrics, Stanford Universicy Schnol of Medicine, Stanford. CA, and the Departments of
Neurology and Neuroscience, Albert Einstein College of Medicine
of Yeshiva University, Bronx, NY.
Accepted for publication Mar 11, 1977.
Address reprint requests to Dr Holtzman, D~~~~~~~~~
ogy, Stanford University School of Medicine, Stanford, CA 94305.
Enzynutir Assays in a Patient with Chronic Hexosarninidme A and B Defrienrj
Enzyme Source
4-MU N-Aceryl-/3-Glucosarninidasea
$TI Heat-Labile
4-MU P-Galactosidase“
Control range
51.2, 88.0
59.2, 69.6
. . .
63.2, 73.0
. . .
. . .
. . .
“Enzymatic activities are expressed in nmol/hr/mg protein for leukocytes and fibroblasts, nmol/hr/ml for plasma.
bThe anticoagulant is moderately inhibitory to enzymatic activity, and these values are lower than expected for serum.
procedures with 4-methylumbelliferyl P-D-galactoside [9]
and 4-rnerhylumbelliferyl A’-acetyl-/3-D-glucosaminide [81
as the substrates. Differential assays of hexosaminidase
isozymes were done by the heat-inactivation procedure 131.
The results of these studies are given in the Table.
4-Methylumbelliferyl Pgalactosidase was normal
in the patient’s leukocytes and fibroblasts. In
contrast, total N-acetyl-Phexosaminidase activity was
consistently much lower than normal. The activities in
the patient’s specimens were generally 5 to 10% of
the control activities. In addition, most of the
hexosaminidase activities in the patient’s leukocytes
and fibroblasts were heat labile at 50°C for three
hours. In plasma, however, only one-third of total
hexosaminidase was heat labile. The patient’s mother
and a sibling showed intermediate hexosaminidase
activities in both plasma and leukocytes.
Our patient has a deficiency of hexosaminidase A and
B associated with slowly progressive spasticity, dystonia, dysmetria, dysarthria, and loss of anterior horn
cells. She has mild dementia, no seizures, and no
evidence of retinal degeneration. A child with a similar clinical course and biochemical findings has been
reported recently [ 101; in addition, this child had
evidence of lipid storage in a skin biopsy (Wood S:
personal communication, 1976). To date our patient
has had no morphological abnormalities of skin o r
leukocytes. Because of her relatively good neurologi-
cal function, biopsy of other tissues has not been
The hexosaminidase levels were the same as those
found in severely affected infants with classic Sandhoff’s disease [6]. The intermediate enzyme levels in
the normal mother and sister imply autosomal recessive inheritance and are comparable to the enzyme
levels in heterozygous family members in the infantile
form of Sandhoff’s disease [4,61.The prolonged clinical course in our patient is similar to that described
in patients with the adult or chronic form of
hexosaminidase A deficiency described by Brett and
associates [ 11 and Rapin et a1 [5]. As with the various
forms of hexosaminidase A deficiency, the clinical
severity and course in patients with hexosaminidase A
and B deficiency do not correlate with peripheral
enzyme levels [ l l .
Biochemical studies, performed in the laboratory of Dr Suzuki,
were supported by Grants NS10885, SS-03356, and HD-01799
from the US Public Health Service.
We are grateful to Dr Howard Cann of the Department of Pediarrics, Stanford University School of Medicine, for performing the
skin biopsy and growing fibroblasts, and to D r Mary M. Herman of
the Department of Pathology, Division of Neuropathology, Stanford University School of Medicine, for light and electron microscopical study of the skin biopsy.
1. Brett EM, Ellis RB, Haas L, et al: Late onset G N
gangliosidosis: clinical, pathological, and biochemical studies
on eight patients. Arch Dis Child 48:775-785, 1973
2. Lowry OH, Roscbrough NJ, Farr AL, et al: Protein measurement with the Folin reagent. J Biol Chem 193:265-275, 1951
Case Report: Goldie, Holczman, a n d Suzuki: Chronic Sandhoff‘s Disease 157
3 . O‘Bricn JS, Okada S, Chen A , et al: Tay-Sachs disease; detecrion of heterozygotes and homozygores by serum
hexosaminidase assay. N Engl J Med 283:15-20, 1970
4. O’Brien JS, Okada S, Ho MW, et al: Ganglioside storage
diseases. Fed Proc 30:956-969, 1971
5 . Rapin I, Suzuki K, Suzuki K: Adult (chronic) GM,
gangliosidosis. Arch Neurol 33:120-130, 1976
6. Sandhoff K, Andreae U, Jatzkewitz H: Deficient
hexosaminidase activity in an exceptional case of Tay-Sachs
disease with additional storage of kidney globoside in visceral
organs. Life Sci 7:283-288, 1068
7. Snyder RA, Brady RO: The use of white cells as a source of
158 Annals of Neurology
Vol 2
No 2
August 1077
diagnostic material for lipid storage discascs. C.lin Chim Acta
251331-338, 1969
8. Suzuki Y , Berman PH, Suzuki K: Detecrion of Tay-Sachs
disease heterozygotes by assay of hexosaminidase A in serum
and leukocytes. J Pediarr 78:643-647, 1971
9. Suzuki Y, Suzuki K: Glycosphingolipid pgalacrosidases: I.
Standard assay procedures and characterization by electrofocussingand gel filtration of the enzymes in normal human liver.
J Biol Chem 249:2098- 2104, 1974
10. Wood S, MacDougall BG: Juvenile Sandhoff disease: some
properties of the residual hexosaminidase in cultured tibroblasts. Am J H u m Genet 28:489-495, 1976
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deficiency, hexosaminidase, chronic
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