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Clinical variation in 2 related children with neuronopathic Gaucher disease.

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Clinical Variation in 2
Related Children with
Neuronopathic Gaucher
Warren D. Grover, MD, Samuel H. Tucker, MD,
and David A. Wenger, PhD
T h e clinical features i n 2 second cousins with
neuronopathic Gaucher disease include slowly progressive ataxia, spasticity, myoclonus, and seizures with relative preservation of intellectual function. Organomegaly was noted only i n Patient 1. Both patients had
diffuse slowing with paroxysmal features in electroencephalograms and a deficiency of fi-glucosidase
activity i n leukocytes and skin fibroblast cultures. T h e
parents of Patient 1 and the related father of Patient 2
had levels of P-glucosidase activity consistent with the
carrier state for Gaucher disease. T h e value of
P-glucosidase activity i n the mother of Patient 2
suggests a different mutation, the result being a defective enzyme component not detectable by measuring
total activity.
Grover WD, Tucker SH. Wenger DA: Clinical
variation in 2 related children with neuronopathic
Gaucher disease. Ann Neurol3:281-283, 1978
Gaucher disease is an autosomal recessive disorder
that can present in at least three clinical forms. Most
common is the adult or nonneuronopathic type 1,
which can be recognized early in life or after several
decades of normal development. O n e usually finds
splenomegaly, anemia, and b o n e changes but not abnormal neurological symptoms. This form occurs
most frequently in families of Ashkenazi Jewish ancestry. T h e infantile or acute neuronopathic type 2 is
often recognized within t h e first few months of life
because of massive splenomegaly, spasticity, cranial
nerve dysfunction, and severe mental retardation.
Death occurs within the first year or two. T h e juvenile
form or subacute neuronopathic type 3 is less well
From the Departments of Pediatrics and Neurology, St. Christopher's Hospital for Children, Temple Health Sciences Center,
the Departments of Pediatrics and Neurology, University of
Pennsylvania School of Medicine, and the Division of Neurology,
Children's Hospital of Philadelphia, Philadelphia, PA, and the Department of Pediatrics, University of Colorado Medical Center,
Denver, CO.
Accepted for publication Aug 25, 1977.
Address reprint requests to Dr Grover, Section of Child Neurology, St. Christopher's Hospital for Children, 2600 N Lawrence
St, Philadelphia, PA 19133.
defined, though splenomegaly, anemia, and neurological abnormalities are often present during the first
decade of life. All forms appear to be caused by a
deficiency of glucosylceramide P-glucosidase (EC activity resulting in t h e storage of glucosylceramide in organs. Glucosylceramide is derived from
the degradation of larger glycosphingolipids such as
gangliosides in brain and viscera, lactosylceramide in
white blood cells and blood group glycosphingolipids,
and globoside of red blood cells.
We describe 2 related children with subacute
neuronopathic Gaucher disease in whom t h e clinical
course suggested different entities.
Leukocytes were prepared from 4 to 10 ml of heparinized
blood using 3 % dextran according to the method of Skoog
and Beck [8]. All leukocyte pellets were frozen after preparation even if they were scheduled for immediate assay.
Fibroblasts were cultured from a forearm skin biopsy in
minimal essential media supplemented with 15% fetal calf
serum. After at least three days of confluency the cells were
harvested by scraping, and the pellets were frozen before
The leukocyte and fibroblast pellets were thawed and
homogenized in distilled water in a Dual1 homogenizer to a
protein concentration of 0.8 to 2 mgper milliliter. The exact
protein concentration was determined by the method
of Lowry and associates [7]. Glucosylceramide and
activities were assayed as described previously [9]. All activities are expressed as nanomoles per milligram of protein per
hour and are the average of at least two determinations. All
samples were obtained with informed consent. The use of
fluorogenic substrate and leukocyte samples to identify patients and carriers of Gaucher disease is described elsewhere
in detail [lo].
Case Reports
Patient 1
A 31-month-old white girl had been born of unrelated
parents after a normal gestation. She acquired motor skills
slowly but regularly until 10 months of age, when development stopped. Spasticity and gaze apraxia were present.
Ocular motility was intact, but visual pursuit could be accomplished only by interruption of fixation and a compensatory head turn. Smooth saccadic ocular movement was
present when the patient attempted to discover the source
of a familiar sound. An electroencephalogram, skull roentgenogram and bone age, examination of spinal fluid, and
standard blood tests were unremarkable. Six months later,
defects included bilateral sixth nerve paresis, hepatosplenomegaly, and recurrent stridor with pneumonias, seizures, myoclonus, and spasticity. The EEG
contained a multifocal spike-wave discharge. Numerous
Gaucher cells were noted in a bone marrow aspirate, and a
deficiency of fi-glucosidase activity was demonstrated in
white blood cells and skin fibroblasts (Table).
0364-5 134/78/0003-0315$01.00 @ 1978 by the American Neurological Association 281
PGlucosihse Activity in Leukocytes and Cultured Skin Fibroblasts
Substrate (nmoledmg proteidhr)
Gaucher obligate heterozygotes
Patient 1
Mother of Patient 1
Father of Patient 1
Patient 2
Mother of Patient 2
Father of Patient 2
Fibroblast cultures
Gaucher obligate heterozygotes
10.61 (N = 20)
1.64 (N = 9)
6.48 (N = 5)
410.25 (N = 35)
29.00 (N = 10)
211.60 (N = 5)
8.49 (N = 82)
1.15 (N = 12)
4.84 ( N = 13)
310.00 (N = 25)
28.53 (N = 7 )
181.84 (N = 6)
5 1.46
Patient 1
Patient 2
Glc-Cer = glucosylceramide; 4-MU-P-Glc = 4-methylumbelliferyl-~-~~ucopyranoside;
N = number of individual subjects.
Patient 2
A 10-year-old girl, second cousin of Patient 1, was born to
unrelated parents and developed normally in the first two
years of life. Over the next eight years, she developed slowly
progressive neurological signs beginning as ataxia with mild
spasticity and evolving to choreoathetoid movements. At
age 4, she was noted to have comitant internal strabismus
which progressed to ocular dyspraxia similar to that in Patient l, and later to complete supranuclear ophthalmoplegia.
Staring spells began at 4 years of age and were followed by
kinetic and myoclonic seizures. Gradually a segmental
myoclonus appeared and progressed to produce continuous,
asynchronous movements of extremities, face, tongue, and
palate, precluding speech and self care. Dementia has not
been a prominent sign, and psychometric testing at age 8
years revealed an IQ of 80. No organomegaly or abnormality of the optic fundus has been noted.
Normal laboratory studies included cerebrospinal fluid
protein and electrophoresis, pneumoencephalogram (age
3), bone survey (age 8), and an appendiceal biopsy
studied by light and electron microscopy (age 6). A frontal
cerebral biopsy [age 8) revealed only slight perivascular
fibrosis with enmeshed gitter cells. No storage material was
identified, and myelin sheaths were well preserved. A
number of electroencephalograms were obtained throughout the disease course and evolved from a normal record at
age 3 to nearly continuous multifocal spikes and waves in
later years. Electroretinography (age 6) demonstrated small
potentials in the first 50 msec, suggesting a retinopathy.
Only one Gaucher cell was noted in several bone marrow
aspirates. The serum acid phosphatase value was mildly
elevated (total, 16 mU/ml; normal, 0-11; prostatic acid
phosphatase, 4.6 mU/ml; normal, 0-4). Because the diagnosis of Gaucher disease was established in her second
cousin, enzyme studies were obtained which demonstrated a
Annals of Neurology Vol 3
N o 3 March 1978
deficiency of P-glucosidase activity in leukocyte and cultured skin fibroblasts (Table).
The neurological findings and clinical course of our
patients are similar to those in families described by
Herrlin and Hillborg [ 3 ] . In Patient 1 the documentation of spasticity, cranial nerve dysfunction, and organomegaly suggested the acute neuronopathic form.
However, the prolonged course, myoclonus, and seizures indicated subacute neuronopathic Gaucher disease. Both patients demonstrated short-amplitude,
asymmetrical, rapid jerks of extremities, trunk, and
face that complicated ambulation, vocalization, and
feeding. The severity of the motor disability contrasts
with the relative preservation of intellectual function.
The myoclonus is similar to that found in other
neurodegenerative diseases including neuronal ceroid
lipofuchsinosis [ 13, Ramsey Hunt syndrome 141,
myoclonic epilepsies [2], subacute sclerosing
panencephalitis [ 5 ] , and myoclonic encephalopathy
161. These diseases could be readily excluded, however, by aspects of the patient’s history and clinical
course and results of neurological and ophthalmologic
examination, the EEG,and lysosomal hydrolase measurement.
Data obtained from investigation of our patients
have further defined the biochemical genetics of subacute neuronopathic Gaucher disease. O n e of us
(D. A. W.) has diagnosed more than 30 patients with all
types of Gaucher disease. All these patients have had a
marked deficiency of glucocerebrosidase activity. The
enzyme values in the 2 patients reported here are
similar to those obtained for all types of Gaucher
disease. The same deficiency of P-glucosidase activity
is found in all the clinical subtypes of this disease.
Other lysosomal enzyme determinations including
hexosaminidase A and B, a-fucosidase, P-galactosidase, a-mannosidase, arylsulfatase A, and
sphingomyelinase were in the normal range in both
patients. Both parents of Patient 1 had P-glucosidase
values in leukocytes consistent with the carrier state
for Gaucher disease (see the Table). The father of
Patient 2, a first cousin of the father of Patient 1, also
had leukocyte P-glucosidase levels in the carrier range
(Table). The mother of Patient 2 had P-glucosidase
values in the normal range when the natural substrate
was used and in the low-normal range when the synthetic substrate was used in the presence of detergents (Table). It is hypothesized that she may have a
different mutation for subacute neuronopathic
Gaucher disease, which would explain the variation in
clinical signs between the 2 patients and would make
Patient 2 a compound heterozygote. It is less likely
that the mother may have produced a gamete with a
mutation at the locus producing P-glucosidase.
Supported in part by National Institutes of Health Training Grant I
TO1 N S 1007201A2 and Grants HD 07773, HD 10494. and N S
10698; General CRC Grants RR-75, RR-5624; and the National
Foundation-March of Dimes. Dr Wenger is a recipient of Research
Career Development Award I KO4 NS 00108.
Presented in part at the American Association ofNeurology, 1977.
The authors wish to acknowledge the contribution of Dr H. Punnett
and Dr N. Brodsky in obtaining fibroblast cultures.
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and symptomatology of the cerebellum. Brain 44:490-538.
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Neurosurg Psychiatry 25:27 1-276, 1962
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8. Skoog WA, Beck WS: Studies of the fibrinogen, dextran and
phytohemagglutinin method of isolating leukocytes. Blood
9. Wenger DA, Sanler M, Clark C, et al: I-cell disease: activities
of lysosomal enzymes toward natural and synthetic substrates.
Life Sci 19:413-420, 1976
10. Wenger DA, Clark C, Sattler M, et al: Synthetic substme
8-glucosidase activity in leucocytes: a reproducible method for
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Clin Genet (in press)
Case Report: Grover et al: Variations in Neuronopathic Gaucher Disease 283
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neuronopathic, clinical, variation, disease, children, related, gaucher
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