NEURORADIOLOGICAL, NEUROPHYSIOLOGICAL AND
MOLECULAR FINDINGS IN INFANTILE KRABBE DISEASE:
TWO CASE REPORTS
Vargiami E, Papathanasiou E, Batzios S, Kyriazi M, Dimitriou E,
Anastasiou A, Michelakakis H, Giese A-K, Zafeiriou DI,
*Corresponding Author: Dimitrios I. Zafeiriou, M.D., Ph.D., Professor in Child Neurology and Developmental
Pediatrics, 1st Department of Pediatrics, Aristotle University of Thessaloniki, Egnatia St. 106, 54622 Thessaloniki,
Greece. Tel./Fax: +30-2310-241-845. Mobile: +30-6944-330-587. E-mail: jeff@med.auth.gr
page: 85
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INTRODUCTION
Krabbe disease or globoid-cell leukodystrophy,
is an autosomal recessive lysosomal disorder that affects
the white matter of both central and peripheral
nervous systems. It is the result of a deficiency of
the lysosomal enzyme β-galactocerebrosidase (galactosylceramidase,
β-GALC or, in very few cases,
it is due to lack of activator saposin A (sphingolipid
activator protein) [1-3]. The gene encoding β-GALC
has been mapped to 14q31. This gene, located on
chromosome 14q31, encodes the β-GALC protein,
which has a hydrolase function critical for glycosphingolipid
catabolism. To date, more than 130
mutations of the GALC gene have been listed in the
Human Gene Mutation Database (HGMD) [1-3]. The early infantile form of the Krabbe disease is the most
common (85.0-90.0% of all cases), with onset in the
early infantile period (before the age of 6 months),
and a clinical picture characterized by hyperirritability
and psychomotor deterioration often associated
with episodes of fever, while many patients develop
peripheral neuropathy with decreased nerve conduction
velocities (NCVs) [1-3]. We report clinical,
neuroradiological, neurophysiological and molecular
findings of two Greek patients with the infantile form
of Krabbe disease.
Case Reports. The first patient was admitted at
the age of 3.5 months, due to generalized hypertonia.
He is the fourth child of healthy, non consanguineous
parents of Caucasian origin. One of his siblings,
a male infant died at the age of 7 months, presumably
due to cerebral atrophy and epilepsy, without a
specific diagnosis. The other two siblings are healthy
females, 13 and 8 years old, respectively.
The patient was delivered normally after an uneventful
gestation at 40 weeks. Generalized hypertonia
was evident already from the first month of life,
according to the family pediatrician.
Physical examination on admission revealed
short stature (below the 3rd percentile), severe hypertonia
of all extremities, absence of head control,
opisthotonus, fisted hands and pyramidal tract signs
with increased deep tendon reflexes, positive Rossolimo
reflexes and clonus bilaterally. Additionally,
a mild convergent squint was noted, with normal
reaction to visual and auditory stimuli.
Magnetic resonance imaging (MRI) of the patient’s
brain demonstrated abnormal signal of the
deep white matter of the cerebellum, the middle cerebellar
peduncles and probably the pyramidal tracts
of the medulla oblongata. Additionally, there was a
mild enlargement of the subarachnoid spaces and
an increased signal of the posterior limbs of the internal
capsule bilaterally and the white matter of the
occipital lobes (Figure 1). Electroencephalogram,
visual and brainstem auditory evoked potentials,
demonstrated normal findings. Both motor and sensory
NCVs were significantly decreased (Table 1)
with normal compound action potentials, suggestive
of demyelination.
Cerebrospinal fluid (CSF) protein was clearly elevated
(80 mg/dL; normal values <10). A subsequent
screening for lysosomal enzymes in leukocytes (at the
Department of Enzymology, Institute of Child Health,
Athens, Greece) demonstrated increased chitotriosidase
activity (1566 nmol/mL/ hour, normal range 0-150) and a severe reduction of β-GALC activity
(0.003 nmol/mg protein/hour, normal range 0.1-0.97),
whereas the activities of α-Ν-acetylglycosaminidase,
β-galactosidase and β-hexosaminidase were normal.
The above biochemical findings were suggestive
of Krabbe disease, a diagnosis that was confirmed
by molecular genetic testing (at the Department of
Genetics, Universitat de Barcelona & Neurogenetics,
Barcelona, Spain, and the Metabolic Disorders
Unit, University of Rostock, Rostock, Germany).
The latter revealed a homozygous c.411_413 delTAA
[p.K139del] deletion on the GALC gene.
The patient’s further course was downhill with
further deterioration. At the last follow-up visit at the
age of 4 years, he was bed-ridden and quadriplegic,
suffering from frequent infections of the respiratory
tract and fed through a gastrostomy catheter. Moreover,
he demonstrated uncoordinated eye movements
without visual contact.
The second patient was transferred to a tertiary
pediatric hospital at the age of 18 months, due to generalized
hypertonia and seizures. He is the only child
of healthy, non consanguineous parents of Caucasian
origin delivered normally after an uneventful 40
weeks’ gestation. His psychomotor development was
normal until the age of 6 months, when he started deteriorating
in terms of motor skills, and 4 months later,
a generalized hypertonia was evident. The brain MRI
showed mild enlargement of both Sylvian fissures, the
subarachnoid spaces of the frontal convexities and
the interhemispheric fissure, as well as an increased
signal of the periventricular white matter. According
to the neuroradiologist, the constellation of the above
findings were compatible with a delayed myelination;
however, the possibility of a leukoencephalopathy
could not be entirely ruled out. Due to the above findings,
physical and occupational therapy were initiated.
At the age of 18 months, he manifested a generalized
status epilepticus. On admission he was febrile,
somnolent and had mild respiratory distress.
Physical examination revealed tonsillitis. Kernig
and Brudzinski signs were negative. Neurological
examination revealed generalized hypertonia with
fisted hands, absent pupillary light reflex, response
solely to painful stimuli, nystagmus, increased deep
tendon reflexes, positive Babinski sign, Rossolimo
reflex and clonus bilaterally.
Examination of the fundus revealed nonresponsive
pupils without papilledema, while the electroencephalogram
disclosed multifocal spikes and sharp waves.
Brainstem auditory evoked and visual evoked potentials
were normal. Motor and sensory NCVs were significantly
delayed with normal compound action potentials,
consistent with peripheral demyelination (Table 1).
A repeated brain MRI performed at the time
(Figure 2), demonstrated increased signal of the
white matter around the occipital horns of the lateral
ventricles with enlargement of lateral ventricles and
the subarachnoid spaces bilaterally. These lesions of
the white matter expanded radially, while additional
small lesions in the anterior fiber bundles of the pons
and the brainstem.
Cerebrospinal fluid protein at that time point was
clearly elevated (110 mg/dL; normal values <10).
A subsequent screening for lysosomal enzymes in
leukocytes (at the Department of Enzymology, Institute
of Child Health, Athens, Greece) demonstrated
mildly increased chitotriosidase activity (217 nmol/nl/
hour, normal range 0-150) and a total lack of β-GALC
activity (0.00 nmol/mg protein/hr, normal range 0.1-
0.97), whereas the activities of arylsulphatase A,
β-galactosidase and β-hexosaminidase were normal.
The total lack of β-GALC activity was confirmed
in a second assay, thus pointing to the diagnosis of
Krabbe disease. The final diagnosis was established
by further molecular genetic testing (at the Department
of Genetics, Universitat de Barcelona & Neurogenetics,
Barcelona, Spain, and the Metabolic Disorders
Unit, University of Rostock, Rostock, Germany),
which revealed the presence of the a homozygous
p.I250T (c.749T>C) mutation on the GALC gene,
with both parents being carriers.
On follow-up at 6 years of age, the patient was
bedridden and quadriplegic with optic atrophy and
contractures of the lower extremities, despite receiving
regular physical therapy. His seizure disorder was
well controlled under treatment with levatiracetam.
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