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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DISCUSSION
Krabbe disease (also known as globoid cell leukodystrophy,
GCL; OMIM #245200) is a rare inherited
lysosomal storage disorder, with a pathology not
completely elucidated. It is caused by a deficiency
of β-GALC (E.C. 3.2.1.46), a lysosomal enzyme involved
in the catabolism of galactosylceramide. The
deficiency of β-GALC impairs the degradation of a
major myelin lipid, galactocerebroside with the subsequent
accumulation of a cytotoxic compound, galactosylsphingosine,
also called psychosine [4]. The
excess of galactosylceramide elicits the formation
of multinucleated macrophages, the globoid cells.
Progressive accumulation of psychosine could explain
the prominent death of oligodendrocytes, thus
contributing to progressive demyelination [5].
Krabbe disease is usually diagnosed before the
first year of life, because of the early onset of developmental
delay or regression, limb spasticity and
extreme irritability [2]. Optic atrophy and sluggish
pupillary reactions to light are common [2,6,7]. Children
with Krabbe disease generally experience severe
neurological deterioration and death before 2 years of
age, although prolonged survival has been reported.
Both index cases could be classified as infantile
onset globoid-cell leukodystrophy [2,5], with a disease
onset at 3.5 and 6 months of age, respectively,
and a rather typical constellation of clinical findings
(developmental delay with subsequent regression,
spasticity and optic atrophy) and neuroradiological
findings (deep white matter leuko-dystrophic alterations).
However, it is worth noticing that the second
patient’s brain MRI at presentation was deceptively
normal, a finding already reported in the literature
[8], underpinning the need for further biochemical
work-up, even in the absence of associated brain MRI
findings, in infants with unexplained developmental
delay and/or regression.
Multimodal evoked potentials in the early infantile
form of Krabbe disease are considerably abnormal
at pronounced stages of the disease [1,5,8]. In
both reported patients, brainstem auditory and visual
evoked potentials were normal at the age of diagnosis.
On the contrary, decreased NCVs of all examined
nerves (motor and sensory) was demonstrated, without
however reaching the markedly reduced values
observed in late infantile Krabbe disease [9]. To
the best of our knowledge, serial NCV findings in
early-infantile Krabbe disease have previously been
reported in another Greek case by Zafeiriou et al.
[8], while a mild increase in polyphasic motor unit
potentials, as demonstrated by electromyography,
was reported by Hogan et al. [10].
Most patients with Krabbe disease, irrespective
of type and age at onset, demonstrate a severe deficiency
in β-GALC activity, as measured in leukocytes
isolated from whole blood or alternatively in cultured
skin fibroblasts [11]. Since the cloning of the human
GALC gene on chromosome 14q31 in 1993 [2], over
130 mutations have been described [2,12]. Different
kinds of genetic alterations have been reported:
missense/nonsense mutations, deletions, splice mutations,
insertions and duplications [2]. According to
one of the largest genotypic analyses of the GALC
gene performed in a European cohort of patients
with Krabbe disease, the GALC mutational profile
in European patients differs from other cohorts; thus,
the most common large deletion, c.1161+6532 plus
three additional mutations [c.1586C>T, c.1700C>T,
c.1472delA (1538 C>T, 1652A>C, 1424delA)], together
account for about 60.0% of patients of European
origin with the classic infantile form [11].
In the index patients, the mutation analysis of
the GALC gene revealed two different mutations in
a homozygous state, the c.749T>C [p.I250T] mutation
and the c.411_413 delTAA [K139del] mutation.
A thorough literature search disclosed five patients
carrying the c.749T>C [p.I250T] mutation. In the first
of those patients, classified as having early infantile
Krabbe disease, the latter mutation was found in a
heterozygous state and associated with the rare find ing of optic nerve enlargement [13], as well as in two
other patients associated with neonatal and infantile
onset of the disease, respectively [12]. The above
mutation in homozygosity was associated with late
infantile Krabbe disease, in a female patient born to
consanguineous parents and manifesting with motor
regression and peripheral neuropathy [8,13], as well
as in four additional patients with early-onset disease
[10]. Interestingly, some of these patients were of
Greek ancestry [11,12], as our index cases.
Regarding the second mutation, the
c.411_413delTAA [K139del], it has recently been described
in two Greek siblings with late-onset slowly
progressive disease [12]. Moreover, the same mutation
has been described in a heterozygous state in an
adult patient of Turkish origin [5]. These data allow
the assumption that the latter mutation in a homozygous
state could be associated with more severe and
earlier-onset forms of the disease, while the heterozygous
state could be associated with a later-onset
and more protracted clinical course.
Further studies are needed in order to elucidate
the genetic landscape and the clinical importance
of specific mutations, as a genotype-phenotype correlation
relationship in Krabbe disease still remains
unclear. This would make it possible to be able to
offer more accurate genetic counseling and suggest
either prenatal diagnosis or pre-implantation genetics
to the affected families [14].
In conclusion, we have presented brain MRI,
neuro-physiological and genetic findings in two additional
Greek cases of early-infantile Krabbe disease.
The above report with the identified mutations add to
the pathogenic mutation database of the GALC gene
and may increase public awareness of Krabbe disease
in Greece and elsewhere. Genotyping of patients with
Krabbe disease is important, in order to contribute
to the development of a European mutation database
and to further study possible genotype-phenotype
correlations of the disease.
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