вход по аккаунту


Autosomal dominant leukodystrophy and childhood ataxia with central nervous system hypomyelination syndrome.

код для вставкиСкачать
Autosomal Dominant Leukodystrophy and
Childhood Ataxia with Central Nervous System
Hypomyelination Syndrome
Pierre Labauge, MD, PhD,1 Antoinette Gelot, MD, PhD,2
Anne Fogli, PhD,3 Odile Boespflug-Tanguy, MD, PhD,3
and Diana Rodriguez, MD, PhD2,4
We read with interest the comments of Ptacek and colleagues1 and van der Knaap and Scheper,2 which highlight
the difficulties in the delineation of the heterogeneous group
of leukodystrophies of unknown origin. In the absence of an
identifiable cause, white matter disorders are classified according to their clinical presentation, mode of inheritance,
magnetic resonance imaging pattern, and neuropathological
characteristics. Using these criteria, childhood ataxia with
central nervous system hypomyelination or vanishing white
matter disease (CACH/VWM) was recognized as a new entity and was shown to be associated with recessive mutations
in the five genes coding for the eIF2B subunits. In the family
we recently reported,3 the patients fulfilled the main diagnostic criteria of CACH/VWM: (1) acute episodes of clinical
deterioration after minor infections or head trauma, (2) vanishing white matter on magnetic resonance imaging and, (3)
increased density of oligodendrocytes with “foamy” cytoplasm and abnormal astrocytes on histological analysis. However, our patients differed from CACH/VWM in the mode
of inheritance and the presence of an unusual hypointense
periventricular rim on T2-weighted images. As van der
Knaap and Scheper2 pointed out and as in our previous
work,4 in 10 to 20% of patients fulfilling CACH/VWM diagnosis criteria, EIF2B gene mutations are not identified and
guanine nucleotide exchange factor activity (GEF) activity of
the eIF2B factor in lymphocytes is normal, suggesting the
involvement of other genes. Several entities have been reported as autosomal dominant forms of leukodystrophies of
unknown cause, including the autosomal dominant leukodystrophy linked to chromosome 5q31 (ADLD) that Ptacek’s group described,5 pigmentary orthochromatic leukodystrophy, and adult-onset leukodystrophy with neuroaxonal
spheroids. We discussed the similarities between dominant
forms of pigmentary orthochromatic leukodystrophy
(POLD) and our patients. We agree with Ptacek and colleagues1 that the “preservation of oligodendrocytes, a peculiar
lack of gliosis, and highly abnormal morphology of astrocytes” present in our patient have been described in both
ADLD and CACH/VWM syndromes. However, our patients lack the early autonomic abnormalities characteristic of
ADLD. In addition, to our knowledge, acute episodes of
neurological deterioration, diffuse involvement of the white
matter with cavitations on magnetic resonance imaging, and
foamy oligodendrocytes have not been reported in ADLD
patients. Unfortunately, linkage to chromosome 5q31 could
not be analyzed in our family. Finally, this report illustrates
the overlap that exists among these well-characterized clinical
entities (CACH/VWM, pigmentary orthochromatic leukodystrophy, and ADLD). The identification of the molecular
defect will help in disease classification. Finally, the broad
clinical spectrum of eIF2B-related disorders4 warrants first to
rule out involvement of these five genes when the corre-
sponding genomic region has not been excluded by linkage
Service de Neurologie, Centre Hospitalo Universitaire,
Montpellier-Nı̂mes, Hôpital Caremeau, Nı̂mes, 2Service de
Neuropédiatrie, Hôpital Armand Trousseau, Paris, 3Institut
National de la Sante et de la Recherche Médicale UMR 384,
Faculté de Médecine, Clermont Ferrand, and 4Institut
National de la Sante et de la Recherche Médicale UMR S
546, Faculté de Médecine Pitié Salpétrière, Paris, France
1. Ptacek LJ, Fu Y-H, Koeppen A. The dominant form of vanishing white matter–like leukoencephalopathy represents autosomal
dominant leukodystrophy. Ann Neurol 2006;59:434.
2. van der Knaap MS, Scheper GC. Non-eIF2B–related cystic leukoencephalopathy of unknown origin. Ann Neurol 2006;59:
3. Labauge P, Fogli A, Castelnovo G, et al. Dominant form of vanishing white matter-like leukoencephalopathy (CACH/VWM).
Ann Neurol 2005;58:634 – 639.
4. Fogli A, Schiffmann R, Bertini E, et al. The effect of genotype
on the natural history of eIF2B-related leukodystrophies. Neurology 2004;62:1509 –1517.
5. Coffeen CM, McKenna CE, Koeppen AH, et al. Genetic localization of an autosomal dominant leukodystrophy mimicking
chronic multiple sclerosis to chromosome 5q31. Hum Mol
Genet 2000;9:787–793.
DOI: 10.1002/ana.20930
Positive Genetic Analysis Provides the Ultimate
Diagnostic Confirmation
Marjo S. van der Knaap, MD, PhD, and
Gert C. Scheper, PhD
Whereas vanishing white matter/childhood ataxia with central hypomyelination (VWM/CACH) was initially defined
by clinical and magnetic resonance imaging (MRI) findings,1
as Labauge and colleagues also explained in their letter in this
issue, this changed when it was shown that VWM/CACH is
caused by mutations in any of the five genes encoding translation initiation factor eIF2B (EIF2B1-5).2 Since that, the
ultimate confirmation that a patient is suffering from VWM/
CACH comes from positive findings in genetic analysis.
We do not share the experience that in 10 to 20% of the
patients fulfilling the initial clinical and MRI criteria for
VWM/CACH no mutations are found in the genes EIF2B15.3 As explained in a review on the subject,3 we performed
DNA analysis in patients from 134 families and found mutations in EIF2B1-5 in patients from 102 families, almost
invariably associated with typical clinical and MRI findings.
In only 2 patients from 2 of the remaining 32 families did
we classify the MRI findings as typical for VWM/CACH
and did we not find mutations. The patients of all other 30
families had atypical MRI findings. A hypointense periventricular rim on T2-weighted images is not part of the initial
MRI criteria.1 We would, therefore, classify the MRI of the
patient who Labauge and colleagues4 described as atypical
and would not be surprised by the negative mutational analysis of EIF2B1-5.
Our most important point is that speaking of “a domi-
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Без категории
Размер файла
43 Кб
autosomal, central, ataxia, nervous, hypomyelination, syndrome, dominantly, leukodystrophy, childhood, system
Пожаловаться на содержимое документа