Natural history of adult-onset eIF2B-related disorders: A multicentric survey of 24 cases

C. Carra-Dalliere, L. Horzinski, X. Ayrignac, S. Vukusic, D. Rodriguez, F. Mauguiere, L. Peter, C. Goizet, F. Bouhour, C. Denier, C. Confavreux, M. Obadia, F. Blanc, J. de Seze, F. Sedel, A.-M. Guennoc, E. Sartori, D. Laplaud, J.-C. Antoine, A. Fogli, O. Boespflug-Tanguy, P. Labauge
Revue Neurologique. 2011-11-01; 167(11): 802-811
DOI: 10.1016/J.NEUROL.2011.03.008

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1. Rev Neurol (Paris). 2011 Nov;167(11):802-11. doi: 10.1016/j.neurol.2011.03.008.
Epub 2011 Jun 14.

[Natural history of adult-onset eIF2B-related disorders: a multicentric survey of
24 cases].

[Article in French]

Carra-Dalliere C(1), Horzinski L, Ayrignac X, Vukusic S, Rodriguez D, Mauguiere
F, Peter L, Goizet C, Bouhour F, Denier C, Confavreux C, Obadia M, Blanc F, de
Seze J, Sedel F, Guennoc AM, Sartori E, Laplaud D, Antoine JC, Fogli A,
Boespflug-Tanguy O, Labauge P.

Author information:
(1)Service de Neurologie, Hôpital Caremeau, CHU de Montpellier-Nîmes, Place du
Professeur-Debré, 30029 Nîmes cedex 4, France.

INTRODUCTION: The childhood ataxia with central nervous system
hypomyelination-vanishing white matter syndrome (CACH-VWM) was first
characterized in children (2-5 years) on clinical and MRI criteria:
cerebellospastic signs associated with episodes of rapid deterioration following
stress and extensive cavitatingleucoencephalopathy. Causative mutations were
found in the five genes encoding the subunits of the eukaryotic initiation
factor 2B (eIF2B), involved in protein synthesis and its regulation under
cellular stresses. A broad clinical spectrum has been subsequently described from
congenital to adult-onset forms leading to the concept of eIF2B-related
disorders. Our aim was to describe clinical and brain magnetic resonance imaging
characteristics, genetic findings and natural history of patients with
adult-onset eIF2B-related disorders.
METHODS: The inclusion criteria were based on the presence of EIF2B mutations and
a disease onset after the age of 16 years. One patient with an asymptomatic
diagnosis was also included. Clinical and MRI findings were retrospectively
recorded in all patients. This multicentric study included 24 patients from
22 families.
RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of
onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20),
psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years,
range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline
in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case
remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients.
Magnetic resonance imaging findings consisted of cerebral atrophy (92%),
extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and
cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed
mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found
at a homozygous state in 58% of the 24 eIF2B-mutated patients.
CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset
inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical
vanishing of the white matter can be absent. Functional and cognitive prognosis
remains severe. Molecular diagnosis is facilitated for these forms by screening
for the recurrent p.Arg113His-eIF2Be mutation.

Copyright © 2011 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.neurol.2011.03.008
PMID: 21676421 [Indexed for MEDLINE]

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