Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases

P. Labauge, L. Horzinski, X. Ayrignac, P. Blanc, S. Vukusic, D. Rodriguez, F. Mauguiere, L. Peter, C. Goizet, F. Bouhour, C. Denier, C. Confavreux, M. Obadia, F. Blanc, J. d. Seze, A. Fogli, O. Boespflug-Tanguy
Brain. 2009-07-22; 132(8): 2161-2169
DOI: 10.1093/BRAIN/AWP171

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1. Brain. 2009 Aug;132(Pt 8):2161-9. doi: 10.1093/brain/awp171.

Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of
16 cases.

Labauge P(1), Horzinski L, Ayrignac X, Blanc P, Vukusic S, Rodriguez D, Mauguiere
F, Peter L, Goizet C, Bouhour F, Denier C, Confavreux C, Obadia M, Blanc F, de
Sèze J, Fogli A, Boespflug-Tanguy O.

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

Mutations in one of the five eukaryotic initiation factor 2B genes (EIF2B1-5)
were first described in childhood ataxia with cerebral hypomyelination–vanishing
white matter syndrome. The syndrome is characterized by (i) cerebellar and
pyramidal signs in children aged 2-5 years; (ii) extensive cavitating
leucoencephalopathy; and (iii) episodes of rapid deterioration following stress.
Since then a broad clinical spectrum from congenital to adult-onset forms has
been reported, 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
(after age 16). 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 (age 16 years) was also included. Clinical and magnetic
resonance findings were retrospectively recorded in all patients. All patients
were examined to assess clinical evolution, using functional, pyramidal,
cerebellar and cognitive scales. This multi-centric study included 16 patients
from 14 families. A sex ratio imbalance was noted (male/female = 3/13). The mean
age of onset was 31.1 years (range 16-62). Initial symptoms were neurologic (n =
11), psychiatric (n = 2) and ovarian failure (n = 2). Onset of the symptoms was
linked to a precipitating factor in 13% of cases that included minor head trauma
and delivery. During follow-up (mean: 11.2 years, range 2-22 years) 12.5% of the
patients died. Of the 14 survivors, 62% showed a decline in their cognitive
functions, and 79% were severely handicapped or bedridden. One case remained
asymptomatic. Stress worsened clinical symptoms in 38% of the patients. Magnetic
resonance imaging findings consist of constant cerebral atrophy, extensive cystic
leucoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted
hyperintensities. All families except one showed mutations in the EIF2B5 gene.
The recurrent p.Arg113His-eIF2Bepsilon mutation was found in 79% of the 14
eIF2B-mutated families, mainly at a homozygous state. The family with a mutation
in EIF2B2 had the relatively prevalent p.Glu213Gly mutation. eIF2B-related
disorder is probably underestimated as an adult-onset inherited
leucoencephalopathy. In this late-onset form, presentation ranges from neurologic
symptoms to psychiatric manifestations or primary ovarian failure. Cerebral
atrophy is constant, whereas the typical vanishing of the white matter can be
absent. Functional and/or cognitive prognosis remains severe. Molecular diagnosis
is facilitated for these forms by the screening of the two recurrent
p.Arg113His-eIF2Bepsilon and p.Glu213Gly-eIF2Bbeta mutations, positive in 86% of

DOI: 10.1093/brain/awp171
PMID: 19625339 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus