title: Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases.
abstract: 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 cases.
authors.affiliation: CHU Nîmes, Service de neurologie, Hôpital Caremeau, place du Professeur-Debré, 30029 Nîmes cedex 4, France. labauge@yahoo.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.forename: Laetitia
authors.initials: L
authors.lastname: Horzinski
authors.forename: Xavier
authors.initials: X
authors.lastname: Ayrignac
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanc
authors.forename: Sandra
authors.initials: S
authors.lastname: Vukusic
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Francois
authors.initials: F
authors.lastname: Mauguiere
authors.forename: Laure
authors.initials: L
authors.lastname: Peter
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Francoise
authors.initials: F
authors.lastname: Bouhour
authors.forename: Christian
authors.initials: C
authors.lastname: Denier
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Michael
authors.initials: M
authors.lastname: Obadia
authors.forename: Frederic
authors.initials: F
authors.lastname: Blanc
authors.forename: Jérome
authors.initials: J
authors.lastname: de Sèze
authors.forename: Anne
authors.initials: A
authors.lastname: Fogli
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D006259:Craniocerebral Trauma / Q000150:complications; D018450:Disease Progression; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016649:Primary Ovarian Insufficiency / Q000209:etiology; D011379:Prognosis; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D020717:Eukaryotic Initiation Factor-2B