title: [Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases].
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service de Neurologie, Hôpital Caremeau, CHU de Montpellier-Nîmes, Place du Professeur-Debré, 30029 Nîmes cedex 4, France.
authors.forename: C
authors.initials: C
authors.lastname: Carra-Dalliere
authors.forename: L
authors.initials: L
authors.lastname: Horzinski
authors.forename: X
authors.initials: X
authors.lastname: Ayrignac
authors.forename: S
authors.initials: S
authors.lastname: Vukusic
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez
authors.forename: F
authors.initials: F
authors.lastname: Mauguiere
authors.forename: L
authors.initials: L
authors.lastname: Peter
authors.forename: C
authors.initials: C
authors.lastname: Goizet
authors.forename: F
authors.initials: F
authors.lastname: Bouhour
authors.forename: C
authors.initials: C
authors.lastname: Denier
authors.forename: C
authors.initials: C
authors.lastname: Confavreux
authors.forename: M
authors.initials: M
authors.lastname: Obadia
authors.forename: F
authors.initials: F
authors.lastname: Blanc
authors.forename: J
authors.initials: J
authors.lastname: de Seze
authors.forename: F
authors.initials: F
authors.lastname: Sedel
authors.forename: A-M
authors.initials: AM
authors.lastname: Guennoc
authors.forename: E
authors.initials: E
authors.lastname: Sartori
authors.forename: D
authors.initials: D
authors.lastname: Laplaud
authors.forename: J-C
authors.initials: JC
authors.lastname: Antoine
authors.forename: A
authors.initials: A
authors.lastname: Fogli
authors.forename: O
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: P
authors.initials: P
authors.lastname: Labauge
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D015331:Cohort Studies; D003625:Data Collection; D018450:Disease Progression; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D020717:Eukaryotic Initiation Factor-2B