Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases
1 CHU de Nîmes, Service de neurologie, Hôpital Caremeau, place du Professeur-Debré, 30029 Nîmes cedex 4, France 2 INSERM UMR931, CNRS 6247, Clermont Université, GRED, Faculté de médecine, 28 place Henri-Dunant, BP 38, 63001 Clermont-Ferrand cedex, France 3 CHU de Clermont-Ferrand, Service de biochimie médicale et biologie moléculaire, Faculté de médecine, 28 place Henri-Dunant, BP 38, 63001 Clermont-Ferrand cedex, France 4 Hôpital neurologique Pierre-Wertheimer, 59 boulevard Pinel 69677 Bron, France 5 APHP, Service de neuropédiatrie, Hôpital Armand-Trousseau 26 avenue du Dr Arnold-Netter, 75012 Paris 12, France 6 CHU de Bordeaux, Service de neurologie B, Hôpital Pellegrin-Tripode, place Amélie-Raba-Leon 33076 Bordeaux cedex, France 7 APHP, CHU Bicêtre, Service de neurologie, 78, rue du Général-Leclerc, Le Kremlin-Bicêtre, 94275 France 8 Fondation Ophtalmologique Rothschild, 119 rue Manin, 75019 Paris, France 9 Service de neurologie. CHU de Strasbourg, 67000 Strasbourg, France 10 CHU de Clermont-Ferrand, Service de génétique médicale, Centre de référence maladies rares leucodystrophies Hôtel-Dieu, boulevard Leon-Malfreyt, 63058 Clermont Ferrand, France
Correspondence to: Pierre Labauge, MD, PhD, Service de neurologie, CHU Nîmes, Hôpital, Caremeau, 2 avenue du Professeur-Debré 30029, Nîmes cedex 4, France E-mail: labauge{at}yahoo.fr
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-eIF2B
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-eIF2B and p.Glu213Gly-eIF2Bβ mutations, positive in 86% of cases.
Key Words: eIF2B-related disorders; CACH/VWM; adult-onset leucodystrophies
Abbreviations: CACH/VWM, childhood ataxia with cerebral hypomyelination—vanishing white matter; eIF2B, eukaryotic initiation factor 2B
Received March 8, 2009. Revised May 15, 2009. Accepted May 20, 2009.