The effect of genotype on the natural history of eIF2B-related leukodystrophies

INSERM UMR 384, Faculté de Médecine, Clermont-Ferrand, France.
Neurology (Impact Factor: 8.3). 06/2004; 62(9):1509-17. DOI: 10.1212/01.WNL.0000123259.67815.DB
Source: PubMed

ABSTRACT Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity.
To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation.
Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis.
Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms.
The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.

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    • "In Group 2, screening of the EIF2B1–5 genes causing the childhood ataxia with CNS hypomyelination disease was systematic (Fogli et al., 2004). "
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    ABSTRACT: Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 12/2014; 138(2). DOI:10.1093/brain/awu353 · 10.23 Impact Factor
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    • "It can be difficult to recognize since clinical presentation comprises a wide range of phenotypes, including seizures, psychiatric symptoms, dementia or motor deterioration [6] [8]. Clinical course is usually more protracted, but sudden deterioration may occur [6] [7]. "
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    ABSTRACT: BACKGROUND: Vanishing white matter is an inherited leukoencephalopathy with typical childhood onset. Late onset forms are rare and may present with an extended range of phenotypes. Case report We present a patient born to consanguineous parents who developed learning disabilities by the age of 16 years. At the age of 25 she had a focal motor seizure with subsequent hemiparesis. After an extensive investigation she was diagnosed and treated as multiple sclerosis. There was progressive memory and planning impairment and, six years later, Sjögren syndrome with central nervous system involvement was diagnosed. For six months she was treated with cyclophosphamide, without any improvement. The next two years she had major clinical deterioration following infections. A homozygous mutation was identified in the EIF2B5 gene at the age of 33, and she died a year later. CONCLUSIONS: VWM leukoencephalopathy is still largely recognized as a pediatric disorder, with many adult neurologists being unfamiliar with the late onset presentations. We wish to draw attention into these forms, avoiding submitting these patients to extensive workup and unnecessary treatments.
    Journal of the neurological sciences 11/2011; 314(1-2):169-70. DOI:10.1016/j.jns.2011.10.021 · 2.26 Impact Factor
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    • "Magnetic Resonance Images of patients with VWM show a diffuse leukoencephalopathy with evidence of progressive disappearance of the cerebral white matter, which is seen on MRI by signals approaching those of cerebrospinal fluid on all pulse sequences including protondensity and FLAIR sequences. Cavitating leukodistrophy has also been described, especially at the later stages of the disease, but this finding must not be considered a crucial exclusion diagnostic criteria [8]. Previous studies have reported cases of VWM in which MRI was strikingly similar to that observed in MS [9]. "
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