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

INSERM UMR 384, Faculté de Médecine, Clermont-Ferrand, France.
Neurology (Impact Factor: 8.29). 06/2004; 62(9):1509-17. DOI: 10.1212/01.WNL.0000123259.67815.DB
Source: PubMed


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 · 9.20 Impact Factor
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    • "Epidemiological investigations have proved that the most prevalent mutations affect the eIF2B5 (57%), eIF2B4 (17%), and eIF2B2 (15%) genes.6,15 In 2004, Fogli et al26 studied 93 patients (78 families) and found that 89% of them had mutations in eIF2B1–5 genes; 64% of them had mutations affecting eIF2B5 and 71% of them had the R113H mutation, the most prevalent mutation. A larger series, reported in 2006 by Van der Knaap, studied 102 families, 69 of whom had mutations in eIF2B5, 18 in eIF2B2, 8 in eIF2B4, 5 in eIF2B3, and 2 in eIF2B1 genes.4 "
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    ABSTRACT: Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor (eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.
    Journal of Central Nervous System Disease 07/2014; 6:59-68. DOI:10.4137/JCNSD.S13540
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    • "EIF2B mutations have been subsequently observed in a wide clinical spectrum from congenital rapidly lethal forms to slowly progressive adult forms associated in some cases with ovarian failure [5]–[9]. A correlation between age at disease onset and disease severity has been established: disease onset <2, from 2 to 5 or >5 years are associated respectively to severe, classical or mild phenotypes [10]. "
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    ABSTRACT: Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains.
    PLoS ONE 06/2012; 7(6):e38264. DOI:10.1371/journal.pone.0038264 · 3.23 Impact Factor
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