Genetic and clinical heterogeneity in eIF2B-related disorder.

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA.
Journal of Child Neurology (Impact Factor: 1.67). 03/2008; 23(2):205-15. DOI: 10.1177/0883073807308705
Source: PubMed

ABSTRACT Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.

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    ABSTRACT: Background Vanishing white matter disease (VWMD) is caused by EIF2B (Eukaryotic Translation Initiation Factor 2B) mutation and is a prevalent cause of inherited childhood leucencephalopathy. Infantile and early-childhood onset forms are associated with chronic progressive neurological symptoms with episodes of rapid, neurological worsening and poor prognosis with death in few months or years. In contrast onset in late-childhood and adult onset is rare, and is associated with long-term survival due to milder symptoms and slow progression. Patient description We report a patient with a genetically proven VWMD, typical brain magnetic resonance imaging, presenting with opsoclonus myoclonus in early-childhood and a delayed development of adult multifocal dystonia and schizoaffective disorder with continued survival. In addition we have also reviewed the relevant literature based on 42 previous papers summarising clinical details of 318 individuals with VWMD (single case reports to case series). In 283, genetic mutation of EIF2B was confirmed with the onset of VWMD reported as antenatal (7), infantile (8), early-childhood (107), in between infantile and early-childhood (20), late-childhood (25), in between early- and late-childhood (3), adult (68), in between late-childhood and adult (21). Conclusions A range of movement disorders as a predominant symptom of VWMD either at presentation (mimicking an opsoclonus myoclonus syndrome) or in adulthood (dystonia and myoclonus) with continuing survival and relatively preserved cognition is a novel presentation and is reported in this paper along with a comprehensive literature review.
    Pediatric Neurology 07/2014; · 1.50 Impact Factor
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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.
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