Leegwater, P. A., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulder, J. & Visser, A. et al. Subunits of translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat. Genet. 29, 383-388

Department of Child Neurology, Free University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 01/2002; 29(4):383-8. DOI: 10.1038/ng764
Source: PubMed


Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.

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Available from: Richard Lemmers, May 12, 2014
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    • "Once in a child was found a mutation, genetic family testing was performed. Sequencing of primers is described elsewhere.20 "
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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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    • "Mutations of the PERK kinase that regulates eIF2 activity cause the Wolcott-Rallison Syndrome (WRS), a form of permanent diabetes [182-184]. Increased levels of eIF4E are found in several cancers [185, 186], including colon adenoma and carcinoma [187], breast carcinoma [188, 189], non-Hodgkin’s lymphoma [190] and primary bladder cancer [191], and in chronic myeloid leukaemia, the expression of the RNA-binding protein hnRNP is abnormally high. Interestingly, hnRNP binds to the 5’ UTR of the CEBPA mRNA thereby inhibiting its translation [192]. "
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    ABSTRACT: Asthma and chronic obstructive pulmonary disease (COPD) are the two most prominent chronic inflammatory lung diseases with increasing prevalence. Both diseases are associated with mild or severe remodeling of the airways. In this review, we postulate that the pathologies of asthma and COPD may result from inadequate responses and/or a deregulated balance of a group of cell differentiation regulating factors, the CCAAT/Enhancer Binding Proteins (C/EBPs). In addition, we will argue that the exposure to environmental factors, such as house dust mite and cigarette smoke, changes the response of C/EBPs and are different in diseased cells. These novel insights may lead to a better understanding of the etiology of the diseases and may provide new aspects for therapies.
    The Open Respiratory Medicine Journal 04/2012; 6(1):1-13. DOI:10.2174/1874306401206010001
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    • "It is a progressive disorder with episodes of rapid and major neurological deterioration induced by stresses, such as fever and minor head trauma [1] [3]. Mutations in one of the five gene subunits encoding the eukaryotic translation initiation factor eIF2B cause the disease [5]. An extremely wide phenotypic variation is known. "
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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 · 2.47 Impact Factor
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