Leukoencephalopathy With Vanishing White Matter

Departments of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 10/2010; 69(10):987-96. DOI: 10.1097/NEN.0b013e3181f2eafa
Source: PubMed


Vanishing white matter (VWM) is one of the most prevalent inherited childhood leukoencephalopathies, but this may affect people of all ages, including neonates and adults. It is a progressive disorder clinically dominated by cerebellar ataxia and in which minor stress conditions, such as fever or mild trauma, provoke major episodes of neurologic deterioration. Typical pathological findings include increasing white matter rarefaction and cystic degeneration, oligodendrocytosis with highly characteristic foamy oligodendrocytes, meager astrogliosis with dysmorphic astrocytes, and loss of oligodendrocytes by apoptosis. Vanishing white matter is caused by mutations in any of the genes encoding the 5 subunits of the eukaryotic translation initiation factor 2B (eIF2B), EIF2B1 through EIF2B5. eIF2B is a ubiquitously expressed protein complex that plays a crucial role in regulating the rate of protein synthesis. Vanishing white matter mutations reduce the activity of eIF2B and impair its function to couple protein synthesis to the cellular demands in basal conditions and during stress. Reduced eIF2B activity leads to sustained improper activation of the unfolded protein response, resulting in concomitant expression of proliferation, prosurvival, and proapoptotic downstream effectors. Consequently, VWM cells are constitutively predisposed and hyperreactive to stress. In view of the fact that VWM genes are housekeeping genes, it is surprising that the disease is primarily a leukoencephalopathy. The pathophysiology of selective glial vulnerability in VWM remains poorly understood.

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    • "Whereas intellectual disability can be due to mutations in synaptic genes (Pavlowsky et al. 2012; Zoghbi and Bear 2012), recent studies have highlighted impairments of basal cellular functions and pathways such as transcription and translation in the etiology of cognitive disorders and neurogenetic syndromes (Najmabadi et al. 2011). Some examples include pontocerebellar hypoplasias, Pol III–related leukodystrophies, X-linked intellectual disability, and leukoencephalopathy with vanishing white matter (Bugiani et al. 2010; Namavar et al. 2011; Borck et al. 2012; Daoud et al. 2013). Complete inactivation of processes such as translation initiation or tRNA transcription is not compatible with life, suggesting that most disease-causing mutations are hypomorphs. "
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    ABSTRACT: RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development. © 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Jan 2015 · Genome Research
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    • "Vanishing white matter disease (VWMD), also known as childhood ataxia with central hypomyelination (CACH),1 is one of the most prevalent hereditary white matter diseases.2 It typically appears in a previously healthy child, and it produces a progressive neurological deterioration with some acute exacerbations in reaction to certain stimuli, such as infections, cranial trauma, and acute fright.3,4 "
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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.
    Full-text · Article · Jul 2014 · Journal of Central Nervous System Disease
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    • "Neuropathological features generally show increasing white matter rarefaction and cystic degeneration, absence of inflammatory signs, diffuse loss of myelin fibers, conservation of grey matter structures, meager astrogliosis with dysmorphic astrocytes , and abnormal, foamy oligodendrocytes [2]. VWMD is caused by mutations in each of the five genes encoding for the five subunits (EIF2B1-5) of eukaryotic translation initiation factor 2B (eIF2B), which is essential for protein synthesis [1] [2]. Because of the fact that EIF2B1-5 are housekeeping genes, many questions remain unanswered with respect to how perturbation of these ubiquitously expressed translation initiation factors should result in a highly selective neurological phenotype. "
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    ABSTRACT: We report a rare autopsy case of early infantile-onset vanishing white matter disease, with a submicroscopic deletion of 14q24.3, which included EIF2B2 and a missense mutation of EIF2B2 (V85E) of the remaining allele. The patient was a 4-year-old boy, who was found to have suddenly died during sleep. Physical and mental development began to deteriorate after convulsions at 10 month of age, and did not recover to baseline measurements. At autopsy, the brain showed a marked decrease in volume of white matter, with no typical cystic rarefaction. Histopathologically, the affected white matter showed diffuse loss of myelin fibers, meager astrogliosis with dysmorphic astrocytes, and loss of oligodendrocytes. Proliferative and apoptotic markers were negative for oligodendrocytes in the severely affected area. These findings may be related to the severity of the disease, and might be a feature of the EIF2B2 mutation pattern of the patient. Additionally, unusual fatty infiltration of both ventricles of the heart was found. These findings were suspected as early pathology of arrhythmogenic right ventricular cardiomyopathy due to characteristic gene mutation in the present case. In the present case, the defect EIF2B2 caused by hemizygosity may be related to early onset of the disease and the unusual pathological changes with vulnerability of oligodendrocytes and astrocytes, as well as cardiac abnormalities and sudden unexpected death.
    Full-text · Article · Jun 2014 · International journal of clinical and experimental pathology
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