scholarly journals Vanishing White Matter Disease in a Spanish Population

2014 ◽  
Vol 6 ◽  
pp. JCNSD.S13540 ◽  
Author(s):  
Eulàlia Turón-Viñas ◽  
Mercè Pineda ◽  
Victòria Cusí ◽  
Eduardo López-Laso ◽  
Rebeca Losada Del Pozo ◽  
...  
Keyword(s):  
White Matter ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Genes Encoding ◽  
Eukaryotic Translation Initiation ◽  
Severe Ataxia ◽  
Vanishing White Matter Disease ◽  
Chronic Course ◽  
Vanishing White Matter

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.

scholarly journals A case report of leukoencephalopathy with vanishing white matter disease

2020 ◽  
Vol 7 (6) ◽  
pp. 1438
Author(s):  
Bommidi Navya ◽  
Vamshi Krishna Kondle ◽  
Komal Uppal
Keyword(s):  
White Matter ◽  
Specific Treatment ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
White Matter Disease ◽  
Eukaryotic Translation ◽  
Genes Encoding ◽  
Eukaryotic Translation Initiation ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Vanishing white matter disease (VWM) is one of the most prevalent inherited childhood leucoencephalopathies. Childhood ataxia and diffuse central nervous system hypomyelination are the common findings. The disease is characterized by chronic progressive and episodic deterioration with ataxia, spasticity and optic atrophy. VWM is caused by mutation in any of the five genes encoding the subunits of eukaryotic translation initiation factor eIF2B. The disease has an autosomal recessive mode of inheritance. The cause of the disease is unknown. Authors are reporting an 8 year old male child presented with complaint of difficulty while walking since one month and history viral fever was present one month back. MRI revealed bilateral symmetrical periventricular T2 hyperintensities with T1 hypointensities. Perivenular sparing was seen and molecular analysis shown eIF2B4 mutations confirmation of vanishing white matter disease. No specific treatment is available and advised to avoid stress and triggers.

Arg113His mutation of vanishing white matter is not present in multiple sclerosis

2007 ◽  
Vol 13 (3) ◽  
pp. 424-427 ◽  
Author(s):  
M. Lucas ◽  
R. Suarez ◽  
A. Marcos ◽  
F. Solano ◽  
A. Venegas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
High Frequency ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cystic Degeneration ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Vanishing White Matter ◽  
Head Neck

Vanishing white matter (VWM) is a childhood leukoencephalopathy with central hypomyelination, white matter rarefaction, and cystic degeneration. Adult onset, variable phenotype, and high frequency characterize Arg113His mutation caused by G338A polymorphism associated with VWM. A patient with trauma-associated onset, and clinical features compatible with multiple sclerosis (MS), was homozygous for G338A mutation of eukaryotic translation initiation factor (eIF2B5). The authors checked a cohort of 101 MS patients, including 19 with head/neck trauma-associated onset, and failed to find the mutation, described above, in MS chromosomes. Our report does not exclude the presence in MS chromosomes of other mutations in the eIF2B gene family. Multiple Sclerosis 2007; 13: 424-427. http://msj.sagepub.com

Eif2b3 mutants recapitulate phenotypes of Vanishing White Matter Disease and validate novel disease alleles in zebrafish

2021 ◽  
Author(s):  
Yu-Ri Lee ◽  
Se Hee Kim ◽  
Afif Ben-Mahmoud ◽  
Oc-Hee Kim ◽  
Tae-Ik Choi ◽  
...  
Keyword(s):  
White Matter ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Vegf Receptor ◽  
Zebrafish Model ◽  
Eukaryotic Translation ◽  
Expression Of Genes ◽  
Novel Variant ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Abstract Leukodystrophy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination (CACH), is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.

096 A 47-year old female with slowly progressive cognitive impairment and motor decline

2018 ◽  
Vol 89 (6) ◽  
pp. A38.2-A38
Author(s):  
Wilson Vallat ◽  
Timothy Kleinig
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Cognitive Dysfunction ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
White Matter Disease ◽  
Adult Onset ◽  
Extrapyramidal Signs ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

IntroductionWe present the case of a woman with an 8 year history of slowly progressive cognitive dysfunction and gait disturbance, and a diagnosis of vanishing white matter disease (VWMD).CaseThe patient struggled at work as an accountant, her hand writing became illegible, she had difficulty judging distances when driving and she had developed gait instability, slowing and falls. Her past medical history was unremarkable save for premature menopause at 35. Examination showed marked cognitive impairment ACE-R 59/100 (attention and orientation – 13/18, memory – 16/26, fluency – 1/14, language – 21/26, visuospatial – 8/16), reduced dexterity of hands, left upper limb ataxia and high- level gait dysfunction. MRI brain showed leukodystrophy with frontal predominance. Relevant investigations – white cell enzymes, very long chain fatty acids, phytanic acid, CSF were normal. In view of the clinical and radiological features genetic testing with leukodystrophy panel was performed which revealed homozygous eukaryotic translation initiation factor B3 (EIF2B3) mutation (p.Ala87Val variant). Adult onset leukodystrophies are rare genetic metabolic disorders of the glial cells. The white matter (WM) degeneration causes disruption of distributed neural networks resulting in variable constellation of cognitive dysfunction, ataxia, pyramidal and extrapyramidal signs. The clinical and radiological phenotypes overlap and there are up to 60 genes that account for adult onset leukodystrophy, which makes diagnosis challenging. Vanishing white matter disease due to EIF2B gene mutation are a group of disorders that result from mutation of any of the EIF2B subunits (1 to 5). Two thirds have associated premature ovarian failure. MRI shows confluent WM T2 high signal, subcortical U Fibre sparing, periventricular WM rarefaction and cerebral atrophy. Management is symptomatic.ConclusionAdult onset VWMD is a rare and devastating condition. When evaluating these patients targeted gene testing guided by clinical and radiological phenotype is likely to provide the highest diagnostic yield. Establishing the diagnosis is important as it has implications on future generations.

scholarly journals De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation

2019 ◽  
Author(s):  
Dongxue Mao ◽  
Chloe M. Reuter ◽  
Maura R.Z. Ruzhnikov ◽  
Anita E. Beck ◽  
Emily G. Farrow ◽  
...  
Keyword(s):  
White Matter ◽  
Translation Initiation ◽  
De Novo ◽  
Febrile Illness ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 2

ABSTRACTEIF2AK1 and EIF2AK2 encode members of the Eukaryotic Translation Initiation Factor 2 Alpha Kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of eight unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/8) or EIF2AK2 (7/8). Features seen in these eight individuals include white matter alterations (8/8), developmental delay (8/8), impaired language (8/8), cognitive impairment (7/8), ataxia (6/8), dysarthria in probands with verbal ability (6/6), hypotonia (6/8), hypertonia (5/8), and involuntary movements (3/8). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and patient-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate Eukaryotic Translation Initiation Factor 2 Subunit 1, (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), a leukoencephalopathy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

Role of Eukaryotic Initiation Factor eIF2B in Vanishing White Matter Disease

2018 ◽  
Author(s):  
Truus E. M. Abbink ◽  
Lisanne E. Wisse ◽  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
White Matter ◽  
Clinical Severity ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Gradual Loss ◽  
Genes Encoding ◽  
Multimeric Protein ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Vanishing white matter (VWM) disease is a recessive disorder characterized by gradual loss of white matter and of myelin. Its clinical severity is high variable. VWM is caused by mutations in any one of the five genes encoding subunits of eukaryotic initiation factor 2B (eIF2B), a ubiquitous, multimeric protein that plays crucial roles in protein synthesis and its control. There are now known to be at least 160 mutations in eIF2B genes that lead to VWM. Where tested, most mutations impair the activity or integrity of the eIF2B complex. However, it remains unclear how and why defects in eIF2B lead to VWM. This article discusses recent advances in understanding the structure and functions of eIF2B and the pathogenic basis of VWM.

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