Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter

Protein synthesis (also termed mRNA translation) is a key step in the expression of a cell's genetic information, in which the information contained within the coding region of the mRNA is used to direct the synthesis of the new protein, a process that is catalysed by the ribosome. Protein synthesis must be tightly controlled, to ensure the right proteins are made in the right amounts at the right time, and must be accurate, to avoid errors that could lead to the production of defective and potentially damaging proteins. In addition to the ribosome, protein synthesis also requires proteins termed translation factors, which mediate specific steps of the process. The first major stage of mRNA translation is termed ‘initiation’ and involves the recruitment of the ribosome to the mRNA and the identification of the correct start codon to commence translation. In eukaryotic cells, this process requires a set of eIFs (eukaryotic initiation factors). During the second main stage of translation, ‘elongation’, the ribosome traverses the coding region of the mRNA, assembling the new polypeptide: this process requires eEFs (eukaryotic elongation factors). Control of eEF2 is important in certain neurological processes. It is now clear that defects in eIFs or in their control can give rise to a number of diseases. This paper provides an overview of translation initiation and its control mechanisms, particularly those examined in neuronal cells. A major focus concerns an inherited neurological condition termed VHM (vanishing white matter) or CACH (childhood ataxia with central nervous system hypomyelination). VWM/CACH is caused by mutations in the translation initiation factor, eIF2B, a component of the basal translational machinery in all cells.

Download Full-text

Vanishing White Matter Disease in a Spanish Population

Journal of Central Nervous System Disease ◽

10.4137/jcnsd.s13540 ◽

2014 ◽

Vol 6 ◽

pp. JCNSD.S13540 ◽

Cited By ~ 11

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.

Download Full-text

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

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.95 ◽

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.

Download Full-text

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

Multiple Sclerosis Journal ◽

10.1177/1352458506070248 ◽

2007 ◽

Vol 13 (3) ◽

pp. 424-427 ◽

Cited By ~ 6

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

Download Full-text

Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease

Brain and Development ◽

10.1016/j.braindev.2015.03.003 ◽

2015 ◽

Vol 37 (10) ◽

pp. 960-966 ◽

Cited By ~ 4

Author(s):

Shino Shimada ◽

Keiko Shimojima ◽

Noriko Sangu ◽

Ai Hoshino ◽

Yasuo Hachiya ◽

...

Keyword(s):

Translation Initiation ◽

Japanese Patients ◽

Translation Initiation Factor ◽

Initiation Factor ◽

White Matter Disease ◽

Eukaryotic Translation ◽

Genes Encoding ◽

Eukaryotic Translation Initiation ◽

Vanishing White Matter Disease ◽

Vanishing White Matter

Download Full-text

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

10.1101/757039 ◽

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.

Download Full-text