Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations

Slynko, Inna; Nguyen, Stephanie; Hamilton, Eline M.; Wisse, Lisanne E.; Esch, Iwan J. P. de; Graaf, Chris de; Bruning, John B.; Proud, Christopher G.; Abbink, Truus E.M.; Knaap, Marjo S. van der

doi:10.1002/mgg3.1593

Cited by 23 publications

(27 citation statements)

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“… 5 , 12 There is clear genotype-phenotype correlation, with mild and severe variants. 4 , 11 , 15 , 16 If a mild and a severe variant are compound heterozygous, disease severity is intermediate. 15 Although patients with the same variants tend to have a similar disease course, variation may be considerable, especially in onset ≥4 years, even within families.…”

Section: Introductionmentioning

confidence: 99%

Therapy Trial Design in Vanishing White Matter

et al. 2022

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Vanishing white matter (VWM) is a leukodystrophy caused by recessive variants in the genes EIF2B1-EIF2B5. It is characterized by chronic neurologic deterioration with superimposed stress-provoked episodes of rapid decline. Disease onset spans from the antenatal period through senescence. Age at onset predicts disease evolution for patients with early onset, whereas disease evolution is unpredictable for later onset; patients with infantile and early childhood onset consistently have severe disease with rapid neurologic decline and often early death, whereas patients with later onset have highly variable disease. VWM is rare, but likely underdiagnosed, particularly in adults. Apart from measures to prevent stressors that could provoke acute deteriorations, only symptomatic care is currently offered. With increased insight into VWM disease mechanisms, opportunities for treatment have emerged. EIF2B1-EIF2B5 encode the 5-subunit eukaryotic initiation factor 2B complex, which is essential for translation of mRNAs into proteins and is a principal regulator of the integrated stress response (ISR). ISR deregulation is central to VWM pathology. Targeting components of the ISR has proven beneficial in mutant VWM mouse models, and several drugs are now in clinical development. However, clinical trials in VWM pose considerable challenges: low numbers of known patients with VWM, unpredictable disease course for patients with onset after early childhood, absence of intermediate biomarkers, and novel first-in-human molecular targets. Given these challenges and considering the critical need to offer therapies, we have formulated recommendations for enhanced diagnosis, drug trial setup, and patient selection, based on our expert evaluation of molecular, laboratory, and clinical data.

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Section: Introductionmentioning

confidence: 99%

Therapy Trial Design in Vanishing White Matter

et al. 2022

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“…Some missense mutations were predicted to show variable structural effects on the protein, including eIF2Bβ[Thr91Bla], eIF2Bβ[Ser171Phe], eIF2Bβ[Gly200Val], eIF2Bγ [Arg91His], eIF2Bδ [Arg264Trp], eIF2Bδ[Arg357Trp], eIF2Bδ[Arg483Trp], eIF2Bε [Thr79Ile], eIF2Bε[Glu81Leu], eIF2Bε[Arg136His], eIF2Bε[Arg195His], eIF2Bε[His269Pro], eIF2Bε[Arg316Gln], eIF2Bε[Thr91Ala], eIF2Bε[Glu213Gly], eIF2Bε[Arg133His], eIF2Bε[Gly386Val], [Ala403Val] and [Thr432Ile]( Slynko et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have reported a certain correlation between the degree of influence of missense mutations on protein structure and phenotypes, but the results are not consistent. Results from protein prediction software or model analysis of the mutation site function prediction revealed that some mutations with multiple or substantial effects on the eIF2B structure were associated with severe phenotypes, such as eIF2Bε[Thr79Ile], eIF2Bε[Glu81Leu], eIF2Bε[Arg136His], eIF2Bε[Arg195His], eIF2Bε[His269Pro], eIF2Bε[Arg269Gln], eIF2Bε[Arg316Gln]; eIF2Bδ[Arg264Trp], eIF2Bδ[Arg357Trp], eIF2Bδ[Arg483Trp], and eIF2Bγ[Arg91His] ( Slynko et al, 2021 ). Mutations such as eIF2Bβ[Thr91Bla], eIF2Bε[Thr91Ala], eIF2Bε[Ala87Val] and eIF2Bε[Glu213Gly], with predicted minimal influence on the eIF2B structure, were associated with mild disease severity.…”

Section: Discussionmentioning

confidence: 99%

“…For example, mutations such as eIF2Bε[Arg133His] and eIF2Bβ[Ser171Phe] were predicted to have a huge effect on protein structure, but they were related to mild phenotype. Mutations such as eIF2Bβ[Gly200Val], eIF2Bε[Gly386Val] [Ala403Val] and [Thr432Ile], with small predict effects, were linked to serious phenotype ( Fogli et al, 2004b ; Campbell and Ashe, 2006 ; Slynko et al, 2021 ). In this study, 303 patients with biallelic missense mutations were analyzed.…”

Section: Discussionmentioning

confidence: 99%

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Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter

et al. 2021

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Purpose: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy caused by mutations in any of the five genes encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). The severity of the disease varies considerably, and its genotypic-phenotypic correlation is still unclear. Age of onset is the only independent clinical predictor for VWM severity. In this study, the correlation between genotype and age at onset of patients was investigated.Methods: Data were collected from patients with VWM in the available literature reports and from those diagnosed in Peking University First Hospital. The age of onset was divided into early-onset (≤4 years) and late-onset type (>4 years) for the analysis of the correlation between genotype and age of onset in patients with VWM.Results: A total of 341 patients were included, 281 were reported in 87 available articles and 60 were diagnosed in our center. A total of 180 different mutations were found, among which 86.1% were missense. The gene (EIF2B1-5) in which the mutation located, and the number of null alleles were not associated with age of onset in these patients. Certain mutations such as eIF2Bε[Arg195His] and eIF2Bε[Arg269Gln] that were predicted to have a serious influence on eIF2B structure were related to earlier age of onset. EIF2Bγ[Ala87Val] which was predicted to have a minimal influence on eIF2B structure, was related to later age of onset. Whereas eIF2Bβ[Glu213Gly], eIF2Bβ[Gly200Val] and eIF2Bε[Thr91Ala], also predicted having a small effect on the structure of eIF2B, did not show correlation with the age of onset. The onset age of patients with one or biallelic missense mutations located in the catalytic domain or other homologous domains in catalytic subunits (eIF2Bγ, ε) was earlier than that of patients with biallelic mutations located in the NT domain.Conclusion: The onset age of patients with different genotypes varied greatly. The degree of influence in protein structure of some missense mutations was correlated with phenotypic severity, but the results were not completely consistent. The combined effect of biallelic mutations, the role of regulatory genes, environmental stress and other potential factors on phenotypes need to be further explored.

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“…Age at onset is the only strong predictor of clinical course and outcome (6,10). Sequence variant information does not add predictive information (11). Patients were therefore stratified into six groups according to age at onset of VWM, as follows: younger than 1 year (group 1), 1 year to younger than 2 years (group 2), 2 years to younger than 4 years (group 3), 4 years to younger than 8 years (group 4), 8 years to younger than 18 years (group 5), and 18 years or older (group 6), as previously described (6).…”

Section: Patients With Vwm and Mri Examinationsmentioning

confidence: 99%

MRI Natural History of the Leukodystrophy Vanishing White Matter

Stellingwerff

Al-Saady

Brug³

et al. 2021

Radiology

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NEURORADIOLOGYI n vanishing white matter (VWM), a form of leukodystrophy, the cerebral white matter is the only or the most prominently affected tissue (1). The MRI feature defining VWM is progressive rarefaction and cystic decay of the cerebral white matter, leading to a white matter signal close to or the same as that of cerebrospinal fluid (CSF) on proton density and fluid-attenuated inversion recovery (FLAIR) images (1). The rarefied and cystic white matter typically contains radiating stripes, suggesting relatively preserved perivascular tissue strands (1). The white matter involvement is extensive or diffuse (1); only the directly subcortical white matter may be spared (2). Neuropathologic evaluation confirms the interpretation of the MRI findings (3).VWM is caused by biallelic sequence variations in any of the EIF2B1-5 genes, which encode the five subunits of the eukaryotic translation initiation factor eIF2B (4,5). The onset of VWM is mainly in early childhood but ranges from the antenatal period to senescence (6). For onset before age 4 years, earlier manifestation is associated with faster clinical disease progression. Patients with onset after age 4 years tend to have a milder disease course, irrespective of the exact age at onset (6).Currently, there is no therapy for VWM, but various drugs are in clinical development and will be assessed in trials (7-9). Although clinical parameters provide primary outcome measures, MRI parameters may serve as secondary or surrogate outcome measures. For the past 3 decades, MRI has played an important role in the diagnosis of VWM (1). The time course of the cerebral white matter decay has, however, not been investigated, and systematic information on MRI evolution for different ages of onset is lacking. For MRI to play a role in therapeutic trials, this basic information is needed. We therefore studied the progression of cerebral white matter abnormalities at MRI in a large group of patients with genetically confirmed VWM, representing all ages of onset.Background: In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking.Purpose: To determine whether nature and progression of cerebral white matter abnormalities in VWM differ according to age at onset. Materials and Methods:Patients with genetically confirmed VWM were stratified into six groups according to age at onset: younger than 1 year, 1 year to younger than 2 years, 2 years to younger than 4 years, 4 years to younger than 8 years, 8 years to younger than 18 years, and 18 years or older. With institutional review board approval, all available MRI scans obtained between 1985 and 2019 were retrospectively analyzed with three methods: (a) ratio of the width of the lateral ventricles over the skull (ventricle-to-skull ratio [VSR]) was measured to estimate brain atrophy; (b) cerebral white matter wa...

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Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations

Cited by 23 publications

References 44 publications

Therapy Trial Design in Vanishing White Matter

Therapy Trial Design in Vanishing White Matter

Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter

MRI Natural History of the Leukodystrophy Vanishing White Matter

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