Association Between Late-Onset Leukoencephalopathy With Vanishing White Matter and Compound Heterozygous EIF2B5 Gene Mutations: A Case Report and Review of the Literature.
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SUBMITTER: Kong F
PROVIDER: S-EPMC9243765 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC8564072 | biostudies-literature
Project description:Vanishing white matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, effects on myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.
| S-EPMC7752137 | biostudies-literature
Project description:Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive disorder with normal early development and, usually, childhood-onset neurological deterioration. At present, diagnosis of VWM is based on clinical examination and the results of repeat magnetic resonance imaging and magnetic resonance spectroscopy, which show that, with time, increasing amounts of the cerebral white matter vanish and are replaced by cerebrospinal fluid. We have performed a genome linkage screening of a panel of 19 families of different ethnic origins. Significant linkage to chromosome 3q27 was observed in a 7-cM interval between markers D3S3730 and D3S3592, with a maximum multipoint LOD score of 5.1 calculated from the entire data set. The results of genealogical studies have suggested that seven parents in four Dutch families with VWM may have inherited an allele for the disease from a common ancestor who lived at least eight generations ago. Analysis of these families provided further evidence for the localization of the gene for VWM to 3q27. The patients shared a haplotype spanning 5 cM between markers D3S1618 and D3S3592. In one family of a different ethnic background, the patient had, in the same region, homozygosity for 13 consecutive markers spanning at least 12 cM, suggesting consanguinity between the parents. A healthy sibling of this patient had the same homozygous haplotype, which suggests that the healthy sibling is presymptomatic for the disease.
| S-EPMC1377979 | biostudies-other
Project description:To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease.Case report.University teaching hospital.A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy.Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T(p.Ala87Val) and c.272G>A(p.Arg91His). To our knowledge,the latter missense mutation has never been previously reported.This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.
| S-EPMC4154510 | biostudies-literature
Project description:Clinicians should consider the EIF2B1 gene defect in any patient with diffuse white matter disease on an MRI of the brain and DKA.
| S-EPMC4974412 | biostudies-literature
Project description:OBJECTIVE:To comprehensively describe the natural history of vanishing white matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials. METHODS:We performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease-specific clinical questionnaire, Health Utilities Index and Guy's Neurological Disability Scale assessments, and chart review. RESULTS:First disease signs occurred at a median age of 3 years (mode?=?2 years, range?=?before birth to 54 years); 60% of patients were symptomatic before the age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. One hundred two patients were deceased. Multivariate Cox regression analysis revealed a positive relation between age at onset and both preservation of ambulation and survival. Absence of stress-provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the 5 eIF2B gene groups. The results confirm the presence of a genotype-phenotype correlation. INTERPRETATION:The VWM disease spectrum consists of a continuum with extremely wide variability. Age at onset is a strong predictor for disease course. Ann Neurol 2018;84:274-288.
| S-EPMC6175238 | biostudies-other
Project description:BackgroundVanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized.Case presentationThe patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients.ConclusionsThe present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1-5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.
| S-EPMC6704498 | biostudies-literature
Project description:Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.
2023-01-02 | PXD030831 | Pride
Project description:Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss-of-function variants in the OTU-deubiquitinase OTULIN suffer from neonatal-onset OTULIN-related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a seven-year-old affected by a life-threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants, however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient-derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.
| S-SCDT-EMM-2021-14901 | biostudies-other
Project description:PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.
| S-EPMC4245359 | biostudies-literature