Article

Ovarian Failure Related to Eukaryotic Initiation Factor 2B Mutations

INSERM Unité Mixte de Recherche 384, Faculté de Médecine, Clermont-Ferrand, France.
The American Journal of Human Genetics (Impact Factor: 10.99). 06/2003; 72(6):1544-50. DOI: 10.1086/375404
Source: PubMed

ABSTRACT Ovarian failure (OF) at age <40 years occurs in approximately 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway.

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    ABSTRACT: We report a rare autopsy case of early infantile-onset vanishing white matter disease, with a submicrosco-pic 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 develop-ment 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. Histo-pathologically, 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 oligodendro-cytes and astrocytes, as well as cardiac abnormalities and sudden unexpected death. Introduction Vanishing white matter disease (VWMD) (OMIM number 603896) is a childhood leukoencepha-lopathy with autosomal recessive traits. How-ever, this disease has an extremely wide phe-notypic variation and may affect people of all ages, including neonates and adults [1, 2]. A characteristic clinical feature of VWMD is that neurological deterioration follows a chronic pro-gressive course, with additional episodes of rapid deterioration by stresses, such as fever and minor head trauma. Neuropathological fea-tures 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 astro-cytes, 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 ques-tions remain unanswered with respect to how perturbation of these ubiquitously expressed translation initiation factors should result in a highly selective neurological phenotype. We report the interesting pathological findings of a boy with VWMD for a missense mutation of EIF2B2 (V85E) caused by hemizygosity due to a de novo deletion. Case report A 4-year-old boy was found to have suddenly died during sleep. The clinical summary of this child up to 2 years, including magnetic reso-nance imaging (MRI) findings and chromosomal microarray testing results, has been reported
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    ABSTRACT: Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited childhood white matter disorders, which caused by mutations in each of the five subunits of eukaryotic translation initiation factor 2B (EIF2B1-5). In our study, 34 out of the 36 clinically diagnosed children (94%) were identified to have EIF2B1-5 mutations by sequencing. 15 novel mutations were identified. CNVs were not detected in patients with only one mutant allele and mutation-negative determined by gene sequencing. There is a significantly higher incidence of patients with EIF2B3 mutations compared with Caucasian patients (32% vs. 4%). c.1037T>C (p.Ile346Thr) in EIF2B3 was confirmed to be a founder mutation in Chinese, which probably one of the causes of the genotypic differences between ethnicities. Our average 4.4 years-follow-up on infantile, early childhood and juvenile VWM children suggested a rapid deterioration in motor function. Episodic aggravation was presented in 90% of infantile cases and 71.4% of childhood cases. 10 patients died during the follow-up. The Kaplan-Meier curve showed that the median survival time is 8.83 ± 1.51 years. This is the largest sample of children in a VWM follow-up study, which is helpful for a more depth understanding about the natural course.
    PLoS ONE 03/2015; 10(3):e0118001. DOI:10.1371/journal.pone.0118001 · 3.53 Impact Factor

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