Ovarioleukodystrophy Due to EIF2B Genes: Systematic Review and Case Report

Abstract

Leukodystrophies comprise a spectrum of genetic disorders affecting white matter (WM) formation in the central nervous system (CNS), of which vanishing white matter disease (VWMD) is one. VWMD presents with progressive neurological deterioration and a variety of manifestations. Ovarioleukodystrophy, a subtype of VWMD, exhibits a distinctive clinical profile encompassing both CNS WM alterations and ovarian dysfunction. Variants in genes of the eukaryotic translation initiation factor 2B (EIF2B) complex affect the full form and are implicated in VWMD, including ovarioleukodystrophy. This work aimed to systematically review all published cases of ovarioleukodystrophy associated with variants in the EIF2B1-5 gene complex based on the first case identified in a Mexican population. We performed a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines of published cases of ovarioleukodystrophy associated with the EIF2B gene complex, including a newly identified case from Mexico. We identified 207 publications using PUBMED, SCOPUS, and PMC databases. One hundred fifty-one publications were eliminated due to duplicates, titles, abstracts, or other reasons, while 56 publications were revised, of which 29 were eliminated because they dealt with other genes or non-human research, and 27 reports were assessed for eligibility. Finally, 14 reports describing ovarian involvement, neuroimaging, and molecular variants were included. Our review identified 20 cases worldwide, with a median age of onset of 19 years. Clinical features included WM involvement, ovarian abnormalities, gait disturbances, epilepsy, cognitive and language impairment, and other neurological manifestations. Neuroimaging showed characteristic WM changes, highlighting the importance of MRI in diagnosis. Missense variants predominated among the identified genetic mutations, especially in the EIF2B4 and EIF2B5 genes. Ovarioleukodystrophy is an ultra-rare disorder with a wide range of clinical manifestations and ovarian changes. Gynecological evaluation is crucial in suspected cases of ovarioleukodystrophy, as ovarian manifestations may precede neurological symptoms. The role of MRI is crucial in the diagnostic approach to this entity. Continued collaborative efforts are essential to elucidate genotype-phenotype correlations, improve clinical management, and promote therapeutic advances for this rare disorder.

Keywords: eif2b1-5 genes; mri imaging; ovarioleukodystrophy; systematic review; vanishing white matter disease.

Figure 1. Flowchart of the search strategy

Figure 2. Neuroimaging findings in ovarioleukodystrophy due to alterations in the EIF2B gene complex

A) Parasagittal T2 FLAIR-weighted image of the patient identified in this report showing subcortical hyperintensities in the WM, generalized cortico-subcortical atrophy, and significant atrophy of the corpus callosum, and C) axial T2 FLAIR-weighted image of the same patient showing periventricular hyperintensities and cystic degeneration of the WM at the level of the frontal horns (arrow). B) and D) similar findings with generalized and corpus callosum atrophy and cystic degeneration, as reported by Rodríguez-Palmero et al. (reproduced under a CC-BY license) [22].

Figure 3. Schematic representation of the identified variants in the EIF2B1-5 gene complex

Homozygous variants are shown in pink, and compound heterozygotes are shown in blue. The patient variant reported in this publication is marked with *.