Early onset or syndromic epilepsy

Gene: EIF2B4

Green List (high evidence)

AR ovarioleukodystrophy and Leukoencephalopathy with vanishing white matter (VWM). Can also be caused by mutations in any of the 5 genes encoding subunits of the translation initiation factor EIF2B (EIF2B1,2,3,4 or 5). It is a neurologic disorder characterised by variable neurological features including progressive cerebellar ataxia, spasticity and cognitive impairement assoc with white matter lesions on brain imaging. Onset from early infancy to adulthood. Episodes of deterioration followed infections and minor head traumas. Shimada et al, 2015 - variants in 6 patients (4 unrelated individ and 2 siblings) in EIF2B genes: 5/6 had seizures - 4 families of these 2 unrelated individuals one hom and one compound het for EIF2B2 missense variants. 1 aff was hom for an EIF2B1 variant. 1 aff was compound het for an EIF2B5 mutation and the two sibs were compound het for EIF2B4 mutations - 1 had epilepsy, 1 didn't. Zhang et al, 2015 - 6 patients with variants in EIF2B4 - 1/6 reported as having seizures. Gungor et al, 2015 - 12 month old boy presented with intractable seizures since 3 months - hom for EIF2B4 variant. Herrera-Garcia et al, 2018 - 41 year old women and her 37 year old sister both developed epilepsy at 13 and 18 resepctively in association with POF. Both were hom for an EIF2B4 variant.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy with vanishing white matter, 603896; Ovarioleukodystrophy, 603896

Publications

• 26043506

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green: Green review by Zornitza, and sufficient cases of epilepsy in Vanishing White Matter (VWM) patients with EIF2B4 variants from the literature (3 cases in PMIDs 25843247, 26043506 and 29331873) for inclusion on the panel.

Created: 27 Nov 2018, 8:49 p.m.

Herrera-García et al, 2018 (PMID:29331873) describe a 41-year-old woman and her 37-year-old sister who developed epilepsy in association with premature ovarian failure at the age of 13 and 18 respectively. In both patients they found the c.1117C>T (p.Arg373Cys) homozygous variant in EIF2B4.

Created: 27 Nov 2018, 8:47 p.m.

Gungor et al (PMID:26043506) report a 12-month old boy presented with intractable seizures present since 3-months of age. A homozygous c.1091G>A variant was detected in the EIF2B4 gene.

Created: 27 Nov 2018, 8:38 p.m.

Shimada et al. (2015, PMID:25843247) analysed genes encoding all five subunits of EIF2B in 22 patients tentatively diagnosed with Vanishing White Matter Disease (VWM). Patients 4 and 5 were brothers, and had variants in EIF2B4; c.556T>A c.1070G>A (p.Y186N, p.R357Q) in compound heterozygosity. Despite the same variants, patient 4 but not his brother (patient 5) had seizures amongst their phenotypes.

Created: 27 Nov 2018, 8:35 p.m.

Green List (high evidence)

Seizures are a feature of this leukodystrophy.

Created: 13 Aug 2018, 11:36 a.m.

Phenotypes
Leukoencephalopathy with vanishing white matter, MIM#603896

Variants in this GENE are reported as part of current diagnostic practice