WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk

Abstract

Objective WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX‐DEE), also known as WOREE (WWOX‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival. Methods We studied 13 patients from 12 families with WWOX‐DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan–Meier method. Results All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day–10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo‐occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p‐value = .0085, log‐rank test). Significance Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration

“…Whether WWOX participates in deciding neuronal migration and positioning in the brain cortex during embryonic development is largely unknown. However, the fact is that newborn patients with WWOX deficiency develop neuronal heterotopia and severe epileptic seizures [ 83 , 84 , 91 , 92 , 93 ]. Without WWOX protein, neurons accelerate their migration and accumulate in the neocortex, known as neuronal heterotopia [ 84 , 94 , 95 ].…”

Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data

“…SCN1B c.363C>G has a MAF of 0.01047% in gnomAD 40,41 and causes autosomal dominant genetic epilepsy with febrile seizures plus (OMIM: 604233) [46][47][48][49] . WWOX c.49G>A has a MAF of 0.01037% in gnomAD 40,41 and causes autosomal recessive developmental and epileptic encephalopathy (OMIM: 616211) [50][51][52] .…”

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in OMIM: 604233)[46][47][48][49] . WWOX c.49G>A has a MAF of 0.01037% in gnomAD40,41 and causes autosomal recessive developmental and epileptic encephalopathy (OMIM: 616211)[50][51][52] .Cohort 1 consisted of 1,573 individuals with different types of epilepsy recruited in Australia or New Zealand as part of the international Epi25 study 53 . Cohort 2 is the UKBB cohort (n=468,481) accessed through project ID 36610 26 .…”

Neuroimaging features of WOREE syndrome: a mini-review of the literature

“…Concurrently, when whole exome sequencing (WES) and targeted gene panel sequencing are performed first, CNV investigation should be carried out, due to deletions and duplications, which often affect the WWOX gene. Furthermore, RNA studies could be useful to investigate if single-nucleotide variants (SNVs) and/or missense variants impair mRNA stability and disrupt the pre-mRNA splicing ( 2 ).…”

“…Early onset epilepsy represented the main feature in these patients and occurred with different semiology. Specifically, early infantile DEE, epilepsy of infancy with migrating focal seizures (EIMFS), and infantile epileptic spasms syndrome (IESS) have been reported ( 2 ). Seizures included generalized tonic, myoclonic, clonic, and tonic-clonic seizures, focal clonic seizures, infantile spasms, eyelid myoclonia, and status epilepticus with refractoriness to ASMs.…”