Abstract found on PubMed
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 analysed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regards to survival.
Methods: We studied thirteen patients from twelve families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms and disease outcome were collected. EEG and brain MRI data were analysed. 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 6/13 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. 11/13 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 (4 deletions; 1 duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = 0.0085, 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.