WWOX-Related Developmental and Epileptic Encephalopathy
Journal
Neurology
Journal Volume
105
Journal Issue
6
Start Page
e213883
ISSN
0028-3878
1526-632X
Date Issued
2025-09-23
Author(s)
Gao, Kelley
Riley, Lisa G.
Raubenheimer, Jacques
Oliver, Karen L.
Wykes, Alexander D.
Mentz, Johann
Pinner, Jason
Cardamone, Michael
Scheffer, Ingrid
Gold, Wendy A.
Abstract
Background and Objectives
WWOX developmental and epileptic encephalopathy (WWOX-DEE), also known as WWOX-related epileptic encephalopathy, is characterized by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. The condition is poorly understood, posing significant challenges to clinical management and prognosis. This study investigated genotype and phenotype correlations of individuals with WWOX-DEE to inform clinical care.
Methods
Participants or guardians of the participants in the study were globally recruited through the WWOX Foundation where, after obtaining informed consent, questionnaires were completed for individuals with WWOX-DEE using Research Electronic Data Capture, providing clinical, demographic, and genetic information. Cases with genetically confirmed biallelic WWOX variants were included in the study. Genotypes were classified as either null/null, null/missense, or missense/missense, from which genotype-phenotype correlations were made using χ2 analyses with the Fisher exact test.
Results
In this study, we have collected and analyzed data from 50 individuals with biallelic WWOX variants across 45 families, identifying 25 variants that have not been previously reported. The median age of the cohort was 2.5 years, with 46% being female. The most common reported clinical features were developmental delay (96%) and seizures (90%). Individuals classified with a null/null genotype (56.8%) were more likely to have hypertonia, seizures and respiratory complications compared with individuals with null/missense (29.5%) or missense/missense (13.6%) variant genotypes.
Discussion
Using information from the largest WWOX-DEE parent-reported survey, we demonstrate a higher risk of developing seizures, respiratory complications, and hypertonia in individuals with biallelic null WWOX variants. To ensure optimal care of individuals with this rare DEE, we recommend their genotype be considered during clinical management. Future studies should consider using long-term natural history studies and detailed medical records to enable deeper phenotyping of each patient.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Type
journal article