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

Medientyp: E-Artikel
Titel: WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk
Beteiligte: Oliver, Karen L.; Trivisano, Marina; Mandelstam, Simone A.; De Dominicis, Angela; Francis, David I.; Green, Timothy E.; Muir, Alison M.; Chowdhary, Apoorva; Hertzberg, Christoph; Goldhahn, Klaus; Metreau, Julia; Prager, Christine; Pinner, Jason; Cardamone, Michael; Myers, Kenneth A.; Leventer, Richard J.; Lesca, Gaetan; Bahlo, Melanie; Hildebrand, Michael S.; Mefford, Heather C.; Kaindl, Angela M.; Specchio, Nicola; Scheffer, Ingrid E.
Erschienen: Wiley, 2023
Erschienen in: Epilepsia
Sprache: Englisch
DOI: 10.1111/epi.17542
ISSN: 0013-9580; 1528-1167
Schlagwörter: Neurology (clinical) ; Neurology
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Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p><jats:italic>WWOX</jats:italic> is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (<jats:italic>WWOX</jats:italic>‐DEE), also known as WOREE (<jats:italic>WWOX</jats:italic>‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of <jats:italic>WWOX</jats:italic>‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We studied 13 patients from 12 families with <jats:italic>WWOX</jats:italic>‐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 <jats:italic>WWOX</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 5), myoclonic (<jats:italic>n</jats:italic> = 2), epileptic spasms (<jats:italic>n</jats:italic> = 2), focal (<jats:italic>n</jats:italic> = 1), and migrating focal (<jats:italic>n</jats:italic> = 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 <jats:italic>WWOX</jats:italic> 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 (<jats:italic>p</jats:italic>‐value = .0085, log‐rank test).</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Biallelic <jats:italic>WWOX</jats:italic> 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 <jats:italic>WWOX</jats:italic> pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.</jats:p></jats:sec>
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