WWOX-related developmental and epileptic encephalopathy (WOREE): A case series of seven patients from Argentina.
TL;DR
WEE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay, which may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.
Abstract
Purpose
WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited.
Methods
We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines.
Results
Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect.
Conclusion
WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.