Daniel Fouz-Ruiz, Álvaro Beltrán-Corbellini, Bert B A de Vries, Lilian Bomme Ousager, Maria Iascone, Claudia Dosi, Geoffroy Delplancq, Alexander Stegmann, Tahsin Stefan Barakat, Yolande van Bever, Marjon van Slegenhorst, Frank Sleutels, Ryan Gates, Claudia Bendl, Antonio Gil-Nagel, Silvestre Cuinat, Ángel Aledo-Serrano
Epilepsy associated with SRRM2 loss-of-function variants typically presents in early childhood, often beginning with atypical febrile seizures and occasionally evolving to focal impaired-awareness seizures. The overall course appears favourable, with good response to treatment and no drug-resistant epilepsy observed in this cohort.
BACKGROUND: Loss-of-function variants in SRRM2, encoding the spliceosomal protein SRm300 involved in pre-messenger RNA splicing, have recently been associated with a neurodevelopmental disorder. Although seizures have been reported in some affected individuals, the electroclinical phenotype of SRRM2-related epilepsy has not been characterized. This study aims to outline the epilepsy phenotype and treatment response associated with SRRM2 loss-of-function variants.
METHODS: We conducted a retrospective international study of individuals with pathogenic and likely pathogenic variants in SRRM2 who had at least one epileptic seizure. Previously unpublished cases were identified through collaborations with neurologists and geneticists and through the GeneMatcher and DECIPHER databases, and additional information was obtained from previously reported individuals. Clinical, genetic, neurodevelopmental, EEG, neuroimaging, and treatment data were systematically reviewed.
RESULTS: Seven individuals (5 females; mean age at inclusion 7.9 years) met inclusion criteria. Variants were de novo in all cases with available parental data. All individuals experienced seizures, with a median age at onset of 18 months (range: 8 months to 38 months). Febrile seizures were the initial manifestation in six individuals, frequently with atypical features such as focal semiology or prolonged duration. Three later developed afebrile focal impaired-awareness seizures at a mean age of 32 months. Electroencephalogram findings were heterogeneous, showing focal epileptiform activity with posterior or occipital predominance in some participants. Four individuals received antiseizure medication, most commonly valproic acid or levetiracetam, achieving seizure control in all treated cases.
CONCLUSIONS: Epilepsy associated with SRRM2 loss-of-function variants typically presents in early childhood, often beginning with atypical febrile seizures and occasionally evolving to focal impaired-awareness seizures. The overall course appears favourable, with good response to treatment and no drug-resistant epilepsy observed in this cohort.