Neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis: A shared phenotype across brain-expressed sodium channelopathies.
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Gverdtsiteli Sopio, Ortiz Sebastian, Brünger Tobias, Furia Francesca, Barba Carmen, Bjørg-Hammer Trine, Borggraefe Ingo, Caraballo Roberto, Cirak Sebahattin, Espeche Alberto, Fazeli Walid, Guerrini Renzo, Juanes Matias, Kassahn Karin, Kinali Maria, Krämer Johannes, Kröll Judith, Herrero Maria Concepción Miranda, Oegema Renske, Ounap Katrin, Peñuela Oscar, Platzer Konrad, Prasad Asuri Narayan, Pujol Aurora, Reinson Karit, Represa Alfonso, Roza Eugenia, Valenzuela Gabriela Reyes, Rodríguez-Palmero Agustí, Sallevelt Suzanne, Sanchez-Albiusa Maria Iciar, Scheffer Ingrid E, Smid Cory, Stafstrom Carl E, Stattin Eva-Lena, Suarez Jen R, Syrbe Steffen, Valente Kette D, Wagner Matias, Wortmann Saskia, Gardella Elena, Lal Dennis, Brunklaus Andreas, Møller Rikke S
Аннотация
METHODS: Individuals with the clinical phenotype of NDEEMA were identified through internal databases, an international network of epileptologists and geneticists, and the literature. Their clinical and genetic information was analyzed. A literature survey was conducted to review studies describing the functional effects of the pathogenic variants.
RESULTS: Of 46 NDEEMA individuals, 25 harbored variants in SCN1A, 13 in SCN2A, one in SCN3A, and seven in SCN8A. Thirty-five different pathogenic/likely pathogenic missense variants were identified, all of which clustered in evolutionary conserved paralogous NaV positions. Five individuals died in utero. Thirty-nine of 41 (95%) liveborn individuals developed neonatal epilepsy with tonic seizures and/or apnea. Thirty-one individuals tried sodium channel blockers, of whom 21 (68%) experienced seizure reduction. All individuals for whom information was available developed movement disorders, with myoclonus, dystonia, and tremor being the most common features. Literature review of functional studies revealed that nine NDEEMA variants, and the corresponding paralogues of 16 additional NDEEMA variants, have been biophysically characterized as GOF.
SIGNIFICANCE: This study expands the phenotype of NDEEMA from SCN1A to its paralogue sodium channel genes expressed in the brain: SCN2A, SCN3A, and SCN8A.