Neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis: A shared phenotype across brain-expressed sodium channelopathies.

objectiveNeonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis (NDEEMA) represents the most severe end of the gain-of-function (GOF) SCN1A disorder spectrum. Sporadic cases of congenital arthrogryposis have also been reported in individuals with SCN2A-, SCN3A-, and SCN8A-related developmental and epileptic encephalopathy. Here, we investigated whether NDEEMA occurs in other brain-expressed sodium channelopathies and characterized its features.

methodsIndividuals 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.

resultsOf 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 Na SIGNIFICANCE: This study expands the phenotype of NDEEMA from SCN1A to its paralogue sodium channel genes expressed in the brain: SCN2A, SCN3A, and SCN8A.