SCN8A-related phenotypes: an overview of the literature
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Background: SCN8A gene encodes for one of the voltage-gated sodium channels widely expressed in neurons of the CNS. In the last years, SCN8A pathogenic variants have been described in different types of early onset neurological disorders, mostly including epilepsy. Objectives: We present a narrative review of the literature about SCN8A-related phenotypes, with the aim of summarizing their clinical features and critically commenting about them. Results: The first SCN8A mutation reported in humans was in a subject with intellectual disability without epilepsy, but only few similar cases have been described. SCN8A infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558) is the most defined phenotype, characterized by early onset drug-resistant seizures, developmental delay, severe intellectual disability, pyramidal and extrapyramidal signs. Other SCN8A-associated phenotypes include benign familial infantile seizures and isolated movement disorder. Discussion: Mutations in SCN8A gene have been associated to a spectrum of neurological disorders of different degrees of severity. Most studies on SCN8A concern EIEE13, a form of developmental and epileptic encephalopathy, whose phenotype is now delineated and has peculiar electroclinical features. This characterization has made it possible to distinguish EIEE13 from other genetic early onset developmental and epileptic encephalopathies, such as SCN1A, SCN2A or KCNQ2-related encephalopathies. Milder epileptic phenotypes have been described with autosomal dominant inheritance pattern. The role of SCN8A in isolated intellectual disability must be better understood and other non-epileptic phenotypes are now emerging. Although genotype-phenotype correlations have been suggested on the base of clinical and functional data, other mechanisms must be discovered to explain different disease severity from the same pathogenic variants.
KEY WORDS: SCN8A gene, developmental and epileptic encephalopathy, familial infantile seizures, myoclonus, myoclonic status epilepticus, intellectual disability.