Developmental Epileptic Encephalopathy Caused by a De Novo Mutation in the SCN8A Gene
摘要
Developmental epileptic encephalopathy is characterized by a malignant course of refractory epilepsy and progressive impairment of mental and motor development. Causative genes have now been identified for most of these conditions. Among the causes of this condition are mutations in the SCN8A gene, which encodes a voltage-gated sodium channel; these mutations are found in approximately 1% of children with early infantile epileptic encephalopathies. Mutations in the SCN8A gene lead to both increased function of the NaV1.6 sodium channel (GOF mutations) and decreased function (LOF mutations), where damage to channels leads to a decrease in current amplitude and a depolarizing shift. GOF mutations are more likely to cause hypotonia, cerebral visual dysfunction, dyskinesia, and ataxia. Epileptic seizures predominantly occur as bilateral tonic focal seizures, and in most cases lead to epileptic encephalopathy. With LOF mutations, seizures (absences, bilateral tonic-clonic, and myoclonic seizures) may be asymptomatic, while cognitive impairment, movement disorders, and autistic features are present. Antiepileptic treatment regimens include non-selective sodium channel blockers, GABAergic agents, Na+ and Ca2+ channel blockers, and other medications. A characteristic feature of the phenotype is the relatively high risk of exacerbation of epilepsy during antiepileptic drug selection, which requires particular care and caution on the part of the physician. We present here a clinical case of severe refractory epilepsy with developmental disabilities in an infant to illustrate the most striking features of the disease. The disease progressed despite all attempts to select a treatment. Treatment with corticosteroids had a temporary effect; discontinuation led to increases in the frequency and severity of seizures, suggesting a GOF scenario for the disease, though it was not possible to obtain genetic confirmation. The authors believe that the prospects for correcting such conditions depend on progress in the development of new drugs, including oligonucleotides and selective NaV1.6 channel blockers.