Two Faces of Genetic Epilepsy Caused by a Mutation in the SCN8A Gene

Introduction: Mutations of genes that encode for cerebral sodium channels are associated with epilepsy of variant severity. Mutations of the SCN8A gene encoding the cerebral sodium channel Nav1.6 have so far been rarely described. Patients: After an uneventful pregnancy, patient A was spontaneously born at term, then showing respiratory distress and hyperexcitability. During the 4th week of life, first generalized tonic seizures occurred which could not be explained though extensive diagnostic tests were performed. At first, seizures were well controlled under anticonvulsant treatment with oxcarbazepine. However, tonic-clonic seizures developed. They became therapy-resistant during the following months. Other antiepileptic drugs such as topiramate, valproic acid, vigabatrin, lamotrigin, high-dosage cortison, and ketogenic diet were all unable to control seizures. The patient finally developed an epileptic encephalopathy with severe psychomotor delay and cluster-like occurrence of tonic-clonic seizures. Furthermore, she repeatedly developed fractures of so far unknown origin. Patient B developed normally until her first tonic seizure at 6 months of age. As electroencephalography and psychomotor development remained normal, Watanabe-epilepsy was suspected. During the following months though, she displayed several episodes with up to 20 tonic-clonic seizures per day. In between these episodes, she showed normal behavior and was still not impaired in her development. Treatment with sultiam, oxcarbazepine, levetiracetam, and lamotrigin did not influence the occurrence of seizures. Result: Both patients finally showed distinct de novo mutations of the SCN8A gene, presumably explaining the earlier described phenotype. Conclusion:SCN8A encodes for the cerebral sodium channel Nav1.6; mutations in the SCN8A gene have previously been associated to epilepsy. We describe two female patients with SCN8A mutations presenting completely different phenotypes. We are currently investigating how the Nav1.6 activity is changed in both patients and whether this can possibly explain the difference between the phenotypes.