Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay1. We performed exome sequencing in 3 probands with MMPSI and identified de novo gain-of-function mutations in the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional patients with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated patients. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non conducting function as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a target for future diagnostic approaches and research in this devastating condition.

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PTC Therapeutics.

Summary: Purpose:In severe myoclonic epilepsy of infancy (SME), multiple drug-resistant focal and generalized seizure types occur. Lamotrigine (LTG), found effective in many generalized and partial seizures, has been little used in severe childhood epilepsy syndromes with multiple seizure types. We studied the effects of LTG in SME.Methods: Twenty-one patients with SME, aged 2-18 years, were treated with LTG, 20 in add-on and one in monotherapy. LTG was started at 0.2-2.5 mg/kg/day and increased to 2.5-12.5 mg/kg/day. For each seizure type, excluding atypical absences, >50% variations compared with the 2 months preceding LTG were considered indicators of response, also taking into account the degree of disability each seizure type produced.Results: LTG induced worsening in 17 (80%) patients, noSevere myoclonic epilepsy (SME) in infants (1) is one of the most disabling epileptic syndromes. Seizures begin during the first year of life in previously normal children as generalized or unilateral attacks, facilitated by fever, and often occurring in the form of status epilepticus. Such seizures are followed later, between ages 1 and 4 years, by myoclonus, atypical absences, and complex partial seizures, accompanied in some children by clinical photosensitivity. Often coinciding with the onset of myoclonus, there is a slowing in psychomotor development, patients being variably mentally retarded from school age on. All seizure types are extremely resistant to drug treatment. Although SME is diagnosed only in -1% of patients with epilepsy (2), the management of these patients is particularly time demanding and costly, as they undergo multiple periods of hospitalization and antiepileptic drug (AED) trials in which almost all combinations of available drugs are tried.Lamotrigine (LTG) has proven to be effective in the