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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 three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. 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 focus for future diagnostic approaches and research for this devastating condition.
First described in 1995, MMPSI is characterized by polymorphous focal seizures and arrest of psychomotor development in the first 6 months of life1. Seizures are pharmacoresistant, and ictal electroencephalogram (EEG) discharges arise randomly from various areas of both hemispheres of the brain and 'migrate' from one brain region to another, conferring the main feature and name to this syndrome. Brain magnetic resonance imaging (MRI) is generally normal at the onset of the disease. To date, approximately 80 individuals with MMPSI have been reported, with males and females being equally affected1-17.
MMPSI belongs to the group of early-onset epileptic encephalopathies (EOEEs) defined as severe age-related disorders where cognitive, sensory and motor impairment is caused by recurrent clinical seizures or prominent interictal epileptiform discharges18. There is growing evidence of genetic etiology in EOEEs, with prevalence ranging from 10% of individuals with Ohtahara syndrome having STXBP1 mutations to 70% of individuals with Dravet syndrome having SCN1A mutations19. Screening for aberrations in voltage-gated ion channel genes already reported in epilepsies (KCNQ2, KCNQ3, SCN1A, SCN2A and CLCN2) did not detect mutations in these genes in MMPSI2. SCN1A mutations were later reported in 2 affected individuals15,16; however, screening for this gene detected no mutations in 13 individuals with MMPSI15.
We collected DNA samples from 12 individuals fulfilling the criteria for diagnosis with MMPSI (Supplementary Table 1). Ictal EEG showed migrating seizures (Supplementary Fig. 1), and brain MRI showed delayed myelination with an...