Abstracts

Rationale: We aimed to identify the gene causing malignant migrating partial seizures of infancy (MMPSI), a rare epileptic encephalopathy of infancy characterized by the occurrence of polymorphous focal seizures and arrest of psychomotor development in the first 6 months of life. Methods: We collected DNA samples from 12 individuals fulfilling the criteria for MMPSI and performed exome sequencing in 3 probands and their unaffected parents. We sequenced the candidate gene and confirmed the functional effect through oovocyte expression system. Results: A single gene, KCNT1, was affected by distinct heterozygous missence variant (p.Arg428Gln and p.Ala934Thr) in 2 unrelated probands. Both mutations were confirmed by Sanger sequencing and occured de novo. Direct sequencing of KCNT1 in the 9 remaining patients identified the same de novo p.Arg428Gln missense mutations in two further patients and 2 distinct de novo mutations p.Arg474His and p.Ile760Met in two other patients KCNT1 encodes a sodium-activated potassium (KNa) channel widely expressed in the nervous system. Its activity contributes to the slow hyperpolarization that follows repetitive firing. Electrophysiological studies of the identified mutations showed a gain-of-function. Conclusions: Our findings further confirm the genetic etiology of MMPSI and ascribe MMPSI to the large family of channelopathies. In addition to regulating ion flux, the KCNT1 channel interacts with the mRNA binding protein, FMRP, whose defect results in the most common form of inherited intellectual disability, namely fragile X syndrome. We thus propose that mutations in KCNT1 provide the first pathophysiological basis of a channelopathy linking dysfunction of firing, thus epilepsy, to impaired function of a protein involved in cognitive development, FMRP, causing arrest of psychomotor development.