Abstracts

Rationale: Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare devastating infantile developmental and epileptic encephalopathy (DEE), characterized by seizure migration between hemispheres, seizure onset before 6 months, and developmental plateau or regression. Here, we report a large international case series of 120 patients and identify novel genes associated with EIMFS in addition to the 20 known genes.  Methods: Patients were recruited to the Epilepsy Genetics Research Program at Austin Health, University of Melbourne, and collaborating groups. The phenotypic and genotypic spectrum of EIMFS was analyzed, including additional molecular analysis of patients who had previously not had their pathogenic variant identified. Results: 120 patients (114 unrelated families, 69 female) were recruited into the study.  79/120 (66%) had pathogenic variants identified, of which 46 were previously reported. 61/79 (77%) cases had dominant mutations and 18/79 (23%) cases had recessive causes. Six novel genes for EIMFS were identified (Dominantly: PIGA, GABRB1, GABRA1, CDKL5, Recessive: ITPA, KARS). Mutations in KCNT1 (31/79, 39% cases) followed by SCN2A (10/79, 13% cases) were the most frequent cause of EIMFS. Mosaicism was observed in two probands; one with SCN2A and one with GABRB3 mutations. Three unaffected mothers of probands with KCNT1 mutations were mosaic carriers. Median age of seizure onset for the cohort was 1 month, onset for the KCNT1 group was 4 weeks compared to day 2 of life for the SCN2A group. The majority of cases had profound to severe developmental impairment, a range of co-morbidities was seen including movement disorders and scoliosis. Mortality was high (35%) at a mean age of 3 years 5 months. Conclusions: EIMFS is a highly genetically heterogeneous disease, following dominant or recessive inheritance. Our study increases the number of genes associated with EIMFS to 26. We show that 66% of EIMFS cases are genetically solved, a greater proportion of patients than previously thought. KCNT1 remains the most frequently implicated gene. The new genes associated with EIMFS are seen in a small number of patients. It will take larger numbers of patients with each gene to dissect whether the comorbidities associated with EIMFS are gene-dependent or relate to this devastating epilepsy syndrome.  Funding: This study was supported by funding from an Australian National Health and Medical Research Council (NHMRC) Program Grant.