The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

• Published in: Annals of neurology 2019-12, Vol.86 (6), p.821-831
• Main Authors: Burgess, Rosemary, Wang, Shuyu, McTague, Amy, Boysen, Katja E., Yang, Xiaoling, Zeng, Qi, Myers, Kenneth A., Rochtus, Anne, Trivisano, Marina, Gill, Deepak, Sadleir, Lynette G., Specchio, Nicola, Guerrini, Renzo, Marini, Carla, Zhang, Yue‐Hua, Mefford, Heather C., Kurian, Manju A., Poduri, Annapurna H., Scheffer, Ingrid E.
• Format: Article
• Language: English
• Subjects: Adolescent; Child; Child, Preschool; Cohort Studies; Convulsions & seizures; Epilepsy; Female; Gene expression; Genes; Genetic Predisposition to Disease - genetics; Genotypes; Heterogeneity; Humans; Infant; Ion channels; KCNQ2 protein; Male; Microencephaly; Mosaicism; Movement disorders; Phenotypes; Potassium channels (voltage-gated); Protein transport; Scoliosis; Seizures; Seizures - diagnosis; Seizures - genetics; Seizures - physiopathology; Spasms; Spasms, Infantile - diagnosis; Spasms, Infantile - genetics; Spasms, Infantile - physiopathology; Spasticity
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25619

Objective Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype–phenotype correlations of a large EIMFS cohort. Methods Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results We ascertained 135 patients from 128 unrelated families. Ninety‐three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X‐linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821–831