2. Academic Validation
  3. The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

  • Ann Neurol. 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619.
Rosemary Burgess 1,  Shuyu Wang 1 2,  Amy McTague 3,  Katja E Boysen 1,  Xiaoling Yang 4,  Qi Zeng 4,  Kenneth A Myers 1 5 6,  Anne Rochtus 7,  Marina Trivisano 8,  Deepak Gill 9,  EIMFS Consortium,  Lynette G Sadleir 10,  Nicola Specchio 8,  Renzo Guerrini 11,  Carla Marini 11,  Yue-Hua Zhang 4,  Heather C Mefford 12,  Manju A Kurian 3 13,  Annapurna H Poduri 7 14,  Ingrid E Scheffer 1 15 16 17
Affiliations

Affiliations

  • 1 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
  • 2 School of Clinical Sciences, Monash University, Monash Health, Melbourne, Victoria, Australia.
  • 3 Molecular Neurosciences, Developmental Neurosciences, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
  • 4 Department of Pediatrics, Peking University First Hospital, Beijing, China.
  • 5 Research Institute of the McGill University Health Centre; Montreal, Quebec, Canada.
  • 6 Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • 7 Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA.
  • 8 Rare and Complex Epilepsies Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, Rome, Italy.
  • 9 T. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
  • 10 Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand.
  • 11 Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
  • 12 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
  • 13 Department of Neurology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom.
  • 14 Department of Neurology, Harvard Medical School, Boston, MA.
  • 15 Florey Institute for Neuroscience and Mental Health, Melbourne, Victoria, Australia.
  • 16 Department of Neurology, Royal Children's Hospital, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
  • 17 Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
PMID: 31618474 DOI: 10.1002/ana.25619
Abstract

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.

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