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

doi:10.1002/ana.25619

Author(s)

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

Publication Date

2019

Abstract

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. Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. 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. 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. This article is protected by copyright. All rights reserved.

Citation

Annals of neurology 2019; 86(6): 821-831

Jornal Title

Annals of neurology

OrcId

0000-0002-2664-4395

0000-0002-2311-2174

0000-0001-7831-4593

Link

https://ahro.austin.org.au/austinjspui/handle/1/21920

Title

Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

Type of document

Journal Article

Austin Health

Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

Files:

Author(s)	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
Publication Date	2019
Abstract	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. Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. 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. 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. This article is protected by copyright. All rights reserved.
Citation	Annals of neurology 2019; 86(6): 821-831
Jornal Title	Annals of neurology
OrcId	0000-0002-2664-4395 0000-0002-2311-2174 0000-0001-7831-4593
Link	https://ahro.austin.org.au/austinjspui/handle/1/21920
Title	Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Type of document	Journal Article