Dataset Information

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

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.

SUBMITTER: Burgess R

PROVIDER: S-EPMC7423163 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

Burgess Rosemary R Wang Shuyu S McTague Amy A Boysen Katja E KE Yang Xiaoling X Zeng Qi Q Myers Kenneth A KA Rochtus Anne A Trivisano Marina M Gill Deepak D Sadleir Lynette G LG Specchio Nicola N Guerrini Renzo R Marini Carla C Zhang Yue-Hua YH Mefford Heather C HC Kurian Manju A MA Poduri Annapurna H AH Scheffer Ingrid E IE

Annals of neurology 20191201 6

<h4>Objective</h4>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.<h4>Methods</h4>Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study.<h4>Results</h4>We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 prev ...[more]

PMID: 31618474

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Project description:SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant's early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.NEW & NOTEWORTHY Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the SCN2A gene encoding NaV1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.

Dataset Information

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

Publications

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.

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