Clinical characteristics and genetic analysis of pediatric patients with sodium channel gene mutation-related childhood epilepsy: a review of 94 patients

Objective This study aimed to examine the clinical and gene-mutation characteristics of pediatric patients with sodium channel gene mutation-related childhood epilepsy and to provide a basis for precision treatment and genetic counseling. Methods The clinical data from 94 patients with sodium channel gene mutation-related childhood epilepsy who were treated at Hunan Children's Hospital from August 2012 to December 2022 were retrospectively evaluated, and the clinical characteristics, gene variants, treatment, and follow-up status were analyzed and summarized. Results Our 94 pediatric patients with sodium channel gene variant-related childhood epilepsy comprised 37 girls and 57 boys. The age of disease onset ranged from 1 day to 3 years. We observed seven different sodium channel gene variants, and 55, 14, 9, 6, 6, 2, and 2 patients had SCNlA, SCN2A, SCN8A, SCN9A, SCN1B, SCN11A, and SCN3A variants, respectively. We noted that 52 were reported variants and 42 were novel variants. Among all gene types, SCN1A, SCN2A, and SCN8A variants were associated with an earlier disease onset age. With the exception of the SCN1B, the other six genes were associated with clustering seizures. Except for variants SCN3A and SCN11A, some patients with other variants had status epilepticus (SE). The main diagnosis of children with SCN1A variants was Dravet syndrome (DS) (72.7%), whereas patients with SCN2A and SCN8A variants were mainly diagnosed with various types of epileptic encephalopathy, accounting for 85.7% (12 of 14) and 88.9% (8 of 9) respectively. A total of five cases of sudden unexpected death in epilepsy (SUDEP) occurred in patients with SCN1A, SCN2A, and SCN8A variants. The proportion of benign epilepsy in patients with SCN9A, SCN11A, and SCN1B variants was relatively high, and the epilepsy control rate was higher than the rate of other variant types. Conclusion Sodium channel gene variants involve different epileptic syndromes, and the treatment responses also vary. We herein reported 42 novel variants, and we are also the first ever to report two patients with SCN11A variants, thereby increasing the gene spectrum and phenotypic profile of sodium channel dysfunction. We provide a basis for precision treatment and prognostic assessment.

[1]  Christopher H. Thompson,et al.  Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties , 2023, The Journal of general physiology.

[2]  Christopher H. Thompson,et al.  Epilepsy-associated SCN2A (NaV1.2) Variants Exhibit Diverse and Complex Functional Properties , 2023, bioRxiv.

[3]  Pu Wang,et al.  Effects of repetitive transcranial magnetic stimulation on motor function and language ability in cerebral palsy: A systematic review and meta-analysis , 2023, Frontiers in Pediatrics.

[4]  I. Scheffer,et al.  Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies , 2023, Neurology.

[5]  I. Scheffer,et al.  Functional correlates of clinical phenotype and severity in recurrent SCN2A variants , 2022, Communications Biology.

[6]  J. Appendino,et al.  SCN2A-related epilepsy of infancy with migrating focal seizures: report of a variant with apparent gain and loss of function effects. , 2022, Journal of neurophysiology.

[7]  Haiqin Liu,et al.  Assessment of event-related evoked potentials and China-Wechsler intelligence scale for cognitive dysfunction in children with obstructive sleep apnea. , 2021, International journal of pediatric otorhinolaryngology.

[8]  M. Hammer,et al.  SCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders. , 2021, Pediatric neurology.

[9]  B. Castellotti,et al.  Paroxysmal tonic upgaze in a child with SCN8A-related encephalopathy. , 2021, Epileptic disorders : international epilepsy journal with videotape.

[10]  Hongxia Ma,et al.  Mutations in the sodium channel genes SCN1A, SCN3A, and SCN9A in children with epilepsy with febrile seizures plus(EFS+) , 2021, Seizure.

[11]  S. Mohammad,et al.  Dominant SCN2A mutation with variable phenotype in two generations , 2020, Brain and Development.

[12]  Mingwu Chen,et al.  Novel mutation of SCN9A gene causing generalized epilepsy with febrile seizures plus in a Chinese family , 2020, Neurological Sciences.

[13]  Flip Mulder,et al.  Modifier genes in SCN1A‐related epilepsy syndromes , 2020, Molecular genetics & genomic medicine.

[14]  Sean K. Simmons,et al.  Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders. , 2019, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[15]  W. Gaillard,et al.  A multi-disciplinary clinic for SCN8A-related epilepsy , 2019, Epilepsy Research.

[16]  E. Bartolini,et al.  Epilepsy and brain channelopathies from infancy to adulthood , 2019, Neurological Sciences.

[17]  B. Ceulemans,et al.  SCN1B‐linked early infantile developmental and epileptic encephalopathy , 2019, Annals of clinical and translational neurology.

[18]  Jacy L. Wagnon,et al.  Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy , 2019, Epilepsia.

[19]  Shannon Rego,et al.  Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B , 2019, American journal of medical genetics. Part A.

[20]  Yuan Shen,et al.  SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine , 2019, Neuroscience Bulletin.

[21]  Yonghua Ji,et al.  Understanding Genotypes and Phenotypes of Voltage-Gated Sodium Channel Mutations in Epilepsy. , 2019, CNS & neurological disorders drug targets.

[22]  B. Xiao,et al.  SCN1B and SCN2B gene variants analysis in dravet syndrome patients , 2019, Medicine.

[23]  I. Scheffer,et al.  Early mortality in SCN8A-related epilepsies , 2018, Epilepsy Research.

[24]  F. Gao,et al.  Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases , 2018, Neurological Sciences.

[25]  L. Lagae,et al.  Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders , 2017, Brain : a journal of neurology.

[26]  S. Petrou,et al.  Role of Sodium Channels in Epilepsy. , 2016, Cold Spring Harbor perspectives in medicine.

[27]  G. Kirov,et al.  Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation , 2016, Psychiatric genetics.

[28]  V. Pascali,et al.  Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing , 2016, International Journal of Legal Medicine.

[29]  E. Gaily,et al.  Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia , 2016, Journal of Neurology.

[30]  J. Payandeh,et al.  The hitchhiker’s guide to the voltage-gated sodium channel galaxy , 2016, The Journal of general physiology.

[31]  H. Deng,et al.  The Molecular Biology of Genetic-Based Epilepsies , 2014, Molecular Neurobiology.

[32]  R. Guerrini.  Dravet syndrome: the main issues. , 2012, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[33]  K. Veeramah,et al.  De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. , 2012, American journal of human genetics.

[34]  W. Catterall,et al.  NaV1.1 channels and epilepsy , 2010, The Journal of physiology.

[35]  J. Trimmer,et al.  Localization and targeting of voltage-dependent ion channels in mammalian central neurons. , 2008, Physiological reviews.

[36]  C. Chabbert,et al.  Molecular diversity of voltage-gated sodium channel alpha subunits expressed in neuronal and non-neuronal excitable cells , 2005, Neuroscience.

[37]  Steven Petrou,et al.  SCN1A mutations and epilepsy , 2005, Human mutation.

[38]  Samuel F. Berkovic,et al.  Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B , 1998, Nature Genetics.