title: Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: associated with loss of function of Na(v) 1.1.
abstract: OBJECTIVE
  Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs.
  
  
  METHODS
  Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high-performance liquid chromatography (dHPLC) and sequencing. Whole-cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Na(v) 1.1 in tsA201 cells.
  
  
  RESULTS
  Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Na(v) 1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED-induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues.
  
  
  CONCLUSIONS
  Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Na(v) 1.1, which may be the basis of seizure aggravation by sodium channel-blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.
authors.affiliation: Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China. wpliao@tom.com
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Liao
authors.forename: Yi-Wu
authors.initials: YW
authors.lastname: Shi
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Long
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.forename: Tian
authors.initials: T
authors.lastname: Li
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Yu
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.forename: Ping
authors.initials: P
authors.lastname: Deng
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Lei
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Xu
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Deng
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Liu
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Sun
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Yi
authors.forename: Zao C
authors.initials: ZC
authors.lastname: Xu
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D053447:Channelopathies / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D004828:Epilepsies, Partial / Q000235:genetics* / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D003294:Seizures, Febrile / Q000235:genetics* / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: D000927:Anticonvulsants; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C470379:SCN1B protein, human; C568251:SCN2A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit