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<p>Febrile seizures (FS) are a common childhood neurological condition triggered by fever in children without prior neurological disorders. While generally benign, some individuals, particularly those with complex FS or genetic predispositions, may develop epilepsy or other neurological comorbidities. The mechanisms underlying this transition remain unclear. Mutations in <i>SCN1A</i>, encoding the Na<sub>V</sub>1.1 sodium channel α-subunit, have been linked to several epilepsy syndromes associated with FS. This study examines phenotypic variability in individuals carrying the same <i>SCN1A</i> c.434T &gt; C mutation, using induced pluripotent stem cell (iPSC)-derived neurons from two siblings with FS. Despite sharing the mutation, only the older sibling developed temporal lobe epilepsy (TLE). Transcriptomic analysis revealed downregulation of GABAergic pathway genes in both siblings’ neurons, aligning with <i>SCN1A</i>-associated epilepsy. However, neurons from the sibling with TLE exhibited additional abnormalities, including altered AMPA receptor subunit composition, changes in GABA<sub>A</sub> receptor subunits and chloride cotransporters expression, and reduced brain-derived neurotrophic factor (BDNF) levels, indicative of developmental immaturity. Voltage-clamp recordings confirmed impaired GABAergic and AMPA receptor-mediated synaptic activity. These findings suggest that combined GABAergic dysfunction, aberrant AMPA receptor composition, and reduced BDNF signaling contribute to the more severe phenotype and increased epilepsy susceptibility.</p>

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Transcriptomic and electrophysiological alterations underlying phenotypic variability in SCN1A-associated febrile seizures

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Stefania Scalise,
  • Alessandro Gaeta,
  • Elio Aprigliano,
  • Valeria Lucchino,
  • Raffaele Covello,
  • Mariagrazia Talarico,
  • Barbara Puccio,
  • Pietro Hiram Guzzi,
  • Pierangelo Veltri,
  • Antonio Gambardella,
  • Lilian Juliana Lissner,
  • Alessandra Morano,
  • Pierangelo Cifelli,
  • Veronica Alfano,
  • Eleonora Palma,
  • Gerardo Perozziello,
  • Gabriele Ruffolo,
  • Giovanni Cuda,
  • Elvira Immacolata Parrotta

摘要

Febrile seizures (FS) are a common childhood neurological condition triggered by fever in children without prior neurological disorders. While generally benign, some individuals, particularly those with complex FS or genetic predispositions, may develop epilepsy or other neurological comorbidities. The mechanisms underlying this transition remain unclear. Mutations in SCN1A, encoding the NaV1.1 sodium channel α-subunit, have been linked to several epilepsy syndromes associated with FS. This study examines phenotypic variability in individuals carrying the same SCN1A c.434T > C mutation, using induced pluripotent stem cell (iPSC)-derived neurons from two siblings with FS. Despite sharing the mutation, only the older sibling developed temporal lobe epilepsy (TLE). Transcriptomic analysis revealed downregulation of GABAergic pathway genes in both siblings’ neurons, aligning with SCN1A-associated epilepsy. However, neurons from the sibling with TLE exhibited additional abnormalities, including altered AMPA receptor subunit composition, changes in GABAA receptor subunits and chloride cotransporters expression, and reduced brain-derived neurotrophic factor (BDNF) levels, indicative of developmental immaturity. Voltage-clamp recordings confirmed impaired GABAergic and AMPA receptor-mediated synaptic activity. These findings suggest that combined GABAergic dysfunction, aberrant AMPA receptor composition, and reduced BDNF signaling contribute to the more severe phenotype and increased epilepsy susceptibility.