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<p>High expression of the voltage-gated sodium channel NaV1.6 is essential for regulating neuronal excitability in both the central and peripheral nervous systems. Dysfunction of NaV1.6 has been associated with movement disorders, intellectual disability, and developmental and epileptic encephalopathy. We describe a patient from a consanguineous family presenting severe developmental and epileptic encephalopathy accompanied by deafness and atypical MRI abnormalities. Biochemical investigations revealed mildly elevated lactate levels in blood and cerebrospinal fluid. Whole-exome sequencing identified a heterozygous missense variant in the SCN8A gene (NM_014191.4: c.2548&#xa0;C &gt; G; NC_000012.12: g.51765674&#xa0;C &gt; G, GRCh38), which was confirmed by Sanger sequencing. Bioinformatic analyses and three-dimensional structural modeling suggested that the p.Arg850Gly variant is highly deleterious and affects the structural stability of the NaV1.6 protein, which plays a key role in neuronal excitability. In addition, WES revealed a novel de novo heteroplasmic mitochondrial variant in MT-ND5 (m.12758T &gt; A; p. Phe141Tyr), predicted to destabilize ND5 and its interaction with ND4, impairing complex I function and then mitochondrial energy production. It could act as a modifier that exacerbates neuronal vulnerability, contributing to hearing loss and atypical MRI findings, which could also be sufficiently related to the <i>SCN8A</i> mutation. These hypotheses are not mutually exclusive and suggest that a combination of primary channel dysfunction and an additional mitochondrial compromise may underlie the observed phenotype. This case highlights the phenotypic complexity of developmental and epileptic encephalopathy and expands the clinical spectrum associated with <i>SCN8A.</i></p>

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Expanding the Clinical Spectrum of SCN8A-Related Epileptic Encephalopathy: Additional Auditory Impairment, Atypical MRI Abnormalities and Putative Mitochondrial Involvement

  • 期刊论文

  • 发表日期：

    2026年2月12日

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  • Marwa Maalej,
  • Lamia Sfaihi,
  • Roeya Kolsi,
  • Olfa Alila-fersi,
  • Marwa Ammar,
  • Thouraya Kammoun,
  • Abdelaziz Tlili,
  • Faiza Fakhfakh

摘要

High expression of the voltage-gated sodium channel NaV1.6 is essential for regulating neuronal excitability in both the central and peripheral nervous systems. Dysfunction of NaV1.6 has been associated with movement disorders, intellectual disability, and developmental and epileptic encephalopathy. We describe a patient from a consanguineous family presenting severe developmental and epileptic encephalopathy accompanied by deafness and atypical MRI abnormalities. Biochemical investigations revealed mildly elevated lactate levels in blood and cerebrospinal fluid. Whole-exome sequencing identified a heterozygous missense variant in the SCN8A gene (NM_014191.4: c.2548 C > G; NC_000012.12: g.51765674 C > G, GRCh38), which was confirmed by Sanger sequencing. Bioinformatic analyses and three-dimensional structural modeling suggested that the p.Arg850Gly variant is highly deleterious and affects the structural stability of the NaV1.6 protein, which plays a key role in neuronal excitability. In addition, WES revealed a novel de novo heteroplasmic mitochondrial variant in MT-ND5 (m.12758T > A; p. Phe141Tyr), predicted to destabilize ND5 and its interaction with ND4, impairing complex I function and then mitochondrial energy production. It could act as a modifier that exacerbates neuronal vulnerability, contributing to hearing loss and atypical MRI findings, which could also be sufficiently related to the SCN8A mutation. These hypotheses are not mutually exclusive and suggest that a combination of primary channel dysfunction and an additional mitochondrial compromise may underlie the observed phenotype. This case highlights the phenotypic complexity of developmental and epileptic encephalopathy and expands the clinical spectrum associated with SCN8A.