SCN8A – Early Infantile Epileptic Encephalopathy-13

SCN8A encodes the voltage-gated sodium channel Nav1.6, broadly expressed in central and peripheral neurons. Heterozygous de novo mutations in SCN8A underlie Early Infantile Epileptic Encephalopathy-13 (EIEE13), characterized by refractory seizures, developmental regression, movement disorders, and elevated SUDEP risk. Genetic testing for SCN8A variants is therefore critical in infants with early-onset epileptic encephalopathy.

Three unrelated probands have been reported with de novo missense SCN8A variants: one presented with neonatal tremor episodes and hyperekplexia-like startles in association with pharmacoresistant epilepsy (PMID:30078772), a second with infantile spasms evolving to focal and generalized tonic-clonic seizures (PMID:35188110), and a third requiring perioperative management under neuraxial anesthesia (PMID:36357057).

Missense variants predominate in EIEE13, particularly in voltage-sensor and pore regions. Recurrent hotspots include p.Thr767Ile (c.2003C>T) and p.Arg1872Trp with gain-of-function effects. Rare loss-of-function alleles present with intellectual disability without seizures, underscoring variant-specific phenotypic spectra.

Inheritance is autosomal dominant with de novo occurrence in all reported EIEE13 cases; no familial segregation of the epileptic phenotype has been documented. Segregation analyses have not identified unaffected carriers among first-degree relatives.

Functional assays in heterologous systems demonstrate gain-of-function mechanisms: p.Thr767Ile shows enhanced channel activation (PMID:24874546), p.Arg233Gly exhibits reduced current amplitude but increased slow ramp response (PMID:25239001), and p.Arg1913Trp impairs inactivation leading to elevated persistent current (PMID:30615041).

Knock-in mouse models recapitulate the human phenotype: Scn8aAsn1768Asp/+ mice develop convulsive seizures and SUDEP (PMID:25227913), while conditional expression of p.Arg1872Trp in excitatory neurons induces early lethality (PMID:30601941).

Collectively, the genetic and experimental concordance supports a Moderate clinical validity for SCN8A-EIEE13. Functional data reach Strong levels under ClinGen criteria. SCN8A testing should be included in gene panels for infantile epileptic encephalopathy, and variant-specific functional classification can inform precision therapy.

Key Take-home: De novo SCN8A gain-of-function variants cause EIEE13; genetic diagnosis enables targeted management and informs antiepileptic drug selection.

References

• Epileptic disorders : international epilepsy journal with videotape | 2018 | Neonatal tremor episodes and hyperekplexia-like presentation at onset in a child with SCN8A developmental and epileptic encephalopathy PMID:30078772
• Acta bio-medica : Atenei Parmensis | 2022 | A Novel SCN8A mutation in a case of early-onset infantile epileptic encephalopathy: A Case Report. PMID:35188110
• Brazilian journal of anesthesiology | 2022 | Neuraxial block anesthetic technique in a patient with SCN8A encephalopathy: case report. PMID:36357057
• Neurobiology of disease | 2014 | A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. PMID:24874546
• Epilepsy research | 2014 | Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. PMID:25239001
• Human molecular genetics | 2015 | Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. PMID:25227913
• Brain : a journal of neurology | 2019 | Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. PMID:30601941

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