Phenotypic and genetic spectrum of SCN 8A‐related disorders, treatment options, and outcomes
Open accessAbstract
Pathogenic variants in SCN 8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN 8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN 8A‐DEE is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic‐clonic manifestations. Spasm‐like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEG s) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild‐to‐moderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN 8A‐DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN 8A‐related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN 8A‐DEE s occur de novo.
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SCBs, particularly carbamazepine and phenytoin, are efficacious in GOF-DEEs due to pathogenic variants in sodium channel (SCN1A, SCN2A and SCN8A) and potassium channel (KCNQ2) genes.
“SCBs, particularly carbamazepine and phenytoin, are efficacious in GOF-DEEs due to pathogenic variants in sodium channel (SCN1A 33 , SCN2A 184 and SCN8A 185 ) and potassium channel (KCNQ2 43 ) genes.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [185]
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Flagged first, then by citations
Research works printed but not linked: 2
- Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014; 55: 994-1000.
- Johannesen KM, Gardella E, Encinas AC, Lehesjoki AE, Linnankivi T, et al. The spectrum of intermediate SCN8A-related epilepsy. Epilepsia 2019; 60: 830-844.
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Developmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 128 · see citing works
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- Authors
- Gardella, E., & Møller, R. S.
- Affiliations
- University of Southern Denmark (DK)
- Corresponding author
- Gardella, Elena
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2019-12
- Volume
- 60
- Issue
- S3
- Pages
- S77-S85
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W2999010344
- Cited by
- 104
- References
- 43
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 19 · 2023: 9 · 2022: 18 · 2021: 21 · 2020: 15 · 2019: 1
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- SCN8A, developmental and epileptic encephalopathy, sodium channelopathy, phenotypic spectrum, intellectual disability, extrapyramidal signs, paroxysmal dyskinesia, status epilepticus, sodium channel blockers, ketogenic diet, levetiracetam, autosomal dominant inheritance, de novo mutations, treatment outcomes
- MeSH terms
- Adolescent, Adult, Brain Diseases, Child, Child, Preschool, Death, Sudden, Electroencephalography, Epilepsy, Female, Humans, Infant, Male, Intellectual Disability, Mutation, Seizures, Young Adult, NAV1.6 Voltage-Gated Sodium Channel
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