P.120 Case series: Clinical and genetic spectrum of SCN8A-related disorders in British Columbia

• Published in: Canadian journal of neurological sciences 2021-11, Vol.48 (s3), p.S53-S53
• Main Authors: Hebbar, M, Al-Taweel, N, Gill, I, Boelman, C, Dean, RA, Goodchild, SJ, Mezeyova, J, Shuart, NG, Johnson, JP, Lee, J, Michoulas, A, Huh, LL, Armstrong, L, Connolly, MB, Demos, M
• Format: Article
• Language: English
• Subjects: Autism; Child Neurology (CACN); Convulsions & seizures; Epilepsy; Intellectual disabilities; Other Child Neurology; Poster Presentations
• ISSN: 0317-1671; 2057-0155
• DOI: 10.1017/cjn.2021.396

Background: Children with pathogenic variations in SCN8A can present with early infantile epileptic encephalopathy-13, benign familial infantile seizures-5 or intellectual disability alone without epilepsy. In this case series, we discuss six children with variants in SCN8A managed at BC Children’s Hospital. Methods: We describe clinical and genetic results on six individuals with SCN8A variants identified via clinical or research next-generation sequencing. Functional consequences of two SCN8A variants were assessed using electrophysiological analyses in transfected cells. Results: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Phenotypes and genotypes in our cohort are described in the table below. Functional analysis supported gain-of-function in P2 and loss-of-function in P4. Conclusions: Our cohort expands the clinical and genotypic spectrum of SCN8A-related disorders. We establish functional evidence for two missense variants in SCN8A, including LoF variant in a patient with intellectual disability, and autism spectrum disorder without seizures. Table for P.120 Patients Age/Sex Development Age of seizure onset Epilepsy type Current antiseizure medication Seizure frequency Gene variant/Function Inheritance P1 14y/F Profound GDD 5m Infantile spasms, LGS, hyperkinetic movements Clobazam Daily c.1238C>A (p.Ala413Asp) De novo P2 6y/F Normal 3-7m Focal epilepsy Carbamazepine Seizure free c.5630A>G (p.Asn1877Ser)/GoF Paternal P3 4y/F Normal 12m Focal epilepsy Clobazam, topiramate Seizure free c.4447G>A (p.Glu1483Lys) De novo P4 6y/F GDD, autism 3y - EEG abnormality only - Sodium valproate (discontinued) No clinical seizure c.971G>A (p.Cys324Tyr)/LoF, VUS in KCNQ3 De novo P5 7y/M GDD 5m Generalized seizures Ethosuximide, acetazolamide Daily c.773C>T (p.Thr258Ile) De novo P6 19y/F Normal 10y Focal epilepsy Carbamazepine Seizure free c.986A>G (p.Asp329Gly) De novo Abbreviations: *Father with similar history, y Years, m Months, GDD Global developmental delay, LGS Lennox-Gastaut syndrome, VUS Variant of unknown significance, LoF Loss-of-function, GoF Gain-of-function, EEG Electroencephalogram, F - Female, M - Male, CBD - Cannabidiol