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

Abstract

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