Scn8a- Understanding The Genotype Implications On Phenotype

Objective- SCN8A-mutations cause developmental-epileptic encephalopathy(DEE),intermediate phenotype(IE), neurodevelopmental disorder-generalised epilepsy(GE). We attempt understanding genotype-phenotype corelation for SCN8A in Indian-cohort. Methods- We circulated predesigned sheet among child-neurologists for data of SCN8A-positive patients. Mutations identified from scn8a.net; classified from published literature. Treatment response noted by development-progression, reduction in seizure frequency. Results- Twelve patients with denovo SCN8A-mutations reported. Seizures onset: mean 9-months(5 days-4 years); unprovoked in 20/21, fever-provoked in 2/21. Seizures semiology: focal, tonic, generalised tonic-clonic, atonic, epileptic-spasms. DEE in 7, IE-7, GE-4, BFIE-3. All patients had delayed development; mild(6), severe(7), isolated social-communication(7), 16/21 regressed after seizure-onset. Neuroimaging suggested prominent CSF-spaces(3), delayed-myelination(3), cortical-cerebellar atrophy(1), normal(10). EEG at presentation: multifocal epileptiform discharges(6), focal discharges(5), hypsarrhythmia(2) normal(8). Subsequent changes: multifocal-discharges(15), LGS-like(2), normal(2). Treatment given: monotherapy: oxcarbazepine(3), topiramate(1), levetiracetam(1),phenytoin(1); polytherapy:valproate(7),topiramate(6),oxcarbazepine(5),levetiracetam(4),clobazam(4), lamotrigine(5),zonisamide(3),vigabatrin(3),phenobarbitone(1),lacosamide(1). 11 denovo-mutations: Reported gain of function(GOF) are Arg1872Trp, Arg1617Pro, Ile1631Met, Arg1617Gln; loss of function(LOF) are Ile1605Tyr, Met1481Ile, Val409Met. Val1473Ile, a known LOF-mutation with GOF-phenotype. Functional status of 10variants unreported-Ile1053Ser,Gly538Ser, Gln74Lys,Asn1109Lys,Ile884Met,Phe540Leu,Phe1459Leu,Cys1171Tyr,Met1530Ile, Chr122901+35C>A. All GOF patients(5/21) had seizure-onset <6months, delayed development before seizure-onset. First EEG showed multifocal-discharges; non-specific MRI findings. Seizures: multiple-semiologies, refractory to treatment; maximum seizure-control with sodium channel blockers. All LOF patients(4/21) had seizure-onset at mean 20-months; normal motor development; severely delayed language, cognition; autistic regression at mean 19-months. Motor development regressed with seizure-onset, improved with seizure control. First EEG-normal; multifocal-discharges on progression. Multiple semiology noted; partial treatment response to sodium channel blockers alone/polytherapy. Conclusion- SCN8A-mutations, LOF/GOF, cause neurodevelopmental-disorders with seizures. Functional status of gene helps drug-selection, prognostication.