Deciphering the Natural History of SCN8A -Related Disorders DOI
Jan Magielski, Stacey Cohen, Michael C. Kaufman

et al.

Neurology, Journal Year: 2025, Volume and Issue: 104(9)

Published: April 14, 2025

SCN8A-related disorders encompass a range of neurodevelopmental and epilepsy phenotypes. However, despite representing one the most common epilepsy-associated channelopathies, its longitudinal phenotypes remain largely uncharacterized. In this study, we harmonized electronic medical record data from 82 individuals with to reconstruct natural history disorder in comparison cohort 2,833 known or presumed genetic epilepsies. Compared other epilepsies, those (mean age = 8.3 years, 52% female) had >10-fold odds bilateral tonic-clonic seizures as early at 1 year (p 1.70 × 10-14, OR 10.56, CI 5.85-18.90). Individuals carrying gain-of-function (GOF) SCN8A variants particularly high seizure risk 6 months 0.007/pthreshold 4.25 10-4, 4.71, 1.36-21.25) an increased global developmental delay 3 0.002/pthreshold 4.72 10-5, 5.67, 1.74-20.23) when compared broader cohort. loss-of-function were more likely have atypical absence seizures, prominently years 0.013/pthreshold 7.08 32.71, 1.44-2,193.51). cohort, recurrent p.Arg850Gln variant infantile spasms p.Arg1872Trp/Gln/Leu hotspot neonatal seizures. p.Gly1475Arg active after 5 age. later childhood, focal prominent p.Arg1617Gln while generalized-onset p.Asn1877Ser variant. We also established effectiveness sodium channel blockers managing GOF whose not been functionally characterized, suggesting that many unstudied may mechanisms. distinguish themselves epilepsies by frequent infancy, epileptic features carriers, unique variants. Our study provides perspective on disorders, paving way for future precision medicine approaches.

Language: Английский

Deciphering the Natural History of SCN8A -Related Disorders DOI
Jan Magielski, Stacey Cohen, Michael C. Kaufman

et al.

Neurology, Journal Year: 2025, Volume and Issue: 104(9)

Published: April 14, 2025

SCN8A-related disorders encompass a range of neurodevelopmental and epilepsy phenotypes. However, despite representing one the most common epilepsy-associated channelopathies, its longitudinal phenotypes remain largely uncharacterized. In this study, we harmonized electronic medical record data from 82 individuals with to reconstruct natural history disorder in comparison cohort 2,833 known or presumed genetic epilepsies. Compared other epilepsies, those (mean age = 8.3 years, 52% female) had >10-fold odds bilateral tonic-clonic seizures as early at 1 year (p 1.70 × 10-14, OR 10.56, CI 5.85-18.90). Individuals carrying gain-of-function (GOF) SCN8A variants particularly high seizure risk 6 months 0.007/pthreshold 4.25 10-4, 4.71, 1.36-21.25) an increased global developmental delay 3 0.002/pthreshold 4.72 10-5, 5.67, 1.74-20.23) when compared broader cohort. loss-of-function were more likely have atypical absence seizures, prominently years 0.013/pthreshold 7.08 32.71, 1.44-2,193.51). cohort, recurrent p.Arg850Gln variant infantile spasms p.Arg1872Trp/Gln/Leu hotspot neonatal seizures. p.Gly1475Arg active after 5 age. later childhood, focal prominent p.Arg1617Gln while generalized-onset p.Asn1877Ser variant. We also established effectiveness sodium channel blockers managing GOF whose not been functionally characterized, suggesting that many unstudied may mechanisms. distinguish themselves epilepsies by frequent infancy, epileptic features carriers, unique variants. Our study provides perspective on disorders, paving way for future precision medicine approaches.

Language: Английский

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