SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.
Adolescent
Adult
Brain
/ diagnostic imaging
Child
Child, Preschool
Epilepsy
/ diagnostic imaging
Female
Fetus
/ diagnostic imaging
Genetic Variation
/ genetics
HEK293 Cells
Humans
Infant
Male
NAV1.3 Voltage-Gated Sodium Channel
/ genetics
Neurodevelopmental Disorders
/ diagnostic imaging
Sodium Channels
/ genetics
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
13
12
2019
revised:
05
05
2020
accepted:
25
05
2020
pubmed:
10
6
2020
medline:
15
12
2020
entrez:
10
6
2020
Statut:
ppublish
Résumé
Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
Identifiants
pubmed: 32515017
doi: 10.1002/ana.25809
pmc: PMC8552104
mid: NIHMS1748544
doi:
Substances chimiques
NAV1.3 Voltage-Gated Sodium Channel
0
SCN3A protein, human
0
Sodium Channels
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
348-362Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : K08 NS097633
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS119977
Pays : United States
Informations de copyright
© 2020 American Neurological Association.
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