SCN3A ‐Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation
Year: 2020
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: 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. METHODS: 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). RESULTS: 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. INTERPRETATION: 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.
Source: Annals of Neurology
DOI: 10.1002/ana.25809
Authors: Tariq Zaman, Katherine L. Helbig, Jérôme Clatot, Christopher H. Thompson, Seok Kyu Kang, Katrien Stouffs, Anna E. Jansen, Lieve Verstraete, Adeline Jacquinet, Elena Parrini, Renzo Guerrini, Yuh Fujiwara, Satoko Miyatake, Bruria Ben‐Zeev, Haim Bassan, Orit Reish, Daphna Marom, Natalie Hauser, Thuy‐Anh Vu, Sally Ackermann, Careni E. Spencer, Natalie Lippa, Shraddha Srinivasan, Agnieszka Charzewska, Dorota Hoffman‐Zacharska, David Fitzpatrick, Victoria Harrison, Pradeep Vasudevan, Shelagh Joss, Daniela T. Pilz, Katherine A. Fawcett, Ingo Helbig, Naomichi Matsumoto, Jennifer A. Kearney, Andrew E. Fry, Ethan M. Goldberg
Institutions: Children's Hospital of Philadelphia, Northwestern University, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Université Libre de Bruxelles, Centre Hospitalier Universitaire de Liège, Meyer Children's Hospital, University of Florence, Yokohama City University Medical Center, Yokohama City University, Tel Aviv University, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Assaf Harofeh Medical Center, Inova Health System, Inova Fairfax Hospital, Children's National, University of Cape Town, Red Cross War Memorial Children's Hospital, Groote Schuur Hospital, Columbia University Irving Medical Center, Instytut Matki i Dziecka, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Princess Anne Hospital, National Health Service, University Hospitals of Leicester NHS Trust, Queen Elizabeth University Hospital, Cardiff University, John Radcliffe Hospital, MRC Weatherall Institute of Molecular Medicine, Medical Research Council, University of Pennsylvania, University Hospital of Wales
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Elucidating genetic cause and patho-mechanism of neuromusucular disorders using long-read sequencer, G2281980412, Disease-related genome analyses by long-read sequencers, G4612446324, G537477223, G6049477632, Comprehensive genomic analysis on perisylvian syndrome, Dynamic two-photon calcium imaging and optogenetic manipulation of epileptic brain circuits in an experimental model of temporal lobe epilepsy, G7609172052, G7901838685, Pathomechanisms of SCN3A-related neurodevelopmental disorder
OpenAlex ID: W3034006522