The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications
Por:
Brunklaus A, Brünger T, Feng T, Fons-Estupina C, Lehikoinen A, Panagiotakaki E, Vintan MA, Symonds J, Andrew J, Arzimanoglou A, Delima S, Gallois J, Hanrahan D, Lesca G, MacLeod S, Marjanovic D, McTague A, Nuñez-Enamorado N, Perez-Palma E, Scott Perry M, Pysden K, Russ-Hall SJ, Scheffer IE, Sully K, Syrbe S, Vaher U, Velayutham M, Vogt J, Weiss S, Wirrell E, Zuberi SM, Lal D, Møller RS, Mantegazza M and Cestèle S
Publicada:
21 nov 2022
Ahead of Print:
13 jun 2022
Resumen:
Brain voltage-gated sodium channel Na(V)1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant Na(V)1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 x 10(-7)). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.
Brunklaus et al. describe a spectrum of novel SCN1A epilepsy phenotypes with gain of function properties ranging from neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis, to early onset developmental and epileptic encephalopathies with and without movement disorder, which respond to sodium channel blocking therapies.
Filiaciones:
Brunklaus A:
Institute of Health and Wellbeing, University of Glasgow, UK
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Brünger T:
Cologne Center for Genomics, University of Cologne, Cologne, Germany
Feng T:
Institute of Health and Wellbeing, University of Glasgow, UK
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Fons-Estupina C:
Pediatric Neurology Department. CIBERER-ISCIII. Sant Joan de Déu Universitary Hospital. Institut de Recerca Sant Joan de Déu, Member of the ERN EpiCARE, Barcelona Spain
Lehikoinen A:
Pediatric Neurology Department, Kuopio University Hospital, Member of the ERN EpiCARE, Kuopio, Finland
Panagiotakaki E:
Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL) and Inserm U1028/CNRS UMR5292, Lyon, France
Vintan MA:
'Iuliu Hatieganu' University of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology and Pediatric Neurology, Victor Babes, 43, 400012, Cluj-Napoca, Cluj, Romania
Symonds J:
Institute of Health and Wellbeing, University of Glasgow, UK
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Andrew J:
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Arzimanoglou A:
Pediatric Neurology Department. CIBERER-ISCIII. Sant Joan de Déu Universitary Hospital. Institut de Recerca Sant Joan de Déu, Member of the ERN EpiCARE, Barcelona Spain
Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL) and Inserm U1028/CNRS UMR5292, Lyon, France
Delima S:
Indiana University School of Medicine, IU Health Riley Hospital for Children, Department of Neurology, Division of Pediatric Neurology, Indianapolis, Indiana, USA
Gallois J:
Louisiana State University Health Sciences Center School of Medicine. New Orleans, Louisiana, USA
Hanrahan D:
Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK
Lesca G:
Department of Medical Genetics, Lyon University Hospital, Member of the ERN EpiCARE, Université Claude Bernard Lyon 1, Lyon, France
MacLeod S:
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Marjanovic D:
The Danish Epilepsy Centre, Member of the ERN EpiCARE, Dianalund, Denmark
McTague A:
Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, UK
Department of Neurology, Great Ormond Street Hospital for Children, Member of the ERN EpiCARE, UK
Nuñez-Enamorado N:
Pediatric Neurology Department. 12 Octubre Universitary Hospital, Madrid, Spain
Perez-Palma E:
Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago, Chile
Scott Perry M:
Jane and John Justin Neurosciences Center, Cook Children's Medical Center, Ft Worth, TX, USA
Pysden K:
Paediatric Neurology Department, Leeds Teaching Hospitals, Leeds General Infirmary, Leeds, UK
Russ-Hall SJ:
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
Scheffer IE:
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
Sully K:
Baylor College of Medicine. Houston, Texas, USA
Texas Children's Hospital. Houston, Texas, USA
Syrbe S:
Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Vaher U:
Children's Clinic of Tartu University Hospital, Faculty of Medicine of Tartu University, Member of the ERN EpiCARE, Tartu, Estonia
Velayutham M:
Birmingham Children's Hospital, Birmingham, UK
Vogt J:
West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK
Weiss S:
Division of Neurology, SickKids, University of Toronto, Toronto, Canada
Wirrell E:
Divisions of Epilepsy and Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA
Zuberi SM:
Institute of Health and Wellbeing, University of Glasgow, UK
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK
Lal D:
Cologne Center for Genomics, University of Cologne, Cologne, Germany
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, USA
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA
Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Møller RS:
The Danish Epilepsy Centre, Member of the ERN EpiCARE, Dianalund, Denmark
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Mantegazza M:
Université Cote d'Azur, 06560 Valbonne-Sophia Antipolis, France
CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), 06560 Valbonne-Sophia Antipolis, France
Inserm, 06560 Valbonne-Sophia Antipolis, France
Cestèle S:
Université Cote d'Azur, 06560 Valbonne-Sophia Antipolis, France
CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), 06560 Valbonne-Sophia Antipolis, France
Institute of Health and Wellbeing, University of Glasgow, UK.; The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK.; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Pediatric Neurology Department. CIBERER-ISCIII. Sant Joan de Deu Universitary Hospital. Institut de Recerca Sant Joan de Deu, Member of the ERN EpiCARE, Barcelona Spain.; Pediatric Neurology Department, Kuopio University Hospital, Member of the ERN Ep
Green Submitted, hybrid
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