Authors :
Andreas Brunklaus, MD – University of Glasgow; Tobias Brünger, PhD – Cologne Center for Genomics, University of Cologne, Cologne, Germany; Tony Feng, Medical Student – Institute of Health and Wellbeing, University of Glasgow, UK; Carmen Fons Carmen Fons, MD – Pediatric Neurology Department. CIBERER-ISCIII. Sant Joan de Déu Universitary Hospital.; Anni Lehikoinen, MD – Pediatric Neurology Department, Kuopio University Hospital; Eleni Panagiotakaki, MD – Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL); Mihaela-Adela Vintan, MD – '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; Joseph Symonds, PhD – The Paediatric Neurosciences Research Group, Royal Hospital for Children; James Andrew, MD – The Paediatric Neurosciences Research Group, Royal Hospital for Children; Alexis Arzimanoglou, MD – Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL); Sarah Delima, MD – Indiana University School of Medicine, IU Health Riley Hospital for Children, Department of Neurology, Division of Pediatric Neurology, Indianapolis, Indiana, USA; Julie Gallois, MD – Louisiana State University Health Sciences Center School of Medicine. New Orleans, Louisiana, USA; Donncha Hanrahan, MD – Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK; Gaetan Lesca, PhD – Department of Medical Genetics, Lyon University Hospital, Member of the ERN EpiCARE, Université Claude Bernard Lyon 1, Lyon, France; Stewart MacLeod, MD – The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK; Dragan Marjanovic, MD – The Danish Epilepsy Centre, Member of the ERN EpiCARE, Dianalund, Denmark; Amy McTague, PhD – Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, UK; Noemi Nuñez-Enamorado, MD – Pediatric Neurology Department. 12 Octubre Universitary Hospital, Madrid, Spain; Eduardo Perez-Palma, PhD – Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago, Chile; M. Scott Perry, MD – Jane and John Justin Neurosciences Center, Cook Children’s Medical Center, Ft Worth, TX, USA; Karen Pysden, MD – Paediatric Neurology Department, Leeds Teaching Hospitals, Leeds General Infirmary, Leeds, UK; Sophie J. Russ-Hall, MD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Ingrid E. Scheffer, PhD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Krystal Sully, MD – Texas Children's Hospital. Houston, Texas, USA; Steffen Syrbe, MD – Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; Ulvi Vaher, MD – Children’s Clinic of Tartu University Hospital, Faculty of Medicine of Tartu University, Member of the ERN EpiCARE, Tartu, Estonia; Murugan Velayutham, MD – Birmingham Children’s Hospital, Birmingham, UK; Julie Vogt, MD – West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK; Shelly Weiss, MD – Division of Neurology, SickKids, University of Toronto, Toronto, Canada; Elaine Wirrell, MD – Divisions of Epilepsy and Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA; Sameer M Zuberi, MD – The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE, Glasgow, UK; Dennis Lal, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, USA; Rikke S. Møller, PhD – The Danish Epilepsy Centre, Member of the ERN EpiCARE, Dianalund, Denmark; Massimo Mantegazza, PhD – Université Cote d'Azur, 06560 Valbonne-Sophia Antipolis, France; Sandrine Cestèle, PhD – Université Cote d'Azur, 06560 Valbonne-Sophia Antipolis, France
This abstract has been invited to present during the Pediatric Epilepsy Highlights platform sessionRationale: Brain voltage-gated sodium channel Na
V1.1 (SCN1A) loss of function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus (GEFS+). Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3 (FHM3). 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.
Methods: 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 vs. variant Na
V1.1 subunits. Findings were related to Dravet syndrome and FHM3 variants.
Results: 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 (
OR = 17.8; CI = 5.4-69.3; P = 1.3 x 10
-7).
Functional studies of both epilepsy and FHM3 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 GOF, FHM3 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 GOF. 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.
Conclusions: 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 FHM3, 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.
Funding: The work of D.L. was supported by funds from the DSF, the BMBF and NIH NINDS. The work of M.M. and S.C. was supported by the Laboratory of Excellence “Ion Channel Science and Therapeutics.”