The spectrum of intermediate SCN8A-related epilepsy.

Katrine M Johannesen, Elena Gardella, Alejandra C Encinas, Anna-Elina Lehesjoki, Tarja Linnankivi, Michael B Petersen, Ida Charlotte Bay Lund, Susanne Blichfeldt, Maria J Miranda, Deb K Pal, Karine Lascelles, Peter Procopis, Alessandro Orsini, Alice Bonuccelli, Thea Giacomini, Ingo Helbig, Christina D Fenger, Sanjay M Sisodiya, Laura Hernandez-Hernandez, Sundararaman Krithika, Melissa Rumple, Silvia Masnada, Marialuisa Valente, Cristina Cereda, Lucio Giordano, Patrizia Accorsi, Sarah E Bürki, Margherita Mancardi, Christian Korff, Renzo Guerrini, Sarah von Spiczak, Dorota Hoffman-Zacharska, Tomasz Mazurczak, Antonietta Coppola, Salvatore Buono, Marilena Vecchi, Michael F Hammer, Costanza Varesio, Pierangelo Veggiotti, Dennis Lal, Tobias Brünger, Federico Zara, Pasquale Striano, Guido Rubboli, Rikke S Møller

Journal: Epilepsia 2020;60(5):830-844

PMID: 30968951

Abstract

OBJECTIVE

Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies.

METHODS

A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study.

RESULTS

We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser.

SIGNIFICANCE

With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.

Address: Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.; Graduate Interdisciplinary Program of Genetics, University of Arizona, Tucson, Arizona.; Folkhälsan Research Center, Helsinki, Finland.; Research Programs Unit, Molecular Neurology and Medicum, University of Helsinki, Helsinki, Finland.; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.; Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.; Department of Pediatrics, Herlev Hospital, Herlev, Denmark.; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.; King's College Hospital, London, UK.; Evelina London Children's Hospital, London, UK.; Medical Research Council Centre for Neurodevelopmental Disorders, King's College, London, UK.; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.; Children's Hospital, Westmead, Sydney, New South Wales, Australia.; Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.; Pediatric Neurology, Pediatric Clinic, University of Pisa, Pisa, Italy.; Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, Giannina Gaslini Institute, University of Genoa, Genoa, Italy.; Department of Neuropediatrics, University Medical Center Schleswig Holstein, Kiel, Germany.; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark.; Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.; Chalfont Centre for Epilepsy, Bucks, UK.; Pediatric Neurology, Banner Children's Specialists, Glendale, Arizona.; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.; Genomic and Postgenomic Center, Scientific Institute for Research and Healthcare (IRCCS) Mondino Foundation, Pavia, Italy.; Child Neurology and Psychiatry Unit, Civilian Hospital, Brescia, Italy.; Department of Pediatrics, Division of Child Neurology, University Children's Hospital Bern, University of Bern, Bern, Switzerland.; Unit of Child Neuropsychiatry, Epilepsy Center, Department of Clinical and Surgical Neuroscience and Rehabilitation, Giannina Gaslini Institute, Genoa, Italy.; Child Neurology Unit, University Children's Hospital, Geneva, Switzerland.; Neuroscience Department, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.; Department of Neuropediatrics, Christian Albrecht University, Kiel, Germany.; Northern German Epilepsy Center for Children and Adolescents, Schwentinental, Germany.; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.; Department of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.; Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.; Neurology Division, Hospital of National Relevance (AORN), Santobono Pausilipon, Naples, Italy.; Pediatric Clinic, Hospital Company, University of Padua, Padua, Italy.; University of Arizona Genetic Core, University of Arizona, Tucson, Arizona.; Brain and Behavior Department, University of Pavia, Pavia, Italy.; Child and Adolescence Neurology Department, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.; Department of Child Neurology, V. Buzzi Children's Hospital, Milan, Italy.; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio.; Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Laboratory of Neurogenetics and Neuroscience, Department of Head-Neck and Neuroscience, Giannina Gaslini Institute, Genoa, Italy.; Pediatric Neurology, Pediatric Clinic, University of Studies of Pisa, Pisa, Italy.; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark.; University of Copenhagen, Copenhagen, Denmark.

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