The spectrum of intermediate SCN8A-related epilepsy

Katrine M Johannesen^{1

2}, Elena Gardella^{1

2}, Alejandra C Encinas³, Anna-Elina Lehesjoki^{4

5}, Tarja Linnankivi⁶, Michael B Petersen^{7

8}, Ida Charlotte Bay Lund⁷, Susanne Blichfeldt⁹, Maria J Miranda⁹, Deb K Pal^{10

11

12

13}, Karine Lascelles¹⁰, Peter Procopis^{14

15}, Alessandro Orsini¹⁶, Alice Bonuccelli¹⁶, Thea Giacomini¹⁷, Ingo Helbig^{18

19}, Christina D Fenger¹, Sanjay M Sisodiya^{20

21}, Laura Hernandez-Hernandez^{20

21}, Sundararaman Krithika^{20

21}, Melissa Rumple²², Silvia Masnada²³, Marialuisa Valente²⁴, Cristina Cereda²⁴, Lucio Giordano²⁵, Patrizia Accorsi²⁵, Sarah E Bürki²⁶, Margherita Mancardi²⁷, Christian Korff²⁸, Renzo Guerrini²⁹, Sarah von Spiczak^{30

31}, Dorota Hoffman-Zacharska³², Tomasz Mazurczak³³, Antonietta Coppola³⁴, Salvatore Buono³⁵, Marilena Vecchi³⁶, Michael F Hammer³⁷, Costanza Varesio^{38

39}, Pierangelo Veggiotti^{40

41}, Dennis Lal^{42

43

44

45

46}, Tobias Brünger⁴⁶, Federico Zara⁴⁷, Pasquale Striano⁴⁸, Guido Rubboli^{1

49}, Rikke S Møller^{1

2}

Affiliations

¹ Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark.
² Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
³ Graduate Interdisciplinary Program of Genetics, University of Arizona, Tucson, Arizona.
⁴ Folkhälsan Research Center, Helsinki, Finland.
⁵ Research Programs Unit, Molecular Neurology and Medicum, University of Helsinki, Helsinki, Finland.
⁶ Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
⁸ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁹ Department of Pediatrics, Herlev Hospital, Herlev, Denmark.
¹⁰ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹¹ King's College Hospital, London, UK.
¹² Evelina London Children's Hospital, London, UK.
¹³ Medical Research Council Centre for Neurodevelopmental Disorders, King's College, London, UK.
¹⁴ Children's Hospital, Westmead, Sydney, New South Wales, Australia.
¹⁵ Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Pediatric Neurology, Pediatric Clinic, University of Pisa, Pisa, Italy.
¹⁷ Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, Giannina Gaslini Institute, University of Genoa, Genoa, Italy.
¹⁸ Department of Neuropediatrics, University Medical Center Schleswig Holstein, Kiel, Germany.
¹⁹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
²⁰ Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.
²¹ Chalfont Centre for Epilepsy, Bucks, UK.
²² Pediatric Neurology, Banner Children's Specialists, Glendale, Arizona.
²³ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
²⁴ Genomic and Postgenomic Center, Scientific Institute for Research and Healthcare (IRCCS) Mondino Foundation, Pavia, Italy.
²⁵ Child Neurology and Psychiatry Unit, Civilian Hospital, Brescia, Italy.
²⁶ Department of Pediatrics, Division of Child Neurology, University Children's Hospital Bern, University of Bern, Bern, Switzerland.
²⁷ Unit of Child Neuropsychiatry, Epilepsy Center, Department of Clinical and Surgical Neuroscience and Rehabilitation, Giannina Gaslini Institute, Genoa, Italy.
²⁸ Child Neurology Unit, University Children's Hospital, Geneva, Switzerland.
²⁹ Neuroscience Department, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.
³⁰ Department of Neuropediatrics, Christian Albrecht University, Kiel, Germany.
³¹ Northern German Epilepsy Center for Children and Adolescents, Schwentinental, Germany.
³² Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
³³ Department of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
³⁴ Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
³⁵ Neurology Division, Hospital of National Relevance (AORN), Santobono Pausilipon, Naples, Italy.
³⁶ Pediatric Clinic, Hospital Company, University of Padua, Padua, Italy.
³⁷ University of Arizona Genetic Core, University of Arizona, Tucson, Arizona.
³⁸ Brain and Behavior Department, University of Pavia, Pavia, Italy.
³⁹ Child and Adolescence Neurology Department, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.
⁴⁰ Department of Child Neurology, V. Buzzi Children's Hospital, Milan, Italy.
⁴¹ L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁴² Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
⁴³ Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio.
⁴⁴ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
⁴⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
⁴⁶ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁴⁷ Laboratory of Neurogenetics and Neuroscience, Department of Head-Neck and Neuroscience, Giannina Gaslini Institute, Genoa, Italy.
⁴⁸ Pediatric Neurology, Pediatric Clinic, University of Studies of Pisa, Pisa, Italy.
⁴⁹ University of Copenhagen, Copenhagen, Denmark.

PMID: 30968951
DOI: 10.1111/epi.14705

The spectrum of intermediate SCN8A-related epilepsy

Katrine M Johannesen et al. Epilepsia. 2019 May.

. 2019 May;60(5):830-844.

doi: 10.1111/epi.14705. Epub 2019 Apr 10.

Authors

Affiliations

¹ Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark.
² Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
³ Graduate Interdisciplinary Program of Genetics, University of Arizona, Tucson, Arizona.
⁴ Folkhälsan Research Center, Helsinki, Finland.
⁵ Research Programs Unit, Molecular Neurology and Medicum, University of Helsinki, Helsinki, Finland.
⁶ Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
⁸ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁹ Department of Pediatrics, Herlev Hospital, Herlev, Denmark.
¹⁰ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹¹ King's College Hospital, London, UK.
¹² Evelina London Children's Hospital, London, UK.
¹³ Medical Research Council Centre for Neurodevelopmental Disorders, King's College, London, UK.
¹⁴ Children's Hospital, Westmead, Sydney, New South Wales, Australia.
¹⁵ Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Pediatric Neurology, Pediatric Clinic, University of Pisa, Pisa, Italy.
¹⁷ Child Neuropsychiatry Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Children's Sciences, Giannina Gaslini Institute, University of Genoa, Genoa, Italy.
¹⁸ Department of Neuropediatrics, University Medical Center Schleswig Holstein, Kiel, Germany.
¹⁹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
²⁰ Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.
²¹ Chalfont Centre for Epilepsy, Bucks, UK.
²² Pediatric Neurology, Banner Children's Specialists, Glendale, Arizona.
²³ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
²⁴ Genomic and Postgenomic Center, Scientific Institute for Research and Healthcare (IRCCS) Mondino Foundation, Pavia, Italy.
²⁵ Child Neurology and Psychiatry Unit, Civilian Hospital, Brescia, Italy.
²⁶ Department of Pediatrics, Division of Child Neurology, University Children's Hospital Bern, University of Bern, Bern, Switzerland.
²⁷ Unit of Child Neuropsychiatry, Epilepsy Center, Department of Clinical and Surgical Neuroscience and Rehabilitation, Giannina Gaslini Institute, Genoa, Italy.
²⁸ Child Neurology Unit, University Children's Hospital, Geneva, Switzerland.
²⁹ Neuroscience Department, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.
³⁰ Department of Neuropediatrics, Christian Albrecht University, Kiel, Germany.
³¹ Northern German Epilepsy Center for Children and Adolescents, Schwentinental, Germany.
³² Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
³³ Department of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
³⁴ Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
³⁵ Neurology Division, Hospital of National Relevance (AORN), Santobono Pausilipon, Naples, Italy.
³⁶ Pediatric Clinic, Hospital Company, University of Padua, Padua, Italy.
³⁷ University of Arizona Genetic Core, University of Arizona, Tucson, Arizona.
³⁸ Brain and Behavior Department, University of Pavia, Pavia, Italy.
³⁹ Child and Adolescence Neurology Department, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.
⁴⁰ Department of Child Neurology, V. Buzzi Children's Hospital, Milan, Italy.
⁴¹ L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁴² Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
⁴³ Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio.
⁴⁴ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
⁴⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
⁴⁶ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁴⁷ Laboratory of Neurogenetics and Neuroscience, Department of Head-Neck and Neuroscience, Giannina Gaslini Institute, Genoa, Italy.
⁴⁸ Pediatric Neurology, Pediatric Clinic, University of Studies of Pisa, Pisa, Italy.
⁴⁹ University of Copenhagen, Copenhagen, Denmark.

PMID: 30968951
DOI: 10.1111/epi.14705

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.

Keywords: SCN8A; epilepsy; epilepsy genetics; intellectual disability; voltage-gated sodium channels.

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The spectrum of intermediate SCN8A-related epilepsy

Affiliations

The spectrum of intermediate SCN8A-related epilepsy

Authors

Affiliations

Abstract

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LinkOut - more resources

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Medical