title: Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?
abstract: We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities.
authors.affiliation: Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Gabriella A
authors.initials: GA
authors.lastname: Horvath
authors.affiliation: Div. of Pediatric Neurology, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Demos
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Allison
authors.initials: A
authors.lastname: Matthews
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Linhua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Race
authors.affiliation: Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Margot I
authors.initials: MI
authors.lastname: Van Allen
authors.affiliation: Department of Psychiatry and Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
authors.forename: Ogan
authors.initials: O
authors.lastname: Mancarci
authors.affiliation: Department of Psychiatry and Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
authors.forename: Lilah
authors.initials: L
authors.lastname: Toker
authors.affiliation: Department of Psychiatry and Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Molecular Genetics, Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Trump
authors.affiliation: Neurometabolic Unit, National Hospital, Queen Square, London, United Kindgdom; Chemical Pathology, Great Ormond Street Hospital, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
authors.affiliation: Neurometabolic Unit, National Hospital, Queen Square, London, United Kindgdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.affiliation: Developmental Neurosciences Programme, UCL Institute of Child Health, and Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: J Helen
authors.initials: JH
authors.lastname: Cross
authors.affiliation: Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada; Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. Electronic address: cvankarnebeek@cw.bc.ca.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
mesh_terms: D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics; D053447:Channelopathies / Q000188:drug therapy / Q000378:metabolism*; D002648:Child; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D059472:Exome; D005260:Female; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008297:Male; D009123:Muscle Hypotonia / Q000209:etiology / Q000235:genetics; D020125:Mutation, Missense; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics; D018377:Neurotransmitter Agents / Q000172:deficiency* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D012640:Seizures / Q000209:etiology* / Q000235:genetics; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D018377:Neurotransmitter Agents; D011954:Receptors, Dopamine; C568251:SCN2A protein, human; C100681:SCN8A protein, human; D015222:Sodium Channels; D013763:Tetrahydrofolates; D006897:Hydroxyindoleacetic Acid; C005984:5-methyltetrahydrofolate; D006719:Homovanillic Acid
keywords: Channelopathy; Dopamine; Na(v)1.2; Na(v)1.6; SCN2A; SCN8A; Seizures; Serotonin; Therapy