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Mol Genet Metab. 2016 Jan;117(1):42-8. doi: 10.1016/j.ymgme.2015.11.008. Epub 2015 Nov 17.

Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

Author information

1
Division of Biochemical Diseases, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
2
Div. of Pediatric Neurology, Dept of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
3
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.
4
Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
5
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
6
Department of Psychiatry and Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
7
Molecular Genetics, Great Ormond Street Hospital for Children, London, United Kingdom.
8
Neurometabolic Unit, National Hospital, Queen Square, London, United Kindgdom; Chemical Pathology, Great Ormond Street Hospital, UCL Institute of Child Health, London, United Kingdom.
9
Neurometabolic Unit, National Hospital, Queen Square, London, United Kindgdom.
10
Developmental Neurosciences Programme, UCL Institute of Child Health, and Great Ormond Street Hospital for Children, London, United Kingdom.
11
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.

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.

KEYWORDS:

Channelopathy; Dopamine; Na(v)1.2; Na(v)1.6; SCN2A; SCN8A; Seizures; Serotonin; Therapy

Comment in

PMID:
26647175
DOI:
10.1016/j.ymgme.2015.11.008
[Indexed for MEDLINE]

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