Neurotransmitters and Sodium Channelopathies; Possible Link?

Abstract

Investigators from the University of British Columbia, Great Ormond Street Hospital for Children, and the National Hospital reported their findings on neurotransmitter deficiencies in two patients with mutations in voltage-gated sodium genes (SCN2A and SCN8A) discovered by whole exome sequencing. In the first patient a de novo SCN2A splice-site mutation (c.2379+1G>A; p.Glu717Glyfs*30) that ultimately causes a premature stop at amino acid position 717 was discovered in a 10-year old male with epilepsy, cerebral/cerebellar atrophy, autism, and global developmental delays. Cerebrospinal fluid (CSF) analysis showed low neurotransmitter levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), neopterin, and tetrahydrobiopterin at 3.7 years; decreased 5-HIAA and HVA levels at 7.5 years, and a slightly lowered HVA level (217; 329-852nmol/L) at 9.6 years. Two separate oral treatments of 5-hydroxytrptophan (5HTP) and L-Dopa/Carbidopa were administered, the first began at 4-years and was stopped after 4 months after a reported decrease in seizure frequency with no improvement in speech and language development. At 7.7-years 5HTP and L-Dopa/Carbidopa were given leading to a 5-month seizure free period after which seizures recurred. A dopa-agonist, pramipexole (0.625 mg TID), was then introduced with a decreased L-Dopa/Carbidopa dosage and no change to 5HTP with seizure frequency dropping to once every 3-4 weeks. The second case involved a 9-year old female with a de novo SCN8A missense mutation (c.5615G>A; p.Arg1872Gln) that presented with early onset drug-resistant epilepsy. CSF analysis revealed decreased 5-methylterahydrofolate (5-MTHF) neurotransmitter level at 6-years; and decreased levels of HVA, 5-HIAA, and 5-MTHF at 8-years. A trial of oral folinic acid (10mg/day) did not lead to clinical improvement and 5HTP and L-Dopa/Carbidopa treatment are being considered. [1]