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

Horvath, Gabriella; Demos, Michelle; Shyr, Casper; Matthews, Allison; Zhang, Linhua; Race, Simone; Stöckler‐Ipsiroglu, Sylvia; Allen, Margot I. Van; Mancarci, B. Ogan; Toker, Lilah; Pavlidis, Paul; Ross, Colin J.; Wasserman, Wyeth W.; Trump, N; Heales, Simon; Pope, Simon; Cross, J. Helen

doi:10.1016/j.ymgme.2015.11.008

Cited by 44 publications

(59 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29 It hypothesizes that disturbances in ion fluxes might impair synaptic vesicle release and cause abnormalities in the secretion/ uptake of neurotransmitters; however, we cannot report consistent findings for GABA levels in CSF and the patients from the cohort with mutations in ion channels (patients P15, P40, and P75). 29 It hypothesizes that disturbances in ion fluxes might impair synaptic vesicle release and cause abnormalities in the secretion/ uptake of neurotransmitters; however, we cannot report consistent findings for GABA levels in CSF and the patients from the cohort with mutations in ion channels (patients P15, P40, and P75).…”

Section: Patients With Confirmed Monogenic Diagnosticmentioning

confidence: 68%

“…Recent work on ion-gated channelopathies and abnormalities in biogenic amines is also relevant. 29 It hypothesizes that disturbances in ion fluxes might impair synaptic vesicle release and cause abnormalities in the secretion/ uptake of neurotransmitters; however, we cannot report consistent findings for GABA levels in CSF and the patients from the cohort with mutations in ion channels (patients P15, P40, and P75).…”

Section: Patients With Confirmed Monogenic Diagnosticmentioning

confidence: 68%

See 1 more Smart Citation

Gamma‐aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders

Cortès‐Saladelafont

Molero-Luís

Cuadras³

et al. 2018

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

Section: Patients With Confirmed Monogenic Diagnosticmentioning

confidence: 68%

Section: Patients With Confirmed Monogenic Diagnosticmentioning

confidence: 68%

Gamma‐aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders

Cortès‐Saladelafont

Molero-Luís

Cuadras³

et al. 2018

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

“…An example from this study was an 8-year-old boy with intellectual developmental disorder, autism, movement disorder, intractable epileptic encephalopathy, and persistently abnormal neurotransmitter profiles (low levels of homovanillic acid, 5-hydroxyindoleacetic acid, and neopterin in cerebrospinal fluid) in whom we identified a de novo pathogenic splice-site variant. This mutation resulted in the deletion of exon 14 in SCN2A , 24 encoding voltage-gated sodium channel type II. Voltage-gated sodium channels are heteromeric complexes that generate and propagate action potentials.…”

Section: Resultsmentioning

confidence: 99%

Exome Sequencing and the Management of Neurometabolic Disorders

et al. 2016

Self Cite

View full text Add to dashboard Cite

BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)

show abstract

“…Treatment of a male patient suffering from drug-resistant epilepsy, resulting from a deleterious de novo sodium voltage-gated channel alpha subunit 2 (SCN2A), gene splice-site mutation, with the 5-HT precursor 5-hydroxytryptophan, led to mild clinical improvement (Horvath et al, 2016). …”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

“…The DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA) improved the clinical outcome of a male patient suffering from intractable epileptic encephalopathy (Horvath et al, 2016), again sustaining an overall anticonvulsant DA-mediated action. Nevertheless, DA concentrations in media collected from neural cultures, derived from induced pluripotent stem cells from a patient with the Dravet syndrome, were higher than those from wild-type neural cultures (Maeda et al, 2016).…”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

View full text Add to dashboard Cite

A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

show abstract

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

Cited by 44 publications

References 30 publications

Gamma‐aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders

Gamma‐aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders

Exome Sequencing and the Management of Neurometabolic Disorders

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Contact Info

Product

Resources

About