Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy

doi:10.1016/j.neulet.2007.12.064

Neuroscience Letters

Volume 433, Issue 1, 5 March 2008, Pages 65-70

https://doi.org/10.1016/j.neulet.2007.12.064 Get rights and content

Abstract

Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.

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Acknowledgements

This work was supported by the Board of Trustees at Cincinnati Children's Hospital Medical Center (KDH), the MCJ foundation (KDH), the Epilepsy Foundation (TAG) and NIH research grants NS34509 (MHM), NS053792 (JAK) and HL56810 (RSK).

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Although the number of affected individuals is relatively low, pathogenic SCN3A variants have been reported in a range of phenotypes, from focal epilepsy to severe developmental and epileptic encephalopathy with polymicrogyria.
Case report and inclusion of current literature.
Here, we report a normally developed boy with self-limiting generalized epilepsy with fever sensitivity due to a likely pathogenic SCN3A variant. He had febrile seizures from the age of one year, which were successfully treated with valproate. After tapering off medication, he only had rare breakthrough seizures, always associated with fever. At the age of 12 he continues to develop normally and have normal cognition. Reviewing the literature, there appears to be a correlation between functional outcome and phenotype. Gain of function SCN3A variants are seen in individuals with a severe epilepsy, cognitive impairment and brain malformations, while loss of function variants are seen in individuals with epilepsy, varying degrees of cognitive impairment, including normal cognition, but no brain malformations.
The genotype-phenotype correlations in SCN3A-related disorders presented here, will be important for families and clinicians alike, for diagnostic as well as possibly future treatment options.
Seizures as the first manifestation of chromosome 2q24.2-q24.3 in a two and a half years old girl: A case report
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Citation Excerpt :
Mutaions in SCN2A are thought to be associated with benign familial neonatal-infantile seizure (BFNIS), Dravet syndrome (DS), genetic epilepsy with febrile seizure plus (GEFS+), and early onset epileptic encephalopathies (EOEE).17–20 Mutations in SCN3A have also been detected in patients with epilepsy,21,22 albeit less frequently. Unfortunately, clinical effects of this haploinsufficiency are not yet clear.
Mutations and/or duplications in the chromosome 2q24.3 region are known to be responsible for various epilepsy phenotypes. However, microdeletion in childhood epilepsy is rarely reported.
A two-and-a-half-year-old girl with no history of hypocalcemia or seizures developed new symptoms of generalized tonic-clonic epilepsy. The clinical manifestations were growth retardation, prominent forehead, closed anterior fontanelle, and poor muscle tension. Peripheral blood, echocardiography, abdominal ultrasound, and electroencephalogram (EEG) examinations were all normal. No karyotype abnormality was found in the patient, but a single nucleotide polymorphism (SNP) array test detected that a 3.5 Mb single-copy microdeletion had occurred in the q24.2-q24.3 region on chromosome 2. Fluorescence in situ hybridization (FISH) tests revealed that the 2q24 fragment was inserted into the q11.2 region of the patient's chromosome 15, as well as that of her sister. In both cases, the patient's mother is the source carrier of the chromosome 15 insertion.
The deletion of the sodium channel gene cluster (SCN1A, SCN2A, and SCN3A), but not SCN1A haploinsufficiency alone, may contribute to complex infant epilepsy syndromes. However, the pathogenic mechanism still needs to be studied further.
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Sodium (Na⁺) channels are the basis for action potential generation and propagation, which play a key role in the regulation of neuronal excitability. SCN3A is a gene encoding for sodium channel protein type 3 subunit alpha (or known as Nav1.3). This study aimed to explore SCN3A genetic variants in a cohort of childhood absence epilepsy (CAE) via whole exome sequencing. A novel SCN3A missense variant (c.A1816G, p.Ser606Gly) was identified in a patient with CAE. This variant had not been reported in both 1000G and ExAC databases. Bioinformatics analysis revealed that this variant was pathogenic and could transform the protein structure of Nav1.3. The reported phenotypes of SCN3A-related central nerve system disorders included multiple seizure types, polymicrogyria and different degrees of developmental delay/intellectual disability. The patient with p.Ser606Gly variant exhibited typical absence seizures. The MRI and CT scan results were normal, and EEG showed that 3-Hz spike-slow wave discharges. In conclusion, our findings not only broaden the pathogenic spectrum of SCN3A, but also extend the clinical phenotypes of SCN3A-related CAE.
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Purpose: To explore disease-causing gene mutations of epilepsy with febrile seizures plus (EFS+) in Southern Chinese Han population.
Methods: Blood samples and clinical data were collected from 49 Southern Han Chinese patients with EFS+. Gene screening was performed using whole-exome sequencing and panel sequencing for 485 epilepsy-related genes. The pathogenicity of variants was evaluated based on ACMG scoring and assessment of clinical concordance.
Results: We identified 10 putatively causative sodium channel gene variants in 49 patients with EFS+, including 8 variants in SCN1A (R500Q appeared twice), one in SCN3A and one in SCN9A. All these missense mutations were inherited from maternal or paternal and were evaluated to be of uncertain significance according to ACMG. The clinical features of patients were in concordance with the EFS+ phenotype of the mutated SCN1A, SCN3A and SCN9A gene. The clinical phenotypes of 11 probands with these gene variants included febrile seizures plus (FS+, n=7), Dravet Syndrome (n=3), FS+ with focal seizures (n=1). Three probands with SCN1A variants (R500Q located in the non-voltage areas, or G1711D in the pore-forming domain) developed severe Dravet syndrome. The affected individuals with the other 6 SCN1A variants located outside the pore-forming domain showed mild phenotypes. Novel SCN3A variant ((D1688Y) and SCN9A variant (R185H) were identified in two probands respectively and both of the probands had FS+.
Conclusion: The SCN1A, SCN3A, and SCN9A gene mutations might be a pathogenic cause of EFS+ in Southern Chinese Han population.
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During prenatal brain development, ion channels are ubiquitous across several cell types, including progenitor cells and migrating neurons but their function has not been clear. In the past, ion channel dysfunction has been primarily studied in the context of postnatal, differentiated neurons that fire action potentials – notably ion channels mutated in the epilepsies – yet data now support a surprising role in prenatal human brain disorders as well. Modern gene discovery approaches have identified defective ion channels in individuals with cerebral cortex malformations, which reflect abnormalities in early-to-middle stages of embryonic development (prior to ubiquitous action potentials). These human genetics studies and recent in utero animal modeling work suggest that precise control of ionic flux (calcium, sodium, and potassium) contributes to in utero developmental processes such as neural proliferation, migration, and differentiation.

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Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy

Abstract

Section snippets

Acknowledgements

Pediatr. Neurol.

J. Biol. Chem.

Lancet

Am. J. Hum. Genet

Neuroscience

Neuron

Seizure

Biophys. J.

FEBS Lett.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia 1

Cardiovasc. Res.

Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons

J. Neurosci.

Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2

Nat. Genet.

Inherited disorders of voltage-gated sodium channels

J. Clin. Invest.

Factors affecting the yield of pediatric EEGs in clinical practice 1

Clin. Pediatr. (Phila)

Resurgence of sodium channel research 4

Annu. Rev. Physiol.