Biallelic <i><scp>SCN</scp>10A</i> mutations in neuromuscular disease and epileptic encephalopathy

Kambouris, Marios; Thévenon, Julien; Soldatos, Ariane; Cox, Allison; Stephen, Joshi; Ben‐Omran, Tawfeg; Al-Sarraj, Yasser; Boulos, Hala; Bone, William P.; Mullikin, James C.; Masurel‐Paulet, Alice; St‐Onge, Judith; Dufford, Yannis; Chantegret, C.; Thauvin‐Robinet, Christel; Al-Alami, Jamil; Faivre, Laurence; Rivière, Jean Baptiste; Gahl, William A.; Bassuk, Alexander G.; Malicdan, May Christine V.; El‐Shanti, Hatem

doi:10.1002/acn3.372

Cited by 24 publications

(26 citation statements)

References 44 publications

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“…Features of Dravet syndrome have not been seen in our cohort, and no abnormal pain sensation have been reported for patients with Dravet syndrome and a (potentially) pathogenic SCN9A variant 43. For SCN10A variants, eight (potentially) pathogenic variants have been report as disease-causing in BrS, AF, SIDS, LGS, FIRES and autism 37–40. Multigenerational segregation with the disease in SFN families and/or functional testing in DRG neurons by cell electrophysiology indicate that the majority of the variants are causative for SFN (table 2).…”

Section: Discussionmentioning

confidence: 57%

“…Eight (potentially) pathogenic SCN10A variants detected in our cohort of patients with pure SFN have been reported in patients with Brugada syndrome (BrS), atrial fibrillation (AF), sudden infant death syndrome (SIDS), Lennox-Gastaut syndrome (LGS), febrile infection-related epilepsy syndrome (FIRES) and autism 37–40. Only the patients with SFN with variant c.41G>T had arrhythmia.…”

Section: Resultsmentioning

confidence: 87%

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Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

Eijkenboom

Sopacua

Hoeijmakers

et al. 2018

J Neurol Neurosurg Psychiatry

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BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 87%

Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

Eijkenboom

Sopacua

Hoeijmakers

et al. 2018

J Neurol Neurosurg Psychiatry

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“…In fact, the channel can be found in the CNS [70], offering the possibility of a broader involvement in neurological diseases. Additionally, recent research from Kambouris et al revealed mutations in SCN10A that can be linked to epilepsy [10].…”

Section: Discussionmentioning

confidence: 99%

“…Excitation/inhibition imbalance is a very popular hypothesis in the pathogenesis of autism [9]. It is known that voltage-gated sodium channels (VGSCs) play important roles in excitability of neurons and the mutations of VGSC genes result in a wide range of peripheral and central nervous system disorders [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence from A Congenital Case with Compound Heterozygous SCN10A Mutations

Heinrichs,

Liu,

Zhang

et al. 2020

Preprint

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BackgroundApart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons.MethodsIn our present study, we present an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Nav1.8, which is preferentially expressed in sensory neurons. We expressed both identified mutations, p.I1511M and p.R512X, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. ResultsThe results of these experiments suggest that both mutations lead to different degrees of loss-of-function of Nav1.8. Behavioral experiments in a Nav1.8 loss-of-function mouse model additionally revealed Nav1.8 may play a role in autistic behavior. LimitationsOur study did not verified the functions of p.I1511M and p.R512X mutations in vivo. The mice with these mutations can be constructed to verify the mutation functions in the future investigations. In addition, since we have only found one ASD patient which may relate to SCN10A mutations, the role of Nav1.8 in ASD needs to be confirmed in more cases. Moreover, the cellular mechanism underlying the effect of Nav1.8 on ASD needed to be explored in future studies.ConclusionsOur results present Nav1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights to the genetic basis of this disease.

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“…Epilepsy is firmly linked to human variants in SCN1A, SCN2A, SCN3A, SCN8A, and SCN1B . Several other subunits, traditionally considered to be expressed at low levels in whole brain assays, have very restricted regional expression, for example, the “cardiac” sodium channel SCN5A within the limbic system and may ultimately prove to play contributory roles (SCN4A,, SCN5A, SCN7A, SCN9A, SCN10A). Although each channel participates in generating an action potential, the alpha subunits populate different neuronal subcompartments, play distinct kinetic roles in membrane electrogenesis, and offer multiple targets for subunit‐specific drugs.…”

Section: Nonuniform Channel Subunit Anatomy: From Single Neuron Compamentioning

confidence: 99%

Predicting the impact of sodium channel mutations in human brain disease

Noebels

2019

Epilepsia

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Genetic alteration of the sodium channel provides a remarkable opportunity to understand how epilepsy and its comorbidities arise from a molecular disease of excitable membranes, and a chance to create a better future for children with epileptic encephalopathy. In a single cell, the channel reliably acts as a voltage-sensitive switch, enabling axon impulse firing, whereas at a network level, it becomes a variable rheostat for regulating dynamic patterns of neuronal oscillations, including those underlying cognitive development, seizures, and even premature lethality. Despite steady progress linking genetic variation of the channels with distinctive clinical syndromes, our understanding of the intervening biologic complexity underlying each of them is only just beginning. More research on the functional contribution of individual channel subunits to specific brain networks and cellular plasticity in the developing brain is needed before we can reliably advance from precision diagnosis to precision treatment of inherited sodium channel disorders. K E Y W O R D Sbrain, development, gene, mutation, sodium ion channel Wiley Periodicals, Inc.

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Biallelic SCN10A mutations in neuromuscular disease and epileptic encephalopathy

Cited by 24 publications

References 44 publications

Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

Yield of peripheral sodium channels gene screening in pure small fibre neuropathy

The Potential Effect of Nav1.8 in Autism Spectrum Disorder: Evidence from A Congenital Case with Compound Heterozygous SCN10A Mutations

Predicting the impact of sodium channel mutations in human brain disease

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