Possible role of <i>SCN4A</i> skeletal muscle mutation in apnea during seizure

Türkdoğan, Dilşad; Matthews, Emma; Usluer, Sunay; Gündoğdu, Aslı Aksoy; Uluç, Kayıhan; Männikkö, Roope; Hanna, Michael G.; Sisodiya, Sanjay M.; Çağlayan, Hande

doi:10.1002/epi4.12347

Cited by 8 publications

(5 citation statements)

References 16 publications

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“…SCN2A -related disorders now include different seizures syndromes ranging from milder phenotypes of neonatal-onset (benign) epilepsy to severe epilepsies at the severe end, such as infantile spasms, and severe early-onset epileptic encephalopathies, including Ohtahara's syndrome and West's syndrome ( Table 1 ). 7 13 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Therefore, there is no unique phenotype, and clinical presentation may vary as follows:…”

Section: Clinical Presentationmentioning

confidence: 99%

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SCN2A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A–benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A-BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A-related epilepsies have not shown a clear genotype–phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no “standardized” treatment for SCN2A-related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital).

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Section: Clinical Presentationmentioning

confidence: 99%

“…85,86 Ketogenic diet was also reported as effective in patients with epileptic encephalopathy due to SCN2A mutations and in a Chinese infant with Ohtahara's syndrome lead to seizures resolution. 54,[87][88][89]…”

Section: Treatmentmentioning

confidence: 99%

SCN2A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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“…SCN4A is physiologically expressed in the skeletal muscle and in cerebral cortex, 12 it encodes the Na v 1.4 sodium channel and it is responsible of the control of muscular excitability. To date, several variants in this gene were related to skeletal muscle channelopathies, 1 , 13 , 16 , 17 and there have been reports of few cases in which SCN4A variants could represent a risk factor of other rare phenotypes such as essential tremor, 12 apnea, 21 severe neonatal episodic laryngospasm, 22 and Sudden Unexpected Death in Epilepsy. 23 The most frequent pathogenic variants are missenses, inherited in autosomal dominant way, and related to the sodium channel myotonia phenotype.…”

Section: Discussionmentioning

confidence: 99%

Idiopathic generalized epilepsy in a family with SCN4A‐related myotonia

Talarico,

Fortunato,

Labalme

et al. 2024

Epilepsia Open

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ObjectivesMyotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non‐dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co‐occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co‐segregates myotonia, JME, or abnormal EEG without seizures was observed.MethodsAll six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant.ResultsFour family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp‐wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified.SignificanceThese results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family.Plain Language SummaryThis study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

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“…Laryngospasm has also been postulated as a contributory mechanism to SUDEP. We recently identified a child with both EEG confirmed epilepsy and a myotonic SCN4A mutation who experienced apnoea during seizures 95 . We postulate the presence of the myotonia mutation may increase the risk of apnoea and that laryngospasm may be a common mechanism in sudden death aetiology although this requires further research.…”

Section: Sudden Infant Deathmentioning

confidence: 99%

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Matthews

Balestrini

Sisodiya

et al. 2020

The Lancet Child & Adolescent Health

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Voltage gated sodium channels are essential for excitability of skeletal muscle fibres and neurones. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm/stridor, congenital myasthenia and myopathy. Recent evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised brain sodium channelopathy phenotypes include several epilepsy disorders and complex encephalopathies. Together these early onset muscle and brain phenotypes have a significant morbidity and an appreciable mortality rate but there have been significant advances in understanding the pathophysiological mechanisms underlying them and these have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. Here, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We outline a diagnostic approach and review the available treatment options.

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Possible role of SCN4A skeletal muscle mutation in apnea during seizure

Cited by 8 publications

References 16 publications

SCN2A and Its Related Epileptic Phenotypes

SCN2A and Its Related Epileptic Phenotypes

Idiopathic generalized epilepsy in a family with SCN4A‐related myotonia

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

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