Gene mutations in comorbidity of epilepsy and arrhythmia.

Epilepsy is one of the most common neurological disorders, and sudden unexpected death in epilepsy (SUDEP) is the most severe outcome of refractory epilepsy. Arrhythmia is one of the heterogeneous factors in the pathophysiological mechanism of SUDEP with a high incidence in patients with refractory epilepsy, increasing the risk of premature death. The gene co-expressed in the brain and heart is supposed to be the genetic basis between epilepsy and arrhythmia, among which the gene encoding ion channel contributes to the prevalence of "cardiocerebral channelopathy" theory. Nevertheless, this theory could only explain the molecular mechanism of comorbid arrhythmia in part of patients with epilepsy (PWE). Therefore, we summarized the mutant genes that can induce comorbidity of epilepsy and arrhythmia and the possible corresponding treatments. These variants involved the genes encoding sodium, potassium, calcium and HCN channels, as well as some non-ion channel coding genes such as CHD4, PKP2, FHF1, GNB5, and mitochondrial genes. The relationship between genotype and clinical phenotype was not simple linear. Indeed, genes co-expressed in the brain and heart could independently induce epilepsy and/or arrhythmia. Mutant genes in brain could affect cardiac rhythm through central or peripheral regulation, while in the heart it could also affect cerebral electrical activity by changing the hemodynamics or internal environment. Analysis of mutations in comorbidity of epilepsy and arrhythmia could refine and expand the theory of "cardiocerebral channelopathy" and provide new insights for risk stratification of premature death and corresponding precision therapy in PWE.

COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.

INTRODUCTION/AIMS: Although we have gained insight into coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 since the beginning of the pandemic, our understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID-19 and COVID-19 vaccination on skeletal muscle channelopathies. METHODS: We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service. RESULTS: Thirty-eight patient responses were received. Six patients had COVID-19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty-six patients had received one or two COVID-19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty-two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported. DISCUSSION: The overall rates of COVID-19 infection were low in our study and COVID-19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post-COVID-19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID-19 infection and vaccination.

1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants.

BACKGROUND: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. RESULTS: We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. CONCLUSION: A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9-1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account.

Recomendaciones para el ejercicio físico en deportistas con cardiopatías familiares (segunda parte) / Recommendations for physical exercise in athletes with inherited heart diseases (second part)

La seguridad de la actividad física y deportiva en pacientes con cardiopatías familiares aún no está bien establecida. Las recomendaciones sobre el ejercicio físico en estos pacientes suele ser bastante restrictiva sin que haya clara evidencia para ello, a pesar de que el deporte haya demostrado importantes beneficios cardiovasculares. La participación en deportes en los adultos con cardiopatías familiares se considera un territorio relativamente poco conocido y muchos clínicos se encuentran con dificultades en el asesoramiento a sus pacientes. El desarrollo de la medicina actual ha supuesto una mejoría significativa en el estudio de las cardiopatías familiares, así como en su diagnóstico precoz y tratamiento. Asimismo, los estudios genéticos han supuestos un pilar fundamental en el seguimiento de estas cardiopatías, guiando de manera más adecuada la actitud terapéutica que debemos seguir. Hasta hace poco tiempo, los pacientes que presentan dichas cardiopatías han sido descalificados de manera frecuente de los deportes competitivos y en muchas ocasiones, se recomienda el cese completo de la actividad física, incluido el deporte tipo recreacional. Sin embargo, las recomendaciones actuales son menos restrictivas, insistiendo en individualizar los diferentes casos en función del tipo de patología, del tipo de actividad física realizada, si éstos presentan la enfermedad o son únicamente portadores de mutaciones genéticas causales, etc. Las investigaciones actuales se centran fundamentalmente en la seguridad de la actividad física en pacientes con cardiopatías familiares, y el temor a que la práctica de actividad física a nivel competitivo pueda aumentar significativamente el riesgo de eventos adversos, especialmente de eventos arrítmicos y muerte súbita. En esta revisión, analizamos numerosos estudios y las guías de práctica clínica, con el fin de establecer las recomendaciones de actividad física, así como sus restricciones en función de los diferentes tipos de cardiopatías familiares

The safety of physical activity and sports in patients with inherited heart disease is not well established. The recommendations on physical exercise in these patients are usually quite restrictive without clear evidence for this, despite the fact that sport has shown important cardiovascular benefits. Participation in sports in adults with inherited heart disease is considered a relatively little known territory and many clinicians find it difficult to advise their patients. The development of current medicine has meant a significant improvement in the study of inherited heart diseases, as well as in their early diagnosis and treatment. In addition, genetic studies have assumed a fundamental aspect in the follow-up of these heart diseases, guiding more appropriately the therapeutic attitude that we must follow. Until recently, patients with such heart disease have been frequently disqualified from competitive sports, and in many cases, complete cessation of physical activity, including recreational sport, is recommended. However, current recommendations are less restrictive, insisting on individualizing the different cases depending on the type of pathology, the type of physical activity performed, whether they present the disease or are only carriers of causal genetic mutations, etc. Current research focuses primarily on the safety of physical activity in patients with inherited heart disease and the fear that the practice of competitive physical activity can significantly increase the risk of adverse events, especially arrhythmic events and sudden death. In this review, we analyzed numerous studies and clinical practice guidelines, in order to establish the recommendations of physical activity, as well as their restrictions depending on the different types of inherited heart disease

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Implantable cardioverter-defibrillator therapy and device-related complications in young patients with inherited cardiomyopathies or channelopathies: a 17-year cohort study.

Aims: To quantify appropriate and inappropriate therapy and complications related to implantable cardioverter-defibrillator (ICD) treatment in young patients receiving an ICD for a hereditary cardiomyopathy or channelopathy. Methods and results: This was a retrospective study including 117 consecutive patients who had received an ICD at Aarhus University Hospital, Denmark from 1 January 1999 to 31 December 2015. Patients were followed from the date of ICD implantation until migration, death, heart transplantation, or end of follow-up on 1 February 2017. Mean age at implantation was 30.5 ± 12.8 years, and the patients were followed for a mean period of 7.1 ± 4.4 years. The cumulative incidence at 1, 5, and 10 years was 17%, 29%, and 48% for appropriate ICD therapy, 6%, 13%, and 20% for inappropriate ICD therapy, and 7%, 18%, and 33% for device-related complications, respectively. Patients with an ICD implanted for secondary prevention had a higher risk of appropriate therapy compared with patients implanted for primary prevention [adjusted hazard ratio (HR) 5.18, 95% confidence interval (CI) 2.22-12.09; P < 0.01]. There was no difference in the risk of inappropriate therapy (adjusted HR 1.58, 95% CI 0.55-4.56; P = 0.40) or device-related complications (adjusted HR 1.22, 95% CI 0.56-2.68; P = 0.62) between patients with primary and secondary preventive indication. Conclusion: We observed high absolute risk estimates for appropriate ICD therapy in young patients with an ICD indicated by a hereditary cardiomyopathy or channelopathy. Also risks for inappropriate ICD therapy and device-related complications were significant.

Primary ventricular tachycardia in paediatric population in a tertiary centre.

OBJECTIVE: To delineate the outcome of ventricular tachycardia (VT) in the paediatric population. METHODS: Patients who developed sustained VT between the ages of 0 and 18 years in a referral centre from 1991 to 2015 were enrolled. RESULTS: A total of 116 patients (67 male/49 female) had documented VT, and 53 (46%) had associated heart disease, namely cardiomyopathy in 20 (17%), structural heart disease in 19 (16%) and channelopathy in 14 (12%), and some of them presented with two types of associated heart disease. Idiopathic VT (63 patients), which presents without associated heart disease, was the most common type. Forty-one patients received catheter ablation, with 37 being successful (90%) and 6 of 37 recurrence (16%). None of the patients died during the 5.8±5.9 year follow-up. VT with cardiomyopathy was associated with the highest mortality rate, particularly in those with hypertrophic and restrictive cardiomyopathy. Among 16 patients initially presenting VT and heart failure, seven exhibited improved heart function after VT control, which could be predicted by benign onset symptoms, monomorphic QRS morphology and the presentation of VT at the initial diagnosis of cardiomyopathy. VT associated with structural heart disease was also associated with a high risk of mortality, but this risk decreased after aggressive intervention in the recent years. VT with channelopathy can be often controlled with medication, except for those with prenatal onset. CONCLUSIONS: Although VT may carry high mortality when associated with structural anomaly or cardiomyopathy, VT presenting to tertiary referral centre often has a favourable outcome after prompt intervention.

Identification of pathogenic variants in genes related to channelopathy and cardiomyopathy in Korean sudden cardiac arrest survivors.

Pathogenic variants in genes related to channelopathy and cardiomyopathy are the most common cause of sudden unexplained cardiac death. However, few reports have investigated the frequency and/or spectrum of pathogenic variants in these genes in Korean sudden cardiac arrest survivors. This study aimed to investigate the causative genetic variants of cardiac-associated genes in Korean sudden cardiac arrest survivors. We performed exome sequencing followed by filtering and validation of variants in 100 genes related to channelopathy and cardiomyopathy in 19 Korean patients who survived sudden cardiac arrest. Five of the 19 patients (26.3%) had either a pathogenic variant or a likely pathogenic variant in MYBPC3 (n=1), MYH7 (n=1), RYR2 (n=2), or TNNT2 (n=1). All five variants were missense variants that have been reported previously in patients with channelopathies or cardiomyopathies. Furthermore, an additional 12 patients (63.2%) had more than one variant of uncertain significance. In conclusion, pathogenic or likely pathogenic variants in genes related to channelopathy and cardiomyopathy are not uncommon in Korean sudden cardiac arrest survivors and cardiomyopathy-related genes should be included in the molecular diagnosis of sudden cardiac arrest in Korea.

Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study).

OBJECTIVES: When the cause of an aborted cardiac arrest is unclear the initiation of therapy, counseling and family screening is challenging. METHODS: We included 43 unselected, prospectively identified cardiac arrest survivors with or without a diagnosis. Family history for cardiac disease and supplemental electrocardiograms were evaluated for additional diagnostic information. RESULTS: 43 cardiac arrest survivors were included, 34 (79%) were male and the average age was 48years (range 23-64, SD 13.0). The most common etiologies identified in cardiac arrest survivors were ischemic heart disease (33%), cardiomyopathies (14%), miscellaneous (e.g. drug induced arrhythmias, coronary spasms) (12%) and channelopathies (5%). Family history of cardiac disease - even inheritable conditions - was not indicative of etiology in cardiac arrest survivors. Supplemental ECGs were abnormal in 10 of 43 patients; in the majority of these patients (7) no conclusive diagnosis was reached. CONCLUSIONS: In this study 16/43 (37%) of unselected, prospectively included cardiac arrest survivors remained without a diagnosis despite exhaustive investigations. We may extract additional diagnostic information from simple maneuvers during the recording of the electrocardiogram. We suggest that these ECG derived clues be investigated in future studies including genetic test results and data from relatives.

Rare neurological channelopathies--networks to study patients, pathogenesis and treatment.

Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials.

Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis.

OBJECTIVE: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). METHODS: We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. RESULTS: Two SCN10A polymorphisms in high linkage disequilibrium (r(2) = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 × 10(-4); rs6801957: p = 0.0025). Patients with MS with rs6795970(AA) genotype performed significantly worse than rs6795970(G) carriers in MSFC (p = 1.8 × 10(-4)) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970(AA) carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants. CONCLUSIONS: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.

The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes.

OBJECTIVES: The short QT syndrome is a cardiac channelopathy characterised by accelerated repolarisation which manifests as a short QT interval on the ECG. The definition of a short QT interval is debated, ranging from <390 to ≤320 ms, and its clinical significance in healthy young individuals is unknown. We assessed the prevalence and medium-term significance of an isolated short QT interval in a diverse young British population. METHODS: Between 2005 and 2013, 18 825 apparently healthy people aged 14-35 years underwent cardiovascular evaluation with history, physical examination and ECG. QT intervals were measured by cardiologists using 4 recommended guidelines (Seattle 2013, Heart Rhythm Society 2013, European Society of Cardiology 2010 and American Heart Association 2009). RESULTS: The prevalence of a short QT interval was 0.1% (26 patients, ≤320 ms), 0.2% (44 patients, ≤330 ms), 7.9% (1478 patients, <380 ms), 15.8% (2973 patients, <390 ms). Male gender and Afro-Caribbean ethnicity had the strongest association with short QT intervals. Athletes had shorter QT intervals than non-athletes but athletic status did not predict short QT intervals. Individuals with short QT intervals ≤320 ms did not report syncope or a sinister family history, and during a follow-up period of 5.3±1.2 years, there were no deaths in this group. CONCLUSIONS: The prevalence of a short QT interval depends on the recommended cut-off value. Even at values ≤320 ms, there was an excellent medium-term prognosis among 14 people followed. We conclude that a definition of ≤320 ms is realistic to prevent overdiagnosis and excessive investigations.

Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue.

Merriam-Webster's online dictionary defines purgatory as "an intermediate state after death for expiatory purification" or more specifically as "a place or state of punishment wherein according to Roman Catholic doctrine the souls of those who die in God׳s grace may make satisfaction for past sins and so become fit for heaven." Alternatively, it is defined as "a place or state of temporary suffering or misery." Either way, purgatory is a place where you are stuck, and you don't want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test-ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant.

Dravet syndrome--from epileptic encephalopathy to channelopathy.

Mutations in the gene encoding the α1 subunit of the voltage gated sodium channel (SCN1A) are associated with several epilepsy syndromes, ranging from relatively mild phenotypes found in families with genetic epilepsy with febrile seizures plus (GEFS+) to the severe infant-onset epilepsy Dravet syndrome. Evidence has emerged of the consequences of SCN1α dysfunction in different neuronal networks across the brain pointing toward a channelopathy model causing the neurologic features of Dravet syndrome that is beyond purely seizure related damage. A genetic change will present according to its severity, the genetic background of the individual, and environmental factors, and will affect a variety of neuronal networks according to channel distribution. This already-vulnerable system may be susceptible to secondary aggravating events such as status epilepticus. The channelopathy model implies that pharmacologic treatment and the restoration of impaired γ-aminobutyric acid (GABA)ergic neurotransmission might not only help prevent seizures but might affect the comorbidities of the syndrome. This critical review explores recent evidence relating to the pathogenicity of SCN1A mutations in Dravet syndrome and the effect these have on the wider disease phenotype and discusses whether knowledge of specific genotypes can influence clinical practice. Genetic technology is currently advancing at unprecedented speed and will increase our knowledge of new genes and interacting genetic networks. Clinicians and geneticists will have to work in close collaboration to guarantee good delivery and counseling of genetic testing results.

Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics.

BACKGROUND: Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. METHODS AND RESULTS: We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). CONCLUSIONS: The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.

Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

Prevalence study of genetically defined skeletal muscle channelopathies in England.

OBJECTIVES: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders. METHODS: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011. RESULTS: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. CONCLUSION: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.