A novel gain‐of‐function mutation in
            <i>SCN5A</i>
            responsible for multifocal ectopic Purkinje‐related premature contractions

Doisne, Nicolas; Waldmann, Victor; Redheuil, Alban; Waintraub, Xavier; Fressart, Véronique; Ader, Flavie; L, Fosse; Hidden‐Lucet, Françoise; Gandjbakhch, Estelle; Neyroud, Nathalie

doi:10.1002/humu.23981

Cited by 23 publications

(39 citation statements)

References 20 publications

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“…Unlike some of the patients with the MEPPC syndrome, 8 our patients did not respond to flecainide, but they had an immediate response to quinidine. 8,14 However, as the amiodarone effect J o u r n a l P r e -p r o o f waned, arrhythmias re-appeared in both of our patients, and addition of a small dose of amiodarone in one of our patients resulted in excellent control. Quinidine has also been reported to be effective in other arrhythmias related to Purkinje system irritation, such as after catheter ablation, myocardial infarction or coronary revascularization procedures.…”

Section: Discussionmentioning

confidence: 62%

Incessant atrial and ventricular tachycardias associated with an SCN5A mutation

Papagiannis

Yang

Glazer

et al. 2021

HeartRhythm Case Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 62%

Incessant atrial and ventricular tachycardias associated with an SCN5A mutation

Papagiannis

Yang

Glazer

et al. 2021

HeartRhythm Case Reports

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“…Published data show that successful antiarrhythmic therapy with sodium channel blockers (quinidine, flecainide, and amiodarone) in SCN5A gene mutations can reverse HF symptoms and restore LV contractile function 5,6,8,16 . This has been shown in particular with R222Q variant but also with other mutations, namely, with recently published A204E 16 variant where quinidine eliminated VA and for L828F 17 variant where flecainide had the same effect. In our patients with R814W variant, we had to include a combination of Class I antiarrhythmics to attain acceptable treatment results.…”

Section: Discussionmentioning

confidence: 93%

“…In our patients with R814W variant, we had to include a combination of Class I antiarrhythmics to attain acceptable treatment results. There is little data on long‐term results of sodium channel blockers' effectiveness (>5 years of treatment) in this specific group of arrhythmogenic DCM patients 16,17 . Also, the advantageous effect of overdrive pacing in the daughter should be emphasized.…”

Section: Discussionmentioning

confidence: 99%

“…There is little data on long-term results of sodium channel blockers' effectiveness (>5 years of treatment) in this specific group of arrhythmogenic DCM patients. 16,17 Also, the advantageous effect of overdrive pacing in the daughter should be emphasized. A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation 4333…”

Section: Antiarrhythmic Treatment In Dilated Cardiomyopathy Caused Bymentioning

confidence: 99%

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A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation

et al. 2020

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SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related premature contractions. Recent data indicate that sodium channel blockers are particularly effective monotherapy in carriers of the R222Q SCN5A variant. Our purpose is to describe the effectiveness of antiarrhythmic treatment in a family with genetically determined arrhythmogenic DCM associated with the R814W variant in the SCN5A gene. We examined a family with arrhythmogenic DCM (multifocal ectopic Purkinje-related premature contractions phenotype, atrial tachyarrhythmias, automatism, and conduction disorders) and described antiarrhythmic treatment efficacy in heart failure symptoms reduction and myocardial function improvement. We found a heterozygotic mutation R814W in SCN5A by whole exome sequencing in the proband and confirmed its presence in all affected subjects. There were two sudden cardiac deaths and one heart transplantation among first-degree relatives. The 58-year-old father and his 37-year-old daughter had full spectrum of symptoms associated with R814W SCN5A mutation. Both had implanted cardioverter defibrillator. In the father, adding mexiletine to quinidine therapy reduced ventricular arrhythmia (50-60% → 6-8% of whole rhythm) and reverted long-standing atrial fibrillation to sinus rhythm. In the daughter, mexiletine and overdrive pacing were effective in ventricular arrhythmia reduction (25% → 0.01%). Because of a growing number of atrial fibrillation recurrences, a reduced dose of quinidine (subsequently flecainide) was added, resulting in arrhythmia significant reduction. In both cases, antiarrhythmic effectiveness correlated with clinical improvement. In SCN5A R814W-associated DCM, a combination of Class I antiarrhythmics and overdrive pacing is an effective treatment of severe ventricular and atrial arrhythmias.

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“…Both↓LOF and ↑GOF mutations may cause DCM and/or AF 25 . ↑GOF MEPPC is a rare cardiac syndrome combining Polymorphic Ventricular Tachycardia (PVT) with DCM 23 .…”

Section: Paralogs or Paralogous Genesmentioning

confidence: 99%

Brugada syndrome: current concepts and genetic background

Pérez‐Riera

Mendes

Silva

et al. 2021

jhgd

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Brugada syndrome (BrS) is a hereditary clinical-electrocardiographic arrhythmic entity with low worldwide prevalence. The syndrome is caused by changes in the structure and function of certain cardiac ion channels and reduced expression of Connexin 43 (Cx43) in the Right Ventricle (RV), predominantly in the Right Ventricular Outflow Tract (VSVD), causing electromechanical abnormalities. The diagnosis is based on the presence of spontaneous or medicated ST elevation, characterized by boost of the J point and the ST segment ≥2 mm, of superior convexity "hollow type" (subtype 1A) or descending rectilinear model (subtype 1B). BrS is associated with an increased risk of syncope, palpitations, chest pain, convulsions, difficulty in breathing (nocturnal agonal breathing) and/or Sudden Cardiac Death (SCD) secondary to PVT/VF, unexplained cardiac arrest or documented PVT/VF or Paroxysmal atrial fibrillation (AF) in the absence of apparent macroscopic or structural heart disease, electrolyte disturbance, use of certain medications or coronary heart disease and fever. In less than three decades since the discovery of Brugada syndrome, the concept of Mendelian heredity has come undone. The enormous variants and mutations found mean that we are still far from being able to concretely clarify a genotype-phenotype relationship. There is no doubt that the entity is oligogenetic, associated with environmental factors, and that there are variants of uncertain significance, especially the rare variants of the SCN5A mutation, with European or Japanese ancestors, as well as a spontaneous type 1 or induced pattern, thanks to gnomAD (coalition) researchers who seek to aggregate and harmonize exome and genome sequencing data from a variety of large scale sequencing projects and make summary data available to the scientific community at large). Thus, we believe that this in depth analytical study of the countless mutations attributed to BrS may constitute a real cornerstone that will help to better understand this intriguing syndrome.

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A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

Cited by 23 publications

References 20 publications

Incessant atrial and ventricular tachycardias associated with an SCN5A mutation

Incessant atrial and ventricular tachycardias associated with an SCN5A mutation

A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation

Brugada syndrome: current concepts and genetic background

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