Case report: an underdiagnosed multifocal ectopic Purkinje-related premature contractions caused by SCN5A mutation

Abstract

Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC) syndrome is a recently recognized rare channelopathy caused by gain-of-function mutations in the SCN5A gene, leading to a high burden of premature ventricular contractions (PVCs) originating from the Purkinje system and often manifesting as a dilated cardiomyopathy-like phenotype. This case report presents a young woman without structural heart abnormalities or a known family history of similar conditions who was initially diagnosed with idiopathic fascicular ventricular arrhythmia (VAs) and underwent two unsuccessful radiofrequency ablations. The arrhythmias were successfully suppressed by flecainide, a sodium-channel blocker, after genetic testing confirmed the diagnosis of MEPPC caused by the R222Q SCN5A mutation. The case underscores the significance of genetic testing for SCN5A mutations in patients with multifocal Purkinje-related VAs, even when they lack structural heart abnormalities or a family history, to facilitate early identification and improve outcomes. Further research is required to fully understand the clinical spectrum of MEPPC and its impact on cardiac function, as well as to develop tailored treatment strategies for affected individuals.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12872-026-05570-w.

Introduction

Since first being described by Laurent and colleagues in 2012 [1], Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC) syndrome has garnered attention. Despite its relatively short history, the accumulated knowledge of MEPPC indicates that it is a unique entity with specific diagnostic and therapeutic implications that should be familiar to physicians. First, it is recognized as a novel phenotype of channelopathy caused by gain-of-function mutations in SCN5A. This gene encodes the pore-forming ion-conducting α-subunit of the cardiac sodium channel (Nav1.5), which leads to hyperexcitability of the fascicular-Purkinje system [2, 3]. Consequently, patients with MEPPC present with typical clinical features, including a high burden of premature ventricular contractions (PVCs) originating from the fascicular-Purkinje fibers, often accompanied by an impairment of the left ventricular ejection fraction (LVEF). Occasionally, ventricular tachycardia (VT) and associated syncope or sudden cardiac death may be observed. Second, and perhaps most importantly, patients with MEPPC require a distinct treatment approach compared to patients with other types of ventricular arrhythmias (VAs). Radiofrequency ablation is generally ineffective in most cases, while sodium-channel blocking antiarrhythmic drugs have successfully suppressed VAs and subsequently reversed left ventricular (LV) dilation and/or systolic dysfunction, conditions that were reported to be refractory to guideline-directed medical therapy [4–7].

Due to its rarity and under-recognition, only a few cases of MEPPC syndrome have been described in the literature [1–17]. The incidence and prevalence of this syndrome remain unknown, and there are currently no established recommendations for its diagnosis and treatment. Furthermore, the clinical manifestations mimic dilated cardiomyopathy (DCM) and idiopathic ventricular arrhythmias (VAs). These mutations have been identified in 1.7% of DCM families [8]. However, an MEPPC phenotype without cardiac structural abnormalities is even more rarely reported, and no prevalence data exist among patients with idiopathic VAs. In this case study, we present the case of a young woman with a structurally normal heart who experienced multifocal PVCs and paroxysmal VTs. She was initially diagnosed with idiopathic fascicular VAs and underwent two unsuccessful radiofrequency ablation therapies. MEPPC was then suspected, and genetic testing confirmed an SCN5A gene mutation. Subsequently, flecainide successfully suppressed the VAs over the following two years. We hope that highlighting this case will raise awareness among physicians about this specific condition and improve its diagnosis and management.

Case report

A 26-year-old woman was admitted to the Department of Cardiology, West China Hospital, Sichuan University due to recurrent palpitations over the past four months. She reported no exertional dyspnea, edema, or weight loss. Her medical history and family history were unremarkable. Upon admission, physical examination revealed no significant findings except for an irregular heart rhythm detected by auscultation. Standard 12-lead ECG revealed sinus rhythm with a normal QRS duration (90 ms) and axis (+ 60°), and a corrected QT interval of 420 ms (calculated via the Bazett formula). A first-degree atrioventricular block was present, with a PR interval of 240 ms. Additionally, multifocal premature ventricular complexes (PVCs) were observed, displaying at least three distinct morphologies. These PVCs exhibited a narrow QRS complex (110 ms), right bundle branch block (RBBB) configuration, and rapid initial deflection (R-wave peak time ≤ 30 ms in limb leads), consistent with a Purkinje fiber origin, likely from the left posterior fascicle (Fig. 1). Further 24-hour Holter monitoring confirmed the presence of multifocal PVCs and nonsustained ventricular tachycardias (VTs), with a total arrhythmia burden accounting for 79% of all QRS complexes. Two predominant PVC morphologies were identified: one originating from the left anterior fascicle (LAF) region and the other from the left posterior fascicle (LPF) region. Laboratory tests indicated normal hematological, hepatic, renal, and thyroid function. Cardiac biomarkers were also within normal limits. Echocardiography showed normal cardiac structure and function (Fig. 2a). Given the high burden of ventricular arrhythmias (VAs), cardiac magnetic resonance imaging (CMR) was performed, which revealed no late gadolinium enhancement (LGE) (Fig. 2b); additionally, the T1 mapping value was within the normal range at 1250 ms (Fig. 2c).

Fig. 1.

The 12-lead electrocardiogram shows degree I AVB (red line), multifocal fascicular PVCs with RBBB type and left axis deviation morphology (blue arrows). AVB, atrioventricular block. PVCs, premature ventricular contractions; RBBB, right bundle branch block

Fig. 2.

a A normal LVEDD (46 mm) and LVEF (55.9%) revealed by M-mode echocardiograpy; b A negative LGE and c normal T1 value on CMR; d genetic testing shows c.655G > A mutation in exon 6 of SCN6A gene. CMR, cardiovascular magnetic resonance; LGE, late gadolinium enhancement; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction

An ablation strategy was planed, and our strategy involved separately mapping and ablating these two dominant PVC morphologies (LAF and LPF). During sinus rhythm, we identified Purkinje potentials to delineate the anatomical distribution of the LAF and LPF regions. For each PVC morphology, we targeted sites exhibiting the earliest bipolar activation (local EGM) and unipolar QS patterns during ectopy. Notably, no prepotentials (e.g., sharp or fragmented Purkinje-like signals) were observed at the earliest activation sites in this case. With radiofrequency application at these sites acute suppression of the ventricular ectopy was obtained. The patient was discharged without any medication. However, she was readmitted due to recurrent palpitations one month later, which were demonstrated to be caused by PVCs. A second radiofrequency ablation was attempted, but it also failed to resolve the issue.

Due to her young age and the presence of multifocal ectopic fascicular beats, genetic testing was suggested. The results revealed presence of a pathogenic heterozygous missense variant in exon 6 of the SCN5A gene c.665G > A (p.Arg222Gln, R222Q) (Fig. 2d). The patient was prescribed flecainide 50 mg twice daily, which effectively suppressed the VAs. During the two-year follow-up, the patient maintained good health with no palpitations reported. The 24-hour Holter monitoring revealed a burden of less than 1% of VA per day.

The patient’s family members were recommended to undergo screening, but only her younger sister consented to the evaluation. Testing revealed that the sister also exhibited multifocal PVCs (Fig. 3a) with narrow QRS duration and with a burden of 2.9% of total QRS complexes. Echocardiographic evaluation demonstrated normal left ventricular structure and systolic function (Fig. 3b). Genetic testing identified the same SCN5A mutation (c.665G > A, p.Arg222Gln [R222Q]) as found in the proband. Given her asymptomatic presentation and the low PVC burden (< 5%), no specific antiarrhythmic treatment was initiated. Instead, a strategy of periodic clinical follow-up with ongoing ECG monitoring was implemented to monitor for potential disease progression.

Fig. 3.

a The multifocal PVCs with a relative narrow QRS duration of 120ms and RBBB type (blue arrows) revealed on 24 h Holter; b a normal LVEDD (45 mm) and LVEF (63%) revealed by M-mode echocardiograpy. Abbreviations were as listed in Figs. 1 and 2

Discussion

As previously mentioned, the electrical features of MEPPC can be easily misdiagnosed as idiopathic VAs in the absence of cardiac abnormalities, especially when there are no myocardial fibrosis on CMR [16]. Our case underscored the importance of recognizing the typical electrical features and recommending genetic screening even in patients without cardiac abnormalities. Furthermore, the current case represented a phenotype of SCN5A mutation that presents with high burden VAs exclusively, confirming the previously reported myocardial scar or DCM phenotype could be the secondary consequence of SCN5A mutations. Regarding management, similar to previous cases of MEPPC syndrome, radiofrequency ablation was ineffective for this specific condition [1, 4, 13] which arose the suspicion of MEPPC for our case. Finally, a precise diagnosis make treatment success.

The Nav1.5 is responsible for the initiation and propagation of action potentials, and its mutation could cause varies arrhythmia, including long QT syndrome, Brugada syndrome, sick sinus syndrome, and conduction disease. The phenotypic diversity associated with SCN5A mutations is partly explained by the various biophysical consequences of individual mutations on channel function that can lead to loss- or gain-of-function as well as other environmental and genetic factors. The MEPPC was a recent recognized electronic disturbance that was thought to be related to a gain-of-function of SCN5A including R222Q, R225P, G213D, R814W, L828F, Q419P and A204E [2–6]. The R222Q was the first and most common reported mutation related to the MEPPC, resulting in inward gating pore currents carried by Na + at negative potentials. These gain-of-function mutations in the SCN5A gene determine an increased activity of sodium channels leading to the onset of action potentials during the repolarization phase of Purkinje cells. Accordingly, Class I antiarrhythmic drugs (AADs) work by reducing the rapid depolarizing sodium influx, slowing depolarization, and reducing the amplitude of action potential, leading to slower conduction and reduced automaticity. Thus, the administration of these drugs may offer a strategy for reducing ventricular ectopy in this syndrome [7]. Class IC AADs, such as flecainide, exert potent inhibition on sodium channels within His-Purkinje tissue and ventricular myocardium. This action reduces the slope of phase 0 of monophasic action potential, resulting in a deceleration of conduction velocity with a prolongation of HV and QRS intervals. From a recent systematic analysis of available literature, flecainide appears to be the most effective drug for treating this syndrome, with a reduction in ventricular arrhythmic events, consensual abolition of symptoms, and restoration of cardiac function in individuals with PVC-induced cardiomyopathies [7].

The relationship between the SCN5A gene mutations, VAs, and DCM is a topic of debate, with questions remaining over whether the genetic mutations directly cause DCM or if DCM is secondary to the burden of VAs. Theoretically, the gain-of-function of Nav1.5 can lead to an cellular Ca²⁺ overload via the sodium calcium exchanger in reverse-mode. This could result in cardiomyopathy through the Ca²⁺ sensitivity of the sarcomeres, or the predisposition to osmotic swelling and mitochondrial dysfunction due to Na⁺ overload². However, some supported the DCM was secondary to the high burden of VAs. It is well known that a PVC burden as low as 10% could lead to reversible cardiomyopathy. Furthermore, a recent systemic review of reported DCM-associated SCN5A variants found that DCM did not occur in the absence of arrhythmias [3]. Additionally, a remarkably reverse remodeling or EF recovery after class IC anti-arrhythmic drug treatment has been documented, suggesting that the burden of arrhythmias may be a predominant factor. We support the latter hypothesis as our case manifested as idiopathic VAs that with no abnormal findings on cardiac structure, function and myocardial fibrosis on CMR.

When should a genetic test be recommended to guide precise therapy? Some features have been suggested as grounds for suspicion, including a young age or childhood onset of symptoms, especially the multifocal PVCs originating from the fascicular Purkinje system, a phenotype resembling DCM, and a family history [1, 2]. However, based on a literature review, most previously reported MEPPC cases were diagnosed with indications such as a family history or left ventricular dilation and/or systolic dysfunction [1, 4–17]. In everyday practice, it is challenging to raise suspicion for MEPPC in a patient without cardiac abnormalities. Because the fascicular VAs are common forms of idiopathic left ventricular VAs, while the association between multifocal ectopic fascicular VAs and SCN5A mutations may be unfamiliar to most physicians. Notably, cascade screening of at-risk relatives is of great importance for patients diagnosed with this autosomal dominant condition; such an approach enables the identification of asymptomatic mutation carriers (as observed in the proband’s sister) who are likely to gain clinical benefit from early initiation of pharmacologic therapy.

Conclusion

Our case emphasize a genetic role in patients with a high-burden multifocal VAs related to Purkinje system, irrespective of family history and cardiac structure and function. Failure to suspect and diagnose MEPPC could result in inappropriate management. Improved recognition of MEPPC will lead to better long-term outcomes for this rare group of patients.

Abbreviations

MEPPC

Multifocal Ectopic Purkinje-related Premature Contractions

PVCs

Premature ventricular contractions

VAs

Ventricular arrhythmia

LVEF

Left ventricular ejection fraction

VT

Ventricular tachycardia

LV

Left ventricular

DCM

Dilated cardiomyopathy

CMR

Cardiac magnetic resonance imaging

LGE

Late gadolinium enhancement

Authors’ contributions

W.C., B.C and X.W: draft manuscript, major revision and figure preparation; X.L: patient care and follow-up; Z.Z. and Z.Y: draft preparation and figure preparation; Q.Z. and W.J.: critical revision; Y.K. and S.C.: writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

This case report was approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University (2022[302]). Informed consent was obtained from all patients.

Consent for publication

Written informed consent has been obtained from the patient to publish this paper.

Competing interests

The authors declare no competing interests.