The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

Abstract

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy

“…From our previous studies, it is clear that the disease caused by this TMEM43 p.S358L mutation is different in men than in women, 6 a situation reflected in other inherited cardiomyopathies. 33,34 In TMEM43 p.S358L ARVC, SCD occurred earlier in males, ICDs were inserted at a younger age (mean age 31years), and the survival benefit of the ICD was substantially larger.…”

“…Thus, many individuals with TMEM43 p.S358L were in the concealed phase of ARVC with a significant risk for SCD, yet undiagnosable using TFC. We previously presented the extensive variability of expression in mutation carriers, 6 reflecting the increasing recognition of clinical overlap in phenotype (eg, presenting with a dilated cardiomyopathy or ARVC) which can confound TFC. Individuals with classical ARVC are present in this population, 6 but their manifestations are not present in everyone.…”

“…PRWP is a clinical feature seen in this genetic subtype of ARVC. 6,25 Eight females (12%) with normal cardiac testing had an ICD based on patient request. To date, 148 individuals have ICDs: 80 males and 68 females (Figure 1).…”

“…Affected individuals (n=393) were defined based on any or all of the following: (1) obligate carrier status by pedigree analysis (an individual with both an affected child and a parent), (2) the presence of the p.S358L TMEM43 mutation and, (3) documented sustained VT/ VF or otherwise unexplained SCD before 50 years of age. 6 Unaffected individuals (n=229) were defined by the absence of the p.S358L mutation. All others (n=240) were considered unknown status (UK; Figure 1).…”

“There are days I wish it wasn’t there, and there’s days I realize I’m lucky”: A qualitative study of psychological sequelae to the implantable cardioverter defibrillator as a treatment for the prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy

“…28 The severity of this genetic subtype of ARVC lends urgency to treatment as family history shows that for many, their first clinical symptom was their last, 29 so it is less surprising that issues other than the SCD risk have been afforded a lower priority. However, ICD therapy is often situated in the context of a family coping with multiple affected family members, the fear of SCD, feelings of guilt and associated psychological sequalea.…”