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Heterogeneous phenotypes and mixed forms of inherited cardiac diseases

Case Presentation:

A 35 years old male was referred for evaluation after ECG findings consistent with Brugada type I pattern in a routine check-up (figure 1A). Echocardiogram and holter were both normal. He had history of 2 episodes of syncope some years ago, one neuromediated (while urinating) and other orthostatic. A list of drugs to avoid and a recommendation to early treatment of fever was given and clinical follow-up was scheduled.



Fig.1: 12 lead ECG of proband (patient A) (1A) and sister (patient B) (1B).

A pedigree was constructed (figure 2). Family screening led to study of 10 first degree relatives. A sister aged 41 years had a remote orthostatic syncope and history of palpitations. ECG showed upper limit PR interval with ST elevation suggestive of Brugada, with type I pattern on drug challenge test (flecainide). Echcocardiogram was unremarkable. Holter failed to demonstrate arrhythmias. She was considered to be at low risk and clinical follow-ups were scheduled.


Figure 2. Family pedigree. Age is indicated for evaluated individuals. Affected individuals are indicated in grey. Wildtype normal individuals are shown in green.

The father, aged 66 years, past smoker and hypertensive, had 2 admissions in the past 12 years because of chest pain. He also had a neuromediated syncope 15 years ago. ECG in all admissions and clinical visits was abnormal with broad P wave, upper limit PR, ST elevation in right precordial and ST depression with negative T wave in left precordial leads, together with slightly broad and high voltaged QRS complex (figure 3a). Exercise test was negative for ischaemia. Echocardiogram showed apical  hypertrophy of 18 mm (figure 3b). Drug challenge test was not performed in this case due to the coexistence of Cardiomyopathy. Alfa-GAL-A activity was 67% (normal > 30%) and Anderson-Fabry disease was excluded.



Figure 3: 12 lead ECG and echocardiogram of the father (patient C). right up corner: four chambers view, right inferior corner apical short axis view, with maximum wall thickness.

All other relatives evaluated had normal ECG and echocardiogram, and all refused to undergo drug challenge test.

Follow-up.

Brother and sister with Brugada pattern have remained asymptomatic to date (5 years follow-up). ECG remains unchanged and last echocardiogram showed no hypertrophy.

The father, now 71 years old, was last year admitted to hospital for angina and a severe focal stenosis of the left anterior descending artery was treated with stent. He also had atrial fibrillation during admission. ECG was unchanged from previous and echocardiogram demonstrated normal systolic function with no changes in the measurements of left ventricular wall thickness. Shortly after this admission (2 months later) the patient was admitted with poorly tolerated monomorphic VT requiring electrical cardioversion. There were not changes in echocardiogram nor coronary stenosis in a new angiogram. Electrophysiologic testing reproduced bundle branch reentrant ventricular tachycardia and demonstrated infrahisian conduction system impairment (HV interval > 100ms). The patient was treated with radiofrequency ablation of right bundle branch and DDD peacemaker implantation.

Genetic testing of SCN5A demonstrated a described mutation E901K. The 3 affected individuals (proband, sister and father) were all carriers. The mutation was not present in any other of the evaluated individuals (represented in green in figure 2).

QUESTIONS
 

- What is the diagnosis of the father?, Would you recommend cardiac magnetic resonance to clarify diagnosis of apical appearance of the left ventricle?
- Would you recommend drug challenge test in the father to clarify diagnosis of probable Brugada?
- Would you recommend ICD implantation in any of the 3 affected relatives?
- Do you think mutations in genes encoding for channels can be cause of cardiomyopathies?

Myocardial Disease


Notes to editor

Presented by:
Antonio Romero, Javier Lacunza, Juan R. Gimeno
Hospital de la Vega Baja, Alicante and Hospital Virgen Arrixaca. Murcia. Spain