Onset and progression of the Anderson–Fabry disease related cardiomyopathy

Abstract

Background

Cardiac involvement is responsible for substantial morbidity and mortality in Anderson–Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients.

Methods

We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy.

Results

In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m^2.7) was found in both males and females (P < 0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07 ± 1.03 g/m^2.7 per year in males and by 2.31 ± 0.81 g/m^2.7 in females (P < 0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m^2.7 per year in males and by 1.80 g/m^2.7 in females (P = 0.12).

Conclusion

AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Introduction

Anderson–Fabry disease (AFD) is a rare, inherited, X-linked error of glycosphingolipid catabolism caused by a deficiency of the lysosomal enzyme α-galactosidase A [1], [2]. The primary manifestations of AFD are thought to occur due to a progressive intralysosomal accumulation of globotriaosylceramide (Gb₃) and related glycosphingolipids in various organs and tissues, including the kidneys, heart, skin, gastrointestinal tract, brain, and elsewhere. The clinical onset typically occurs in childhood and adolescence and is characterized by acroparesthesias, angiokeratoma, corneal and lenticular opacities, and hypohidrosis [3]. As the disease progresses kidney function declines beginning in the third decade of life, deteriorating to end-stage kidney disease in males [4]. Cardiac involvement is common [5], [6], [7], [8], [9], [10], as are structural and functional changes in the cerebral circulation [11], [12], [13]. Female heterozygotes had been considered unaffected carriers, but it is increasingly clear that females may experience all the signs and symptoms of AFD, although with a delayed onset and a heterogeneous expression and everity compared to males [14], [15]. Kidney, heart, and cerebrovascular disease contribute to premature death in both male and female AFD patients [16], [17], [18].

Cardiac manifestations of AFD include left ventricular hypertrophy, valvular dysfunction, and conduction abnormalities [19], [20]. Left ventricular wall thickening is the most common cardiac sign in AFD, with the increases so large in some cases that is mimics hypertrophic cardiomyopathy [20], [21]. Although deposition of Gb₃ within cardiac myocytes contributes to the hypertrophy, the total mass of Gb₃ is reported to be less than 3% of total myocardial mass [19]. Myocardial fibrosis is commonly observed in AFD patients [21], and left ventricular contractility and diastolic function deteriorate progressively as LVH develops [22]. All of these cardiac signs and symptoms are commonly found in female AFD patients [14], [17], [23]. Here we report the results of a study designed to describe the prevalence and extent of left ventricular hypertrophy in a population of enzyme replacement therapy (ERT)-naïve male and female AFD patients.