Fatigue as hallmark of Fabry disease: role of bioenergetic alterations

Abstract

Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The “metabolic hypothesis” to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.

Cardiopulmonary determinants of reduced exercise tolerance in Fabry disease

“…The buildup of glycosphingolipids and Gb3 occurs in all cardiac cell types including myocytes, endothelial and smooth muscle cells of intramyocardial vessels, endocardium, valvular fibroblasts, and conduction tissue probably culminating in inflammation, necrosis, fibrosis, and hypertrophic myocardial disarray ( 26 , 27 ). However, Gb3 accumulation in the heart is per se not sufficient to explain the whole spectrum of cardiac manifestations and it has emerging the hypothesis that the primary enzymatic defect in FD triggers other processes that result in biochemical and functional alterations including autophagy alterations, mitochondrial defects, and energetic failure ( 25 , 28 ). The energy depletion may activate pro-hypertrophic pathways, common to other hypertrophic cardiomyopathies, and may affect cardiac responsiveness to stress.…”

Diet and Physical Activity in Fabry Disease: A Narrative Review

“…Few published studies have been done on exercise in FD patients. In general terms, it is well recognized how essential PA is for preserving and enhancing muscular fitness and the cardiovascular system, as well as how crucial it is to manage these variables in systemic diseases [79].…”