Physical performance and nutritional status in patients with Fabry disease: study design of an Italian multicenter cross-sectional study

Fabry disease (FD) is a rare X-linked hereditary lysosomal disease caused by a deficiency of the enzyme α-galactosidase, leading to the accumulation of glycosphingolipids in several organs and tissues [1]. This multisystemic disease manifests with heterogeneous clinical phenotypes, affecting multiple organs such as kidneys, heart, gastrointestinal tract, and the central and peripheral nervous system. The severity of Fabry disease depends on gene mutations, enzyme activity levels, and gender [2]. Subjects with Fabry disease often experience early-onset exercise intolerance and fatigue, which are attributed to a combination of skeletal and muscular impairment, peripheral neuropathy, and cardiovascular complications [3]. According to the “metabolic hypothesis,” skeletal muscle symptoms and fatigability are linked to (a) disruptions in metabolic flexibility, leading to a shift towards anaerobic metabolism in skeletal muscle; (b) reduced oxygen delivery to muscles due to vascular damage and decreased blood flow; (c) presence of muscle atrophy areas (granules); and (d) neuronal degeneration of small fibers (C-fibers) and impaired function of ion channels, such as HCN2 and NaV1.7 sodium channel [4]. Assessing exercise tolerance in Fabry disease subjects is crucial for the early identification of organ dysfunction and for starting appropriate exercise training to counteract physical inactivity [5]. Among the available tests, the cardiopulmonary exercise test (CPET) is widely used to assess exercise tolerance, cardiac function, and aerobic fitness. Lobo et al. demonstrated that Fabry disease individuals had lower exercise capacity on the cardiopulmonary exercise test compared to age-, sex-, and size-matched healthy controls [6]. Additionally, another study revealed that Fabry disease patients exhibited impaired cardiopulmonary exercise capacity and failed to reach their maximum heart rate [7]. To manage exercise intolerance and fatigability, available treatments, such as enzyme replacement therapy (ERT) or chaperones, are effective when started early [8]. However, these symptoms often persist in treated Fabry disease individuals, significantly affecting their quality of life. As a result, there is growing emphasis on prescribing non-pharmacological therapies, such as physical activity and nutritional interventions, to address exercise intolerance and fatigue [9]. Nonetheless, no data on the interplay between the physical and nutritional status of Fabry disease patients are currently available. Therefore, we designed a multicenter cross-sectional study to investigate the relationship between physical performance, evaluated through cardiopulmonary exercise test, and nutritional status, assessed via bioimpedance analysis (BIA), in Fabry disease individuals. As a secondary objective, we will explore the association of physical performance with psychosocial conditions, health-related quality of life, and biochemical data.