Editorial: Target Organ Damage in Fabry Disease

Guido Iaccarino^1*Francesca Graziani²

• ¹Program for Adapted Physical Activity Prescripriton for Chronic Conditions, Federico II University Hospital, Napoli, Italy
• ²Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

The body of research dedicated to Fabry Disease (FD) has grown significantly in the last 25 years, concurrent the availability of therapies for the disease. At the moment, consolidate therapies include enzyme replacement and chaperone therapy. Experimental therapeutics involve gene therapy and substrate supplementation, that are in to the pipeline to be deployed in clinical realm.With greater awareness among clinicians and researchers, the number of diagnosed cases has risen, along with the identification of putative pathogenic mutations in the GLA gene (encoding GalA). To date, more than 1,500 such mutations have been reported, and the number continues to grow , and same mutations have a clear impact on the disease, some other remain of uncertain clinical relevance 1 .As more clinical cases are studied, the heterogeneity in the disease's clinical presentation has become increasingly apparent. The relationship between genotype and phenotype appears to be less straightforward than initially assumed, and target organs might be affected differently despite the presence of similar or even the very same mutation, in particular with variants of unknown significance. Notably, since the GLA gene is located on the X chromosome, significant sex-based differences in clinical manifestation have been observed 2 . Males typically exhibit a more severe disease phenotype, with greater target organ involvement and shorter survival, while females often present with a milder clinical course and longer life expectancy 3 . This calls for a different management between women and men Fabry patients, as pointed out by Tuttolomondo https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2025.1536114/full et al.All of the above suggests that the mechanisms of FD might be more complicated than originally thought. In a classical vision, the damage of target organs such the heart, the kidney, the brain, the bowel and the vasculature, is due to the intracellular accumulation of globotriaosylceramide (Gb3), which leads to cellular dysfunction and therefore loss of organ function 4 . Such a vision, though, implies an important GB3 intracellular accumulation that in some cases is missing or barely present. Although lysosomal dysfunction can be considered the ignition of cellular dysfunction, other mechanisms need to be taken into account that might accelerate or delay the onset of the target organ damage associated with the disease 5 . (Figure 1)In this Research Topic dedicated to the Target Organ Damage (TOD) in FD, we focused on the current, modern interpretation of clinical manifestation.Twelve papers, over 100 authors, and more than 18.000 total views at the time this editorial is written confirm the renewed interest in this condition.The heart is the target organ of FD that has been more often investigated. In this RT, it emerges clear that the cardiac US remains still the easiest and more accessible way to assess cardiac damage also in FD. All cardiac structures, such as the left ventricle and the left atrium, the aorta, the right sections, and the heart valves can be affected by morphological and functional abnormalities. Conte et al https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1467815/full state that standard echocardiography has a crucial role in the characterization of FD cardiomyopathy and provide a comprehensive review on the topic. Furthermore, echocardiographic evaluation is the essential imaging method to support the physician in the follow-up and risk stratification. Spinelli et al https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1440636/full suggest that techniques such as tissue Doppler imaging and speckle-tracking echocardiography (STE) allow detection of subclinical changes in left ventricular (LV) systolic and diastolic function, particularly reductions in global longitudinal strain and circumferential strain gradients. These techniques are also valuable for evaluating right atrial and ventricular involvement, often preceding hypertrophy. Lillo and collaborators https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2025.1496534/full performed STE analysis of the right atrium and revealed impaired strain values of this structure and all RA strain phases in patients with FD compared with control patients. When considering FD patients without LVH, RA reservoir and contractile strains were significantly reduced. Right atrium is therefore another candidate parameter to monitor cardiac TOD in FD.Indeed, the most advanced technology for the analysis of cardiac structural abnormalities is the MRI, which can still provide further insight as for the description of features of the cardiac hypertrophy of the Fabry patient. Tondi et al https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1458705/full show that Papillary Muscle hypertrophy is more pronounced in FD, and mitral valve anatomy alterations progressively worsened with advancing FD stages. The findings highlight papillary muscle hypertrophy and mitral valve anatomy abnormalities as potential early markers of cardiac involvement in FD and recommend their routine assessment during CMR in patients with hypertrophic cardiomyopathies.Finally, FD often associates with arrhythmias that need to be monitored. To this aim, Roy et al. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1323214/full demonstrate that the implantable loop recorders might help to explore the impact of the disease, irrespective of left ventricle hypertrophy.Kidney failure is another typical manifestation of the TOD in FD. Rozenfeld and al https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1386042/full focus on Renal fibrosis and consider it as the end result of multiple damages, including inflammation, cell migration, differentiation, and increased extracellular matrix production. In Fabry nephropathy, these effects occur within the kidney tubule, following the initial damage caused by lysosomal dysfunction and disruption of Gb3-LysoGb3 activity. Concurrent to mitochondrial failure, kidney tubular cells requiring healthy energetic metabolism to function are the first cells to be damaged in the kidney. Therefore, the contribution of the tubular epithelial cells and the interstitial space to Fabry nephropathy is important from its initiation to its progression and may contribute to the pathogenesis of renal injury.Energetic metabolism is also considered a mechanism to fatigue and reduced exercise tolerance in FD, according to De Marco et al. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1396996/full and to Gambardella et al. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1341590/full Fatigue, often an early and independent symptom, can be due to cardiac and pulmonary dysfunction as well as impairment in skeletal muscle. In FD, skeletal muscle bioenergetic alterations such as mitochondrial impairment, metabolic inflexibility, and increased glycolysis might explain the fatigue. Other mechanisms such as inflammation, muscle atrophy, and vascular and neuronal dysfunction further contribute. Cardiopulmonary exercise and biomarkers like lactate and mitomiRs might help in the stratification of the clinical condition of patients with FD diagnosis. Enzyme replacement therapy offers limited relief, while personalized exercise programs might offer a more tailored approach to improve patient care and quality of life.Inflammation is an emerging mechanism for TOD in FD. Reading the review of Kurdi et al., https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1420067/full the main activator of inflammation is the accumulation of sphingolipids, resulting from the deficiency of alpha galactosidase, which triggers cellular stress. Acute, chronic and resolving stages are a continuum rather than strictly distinct, although each stage has a recognised hallmark. There are also overlaps between the innate and adaptive immune responses, suggestive of an autoinflammatory component to FD. Infalmmation is the possible mechanism to endothelial dysfunction in FD, which can be monitored through serum levels of VEGF. According to Lund et al. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1355033/full this parameter correlates with markers of renal and cardiac damage in FD patients and can be considered a useful biomarker for endothelial dysfunction.The research in FD is far from having answered all the questions, opposite it has opened new fields of investigation. The success of this RT testifies it and poses the bases for a new call for papers for the "Frontiers in Research topic: Target Organ Damage in Fabry Disease 2.0".