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Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics
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Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 8108

Special Issue Editors

Dr. Yuri Battaglia

E-Mail Website
Guest Editor
1. Department of Medicine, University of Verona, 37129 Verona, Italy
2. Nephrology and Dialysis Unit, Pederzoli Hospital, 37019 Verona, Italy
Interests: fabry disease; physical exercise in kidney disease; ultrasound imaging in kidney disease; dialysis
Special Issues, Collections and Topics in MDPI journals
Dr. Concetto Sessa

E-Mail Website
Co-Guest Editor
Azienda Sanitaria Provinciale 7-Ragusa, ASL Ragusa,UOC Nefrologia e Dialisi, Ospedale Maggiore "Nino Baglieri", 97015 Modica, Italy
Interests: hemodialysis; chronic renal failure; kidney transplantation; clinical nephrology; acute kidney injury; peritoneal dialysis; renal failure; nephrotoxicity; catheters; chronic kidney disease

Special Issue Information

Dear Colleagues,

Fabry disease, a rare X-linked lysosomal storage disorder, results from mutations in the GLA gene, leading to deficient α-galactosidase A enzyme activity. This deficiency causes glycosphingolipids to accumulate in various tissues, affecting the kidneys, heart, skin, and nervous system. Recent research has advanced our understanding of Fabry disease's pathophysiology, clinical manifestations, and treatment options, including enzyme replacement therapy (ERT) and chaperone therapy. However, challenges remain in early diagnosis, disease management, and the development of more effective adjuvants and specific treatments.

This Special Issue aims to consolidate cutting-edge research and foster multidisciplinary collaboration to address these challenges. Original research articles and reviews that explore novel diagnostic biomarkers, genetic and molecular basis, and innovative therapeutic approaches. Clinical studies that offer new insights and advancements in imaging findings, patient-reported outcomes, and the long-term efficacy of current treatments are also encouraged.

Dr. Yuri Battaglia
Dr. Concetto Sessa
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fabry disease
  • lysosomal storage disorder
  • GLA gene mutations
  • enzyme replacement therapy
  • chaperone therapy
  • physical activity
  • imagining

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Published Papers (6 papers)

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Research

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12 pages, 2511 KiB  
Article
MRI T2 Mapping of Dorsal Root Ganglia Reveals Increased T2 Relaxation Time in Classical Fabry Disease
by Simon Weiner, Sarah Perleth, Thomas Kampf, Kolja Lau, Florian Hessenauer, György Homola, Peter Nordbeck, Nurcan Üçeyler, Claudia Sommer, Mirko Pham and Magnus Schindehütte
Biomedicines 2025, 13(3), 592; https://doi.org/10.3390/biomedicines13030592 - 28 Feb 2025
Viewed by 626
Abstract
Background/Objectives: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterised by progressive glycolipid accumulation affecting multiple organs, including the peripheral nervous system. The dorsal root ganglia (DRG) play a key role in Fabry-related neuropathy, but non-invasive biomarkers of DRG involvement [...] Read more.
Background/Objectives: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterised by progressive glycolipid accumulation affecting multiple organs, including the peripheral nervous system. The dorsal root ganglia (DRG) play a key role in Fabry-related neuropathy, but non-invasive biomarkers of DRG involvement and their association with overall disease severity remain limited. This study evaluated lumbosacral DRG T2 relaxation time (DRG-T2) in FD patients as a potential imaging biomarker of FD severity. Methods: In a prospective, single-centre study, 80 genetically confirmed FD patients underwent 3T MRI with quantitative T2 mapping of the lumbosacral DRG. DRG-T2 was analysed in relation to sex, genetic subtype and Fabry-specific biomarkers. Results: Results showed that DRG-T2 was higher in patients with classical FD mutations than in those with nonclassical mutations (p = 0.03). Furthermore, DRG-T2 showed a negative correlation with body weight (ρ = −0.31, p = 0.005) and BMI (ρ = −0.32, p = 0.004), while no associations were found with lyso-Gb3 levels or alpha-galactosidase A activity. The inter-rater and test–retest reliability of DRG-T2 were good to excellent (ICC = 0.76 and 0.89, respectively). Conclusions: These results demonstrate DRG-T2 as a marker of neuronal involvement, making it a strong and reliable imaging biomarker of disease severity in FD. However, future studies need to correlate its changes with clinical and histological studies. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
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32 pages, 8096 KiB  
Article
Reversing Pathology in an Aggravated Fabry Mouse Model Using Low-Dose Engineered Human Alpha-Galactosidase A AAV Gene Therapy
by Wanida Ruangsiriluk, Mugdha Deshpande, Natalia Boukharov, Girija Rajarshi, Shreya Mukherji, Shipeng Yuan, Jennifer Wiseman, Nancy Chen, Eric Park, Hyelim Cho and Rizwana Islam
Biomedicines 2025, 13(3), 577; https://doi.org/10.3390/biomedicines13030577 - 25 Feb 2025
Viewed by 1473
Abstract
Background/Objectives: Fabry disease is an X-linked disorder caused by lysosomal accumulation of glycosphingolipids due to the deficiency of α-Galactosidase (α-GAL), which leads to pathology in multiple organ systems. The standard of care is enzyme replacement therapy (ERT) with recombinant native α-GAL protein. [...] Read more.
Background/Objectives: Fabry disease is an X-linked disorder caused by lysosomal accumulation of glycosphingolipids due to the deficiency of α-Galactosidase (α-GAL), which leads to pathology in multiple organ systems. The standard of care is enzyme replacement therapy (ERT) with recombinant native α-GAL protein. Shortcomings of the native α-GAL include low stability, a short circulating half-life, and inadequate uptake by affected tissues that limits the efficacy of ERT and could potentially reduce AAV gene therapy (GT) benefits. Cross-correction by secreted α-GAL is essential for liver-targeted as well as ubiquitous AAV GT due to poor transduction and/or short half-life of some of the significantly affected cell types. Methods: To overcome potential limitations of AAV GT delivering native α-GAL, we used an engineered GLA transgene product to improve enzyme stability and reduce predicted immunogenicity. Results: The stabilized α-GAL variant, Eng-C, had an extended circulatory half-life, allowing for enhanced distribution and efficient uptake by target organs. AAV gene therapy with Eng-C demonstrated significantly greater substrate reduction in the severe Fabry G3Stg/GlaKO mouse model across all affected tissues. Efficacy of the Eng-C AVV GT was equal to or greater than the efficacy of the higher doses of the AAV GT with native α-GAL. Furthermore, this study is the first to demonstrate that the pre-existing pathology in some tissues in G3Stg/GlaKO mice can be reversed with efficient treatment. Conclusions: Our findings demonstrate that an AAV-based gene therapy expressing an engineered α-GAL with improved stability and lower immunogenicity could be effective at lower doses than other AAV GTs, potentially offering lower safety risks typically associated with high AAV vector doses. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
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10 pages, 227 KiB  
Article
Dizziness in Fabry Disease
by Aslak Broby Johansen, Ulla Feldt-Rasmussen and Mads Klokker
Biomedicines 2025, 13(2), 249; https://doi.org/10.3390/biomedicines13020249 - 21 Jan 2025
Viewed by 838
Abstract
Background/Objectives: Fabry disease is an X-linked lysosomal storage disease. Earlier studies have mentioned dizziness/balance issues and vestibular involvement as a symptom of Fabry disease. Research on the matter remains scarce. This pilot study aims to show the prevalence of dizziness/balance issues and [...] Read more.
Background/Objectives: Fabry disease is an X-linked lysosomal storage disease. Earlier studies have mentioned dizziness/balance issues and vestibular involvement as a symptom of Fabry disease. Research on the matter remains scarce. This pilot study aims to show the prevalence of dizziness/balance issues and whether it is due to peripheral, central, or other factors. Methods: A Dizziness Handicap Inventory, with added questions, was sent out to 91 Fabry patients to estimate the prevalence of dizziness/balance issues. Additionally, this study reports analyses from eight Fabry patients with self-reported dizziness/balance issues who were offered referrals for in-depth investigations of their condition. All eight underwent a comprehensive oto-neurological examination, Videonystagmography, a Video Head impulse test, vestibular myogenic evoked potential, and audiometry. Results: A total of 55 of the 91 patients with Fabry disease answered the survey. Of these, 78.2% felt symptoms of dizziness/balance issues. The most common form of dizziness/balance issues was short-lasting attacks. All eight ENT-examined patients had normal outer and middle ear conditions. Five of eight Fabry patients had abnormal results in the optokinetic test and audiometry. Conclusions: The survey showed a high prevalence of dizziness/balance issues in Fabry patients. The abnormal optokinetic test suggested a central cause and was the only objective measurement we found that could lead to an explanation for dizziness/balance issues. Polypharmacy was present in all eight examined patients and could also explain the dizziness/balance issues in Fabry patients. There is no other clear pattern regarding the characteristics of dizziness/balance issues in Fabry patients in this exploratory study. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
7 pages, 1355 KiB  
Communication
A Non-Invasive Technique to Unveil Renal Implications in Anderson–Fabry Disease
by Matteo Gravina, Dario Troise, Barbara Infante, Luciano Tartaglia, Bruno Minopoli, Costanza Allegra, Grazia Casavecchia, Marcella Gambacorta, Carmen Montanile, Silvia Mercuri, Luca Macarini and Giovanni Stallone
Biomedicines 2024, 12(9), 1950; https://doi.org/10.3390/biomedicines12091950 - 26 Aug 2024
Viewed by 1491
Abstract
Background: Anderson–Fabry disease (AFD) is a rare genetic disorder characterized by a deficiency of α-galactosidase A activity and the accumulation of glycosphingolipids in tissues, which leads to multiorgan damage. Cardiovascular magnetic resonance (CMR) and the T1 mapping technique are essential tools for the [...] Read more.
Background: Anderson–Fabry disease (AFD) is a rare genetic disorder characterized by a deficiency of α-galactosidase A activity and the accumulation of glycosphingolipids in tissues, which leads to multiorgan damage. Cardiovascular magnetic resonance (CMR) and the T1 mapping technique are essential tools for the assessment of AFD cardiac involvement. Moreover, the T1 mapping technique has proved to be a successful non-invasive method for the early detection of patients most at risk for kidney disease. We evaluated the application of MRI in patients with AFD to assess renal involvement. Methods: We conducted a retrospective analysis of 19 patients (Group A) with histologically proven AFD who underwent routine CMR examinations for the evaluation of cardiac involvement, selecting specific sequences that also showed the left kidney, compared to a control population (Group B, 19 patients) without kidney disease. A Spearman’s rank-order correlation was run to assess the relationship between the T1 mapping values of the heart and kidney in Group A and between the kidneys of Groups A and B. Results: There was a positive correlation between the heart and kidney T1 values in Group A (rho = 0.32). More interestingly, we observed a negative correlation between the kidney values of both groups (Group A mean 1284 ± 137 ms, Group B mean 1073 ± 57 ms, rho = −0.38), which is probably related to the presence of microvascular damage and infiltrates in the kidneys of AFD patients. Conclusions: To our knowledge, these results are the first to highlight the key value of T1 mapping in assessing pathological changes and aiding in the non-invasive diagnosis of renal involvement in AFD. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
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Review

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14 pages, 6760 KiB  
Review
The Role of Kidney Biopsy in Fabry Disease
by Irene Capelli, Laura Martano, Gian Marco Berti, Gisella Vischini, Sarah Lerario, Vincenzo Donadio, Alex Incensi, Valeria Aiello, Francesca Ciurli, Benedetta Fabbrizio, Stefano Chilotti, Renzo Mignani, Gianandrea Pasquinelli and Gaetano La Manna
Biomedicines 2025, 13(4), 767; https://doi.org/10.3390/biomedicines13040767 - 21 Mar 2025
Viewed by 720
Abstract
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease [...] Read more.
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
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26 pages, 2548 KiB  
Review
Fabry Disease: Insights into Pathophysiology and Novel Therapeutic Strategies
by Sophie Elizabeth Thompson, Ashwin Roy, Tarekegn Geberhiwot, Katja Gehmlich and Richard Paul Steeds
Biomedicines 2025, 13(3), 624; https://doi.org/10.3390/biomedicines13030624 - 4 Mar 2025
Cited by 1 | Viewed by 2194
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone [...] Read more.
Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone therapy (OCT) have limited efficacy, particularly in advanced disease, prompting a need for innovative therapeutic approaches targeting underlying molecular mechanisms beyond glycosphingolipid storage alone. Recent insights into the pathophysiology of FD highlights chronic inflammation and mitochondrial, lysosomal, and endothelial dysfunction as key mediators of disease progression. Adjunctive therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRAs) demonstrate significant cardiovascular and renal benefits in conditions including heart failure and chronic kidney disease. These drugs also modulate pathways involved in the pathophysiology of FD, such as autophagy, oxidative stress, and pro-inflammatory cytokine signaling. While theoretical foundations support their utility, dedicated trials are necessary to confirm efficacy in the FD-specific population. This narrative review highlights the importance of expanding therapeutic strategies in FD, advocating for a multi-faceted approach involving evidence-based adjunctive treatments to improve outcomes. Tailored research focusing on diverse FD phenotypes, including females and non-classical variants of disease, will be critical to advancing care and improving outcomes in this complex disorder. Full article
(This article belongs to the Special Issue Advances in Fabry Disease: From Molecular Insights to Innovative Therapeutics)
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