Introduction
Fabry disease, initially described in the late 19th century as "Diffuse angiokeratoma," has since been recognized as an X-linked
multisystem lipid storage disorder caused by mutations in the GLA gene, re-sponsible for encoding the lysosomal enzyme a-galactosidase A (a-Gal A). This genetic defect leads to the accumulation of glycolipids, primarily globotriaosylceramide (Gb3), and its deacylated form glo-botriaosylsphingosine (lyso-Gb3), in lysosomes throughout the body (Fabry J, 1898; Azevedo et al., 2020; Cybulla et al., 2022; Mehta et al., 2006; Sweeley and Klionsky, 1963).
With over 1000 genetic variants identified in the GLA gene to date, Fabry disease presents a wide spec-trum of clinical manifestations, ranging from the classic phenotype with severely reduced a-Gal A ac-tivity to the late phenotype characterized by milder enzyme deficiency and later onset of organ compli-cations (Bernardes et al., 2020; Mehta and Hughes, 2002). Affected individuals experience progressive cellular dysfunction, microvascular damage, and metabolic disturbances, ultimately leading to irre-versible fibrosis in vital organs such as the heart, kidneys, blood vessels, and nervous system (Popli et al., 1990; Vedder et al., 2006; Kubota et al., 2022).
Recent advancements in Fabry disease research have focused on innovative therapeutic strategies aimed at addressing the underlying genetic defect and preventing disease progression. One notable approach involves precision medicine, leveraging genetic sequencing technologies to tailor personalized treat-ment regimens based on individual genetic profiles. By understanding the specific mutations in the GLA gene, researchers aim to develop targeted therapies that can effectively restore enzyme function and reduce the accumulation of toxic metabolites (Branton et al., 2002; Meikle et al., 1999; Spada et al., 2006).
Gene therapy has emerged as a promising avenue for the treatment of Fabry disease, with ongoing re-search focusing on the delivery of corrected genes to replace or repair defective GLA gene variants. By harnessing viral vectors and gene editing technologies, scientists seek to develop curative gene therapies that can provide long-term benefits for patients by addressing the root cause of the disease at a molecu-lar level (van der Tol et al., 2014).
In addition to gene-based approaches, advancements in enzyme replacement therapies (ERTs) continue to enhance treatment options for individuals with Fabry disease. Next-generation ERTs with improved tissue targeting, extended half-lives, and reduced immunogenicity are being developed to optimize effi-cacy and patient outcomes. Furthermore, small molecule chaperones that stabilize mutant enzymes and enhance their activity represent a promising avenue for the development of novel therapeutic interven-tions (Kubota et al., 2023).
Combinatorial therapies combining ERTs, chaperone therapies, and gene therapy are being explored to harness synergistic effects and improve treatment outcomes in Fabry disease patients. Additionally, the identification of reliable biomarkers for disease monitoring and treatment assessment is a key area of research, enabling clinicians to better track disease progression and therapeutic response (Kubota et al., 2023).
By continuing to innovate in the fields of precision medicine, gene therapy, enzyme replacement, and biomarker discovery, researchers are making significant strides towards advancing therapeutic ap-proaches for Fabry disease. These promising developments offer hope for improved outcomes and quality of life for individuals affected by this rare genetic disorder.
Clinical manifestations
FD is characterized by a multisystem phenotype, including cardiomyopathy, kidney failure, vas-culopathy, sweating disorders, acroparesthesia, angiokeratomas, and gastrointestinal symptoms. It is customary to distinguish two phenotypes: the early classical form and the late form, which is often characterized by damage to one organ (Muntean et al., 2022).
Mutations in gene GLA, causing practically zero enzymatic activity, are associated with relatively severe and early classical phenotypes, which are characterized by the occurrence of clinical manifesta-tions in childhood or adolescence, such as acroparesthesia, neuropathic pain, hypohidrosis, intolerance to high temperatures, cold and physical activity, angiokeratomas, gastrointestinal symptoms and mi-croalbuminuria. With age, organ dysfunction becomes more and more evident: proteinuria, albuminu-ria and decreased kidney function develop, which can progress to end-stage renal disease with the need for dialysis or kidney transplantation (Duro et al., 2018).
Cardiac lesions are different, they range from progressive left ventricular hypertrophy to heart failure, the need for heart transplantation, and sudden cardiac death. Repeated episodes of cerebrovas-cular accident or even stroke is a sign of damage to the central nervous system, often of a disabling na-ture.
In contrast, mutations in gene GLA leading to residual enzymatic activity are associated with mild and late occurring phenotypes, which are characterized by the development of cardiac, kidney and/or cerebrovascular manifestations in adulthood (Kubota et al., 2023; Arends et al., 2017; Azevedo et al., 2020a; Azevedo et al., 2020b). Due to significant advances in the treatment of kidney damage, cardiovascular diseases have become the leading cause of death in patients with FD (Meikle et al., 1999). Patients with FD most often have left ventricular hypertrophy (LVH), which is not explained by ab-normal cardiac loading conditions (such as hypertension or aortic stenosis) and it is sometimes noted to be a predominant or isolated feature (the so-called “cardiac variant”) (Kubota et al., 2023; Whybra et al., 2001).
Diagnostics
The average time from the occurrence of the first clinical manifestations to confirmation of the diagnosis of FD is on average 10.5 years (Spada et al., 2006). This delayed diagnosis occurs due to the wide variety of phenotypic presentations. Considering the availability of pathogenetic therapy, early di-agnosis for FD is of the highest significance. In order to make an early diagnosis, it is advisable to con-duct a screening of risk groups and diagnose the disease as early as possible. Once diagnosis is estab-lished, the patient requires an interdisciplinary approach and must be closely monitored by specialists and receive pathogenetic therapy.
To establish the diagnosis of FD in men, measurement of the enzyme activity of a-Gal A and lyso-Gb3 from a dried drop of blood is used. In most men, enzyme activity decreases to less than 30% of normal, while in some men there is no its activity at all. The diagnosis is confirmed by molecular ge-netic testing, detecting the causative mutation (van der Tol et al., 2014; Desnick et al., 1989). In women, molecular genetic testing is mandatory to establish a diagnosis because a-Gal A activity in leukocytes may be normal despite low levels in other organs. At present, lyso-Gb3 isolated from blood plasma is the optimal biomarker for diagnosing FD.
An important step in diagnosing FD is the genealogical method. By analyzing a patient's genealogy based on the mode of inheritance of the disease, several additional patients in the family may be identi-fied. Therefore, all patients with a suspected or established diagnosis require medical genetic consulting to determine the risk group and to conduct an examination (Stroh, 2011).
Therapy
Until 2001, there was no specific therapy available for FD; the disease could only be treated symp-tomatically. This determined an unfavorable prognosis, especially in classic variants of the disease with multisystem manifestations (Oder et al., 2016). The use of enzyme replacement therapy (ERT), first approved in 2001, has led to significant improvements in morbidity and early mortality.
Biotechnologically produced a-Gal A is administered intravenously at two-week intervals. Two medicines are available: agalsidase alfa, derived from human cells, and agalsidase beta, derived from Chinese hamster ovary cells. However, ERT has not been shown to prevent further progression when started late in the disease (Germain et al., 2015; Weidemann et al., 2013).
The International FD Outcome Study (FOS) was initiated in 2001 to collect long-term clinical and safety data for individuals with confirmed FD who either received a-Gal A treatment or do not receive ERT. This database has contributed to the study of many aspects of FD and the consequences of ERT, including renal and cardiac outcomes (Nakamura et al., 2023; Mehta et al., 2009; Beck et al., 2022; Schwarting et al., 2006; Linhart et al., 2007; Mehta e tal., 2004). The results of this retrospective compar-ison of FOS data confirm the long-term efficacy of a-Gal A in the treatment of FD. The results show that a-Gal A treatment slowed the decline in kidney function and slowed or stabilized the progression of cardiomyopathy.