Fabry disease cardiomyopathy: A state-of-the-art review

Abstract

Fabry disease or Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA), leading to systemic accumulation of globotriaosyl-ceramide (Gb3). Initially described in 1898 as a dermatological condition, Fabry disease is now recognized as a progressive multisystem disorder with significant cardiac involvement. Cardiomyopathy in Fabry disease arises from Gb3 accumulation in cardiac tissue, resulting in fibrosis, left ventricular hypertrophy (LVH), diastolic dysfunction, and heart failure. The deacylated derivative, lysoGb3, serves as a biomarker of cardiac involvement. Diagnosis relies on enzyme assays, genetic testing, and advanced cardiac imaging modalities like echocardiography and cardiac MRI. Management strategies are centered around enzyme replacement therapy, and prognosis varies due to phenotypic heterogeneity and severity of disease progression. Psychological and social burdens further complicate patient care. However, underdiagnosis remains a concerning issue, particularly in individuals with unexplained cardiomyopathies. Early recognition through increased clinical awareness and genetic screening is crucial for timely intervention. Ongoing research is essential to develop new therapies targeting the genetic and metabolic roots of the disease. This systematic review comprehensively examines current evidence regarding the mechanisms, diagnosis, treatment, and prognosis of cardiomyopathy associated with Fabry disease, providing insights that may enhance clinical practice and guide future research initiatives.

Introduction

Fabry disease (also known as Anderson-Fabry disease), an X-linked lysosomal storage disorder, is characterized by a deficiency of the enzyme α-galactosidase A (GLA), resulting in the accumulation of globotriaosyl-ceramide (Gb3) within various tissues (Fig. 1).

Fig. 1.

Pathogenesis of Fabry disease.

Mutations in the GLA gene result in deficiency of the enzyme α-galactosidase A (GLA) which consequently results in impaired breakdown of globotriaosyl-ceramide (Gb3) to lactosyl-ceramide. Subsequent accumulation of Gb3 leads to a progressive build-up of its deacylated form (Lyso-Gb3) in lysosomes and deposition within cells.

First described in 1898 by English surgeon William Anderson ¹ and independently by German dermatologist Johannes Fabry ², who observed patients with angiokeratomas and systemic symptoms, Fabry disease was initially considered a skin condition, and only later was it understood to be a systemic metabolic disorder (Table 1). In the mid-20^th century, researchers began linking Fabry disease to X-linked inheritance, explaining its more severe manifestation in males and variable symptoms in heterozygous females. By the 1960s and 70s, biochemical assays enabled diagnosis through enzyme activity testing, and genetic testing followed in the 1990s. This disorder is linked to significant morbidity and mortality, particularly due to its cardiac manifestations, which include left ventricular hypertrophy (LVH), dyastolic dysfunction, arrhythmias, and heart failure (HF).

Table 1.

Chronology of major discoveries and milestones in Fabry disease research and clinical care.

Year	Discovery / Milestone	Significance
1898	Johann Fabry and William Anderson independently describe angiokeratomas 1, 2, 592–594	First clinical descriptions of what would later be called Fabry disease
1960	Cardiopulmonary phenotypes observed in Fabry disease 594	First published evidence of myocardial damage in Fabry disease
1960s	Accumulation of globotriaosyl-ceramide (Gb3) identified as pathogenic mechanism 595 596	Elucidated the substrate responsible for tissue damage
1965	Accumulation of lipid filled lysosomes observed in multiple cell types 597	Lysosomal enzyme defect was suggested as causative factor in Fabry disease
1965	Fabry disease proposed as an X-linked disorder 598	Inheritance pattern clarified; helped distinguish it from other storage disorders
1967	Identification of deficiency in alpha-galactosidase A (GLA) enzyme 596	Established Fabry as a lysosomal storage disorder
1973	Administration of human placental ceramidetrihexosidase (GLA) shown to decrease levels of Gb3 in patients 599	Laid the foundation for developing ERT for treating Fabry disease
1985	Cloning of the GLA gene 600	Enabled genetic diagnosis and identification of mutations
2003	FDA approval of agalsidase beta (Fabrazyme)	First enzyme replacement therapy (ERT) available for Fabry disease
2016 & 2018	First reports of migalastat (chaperone therapy) approved in Europe and USA	Oral therapy targeting amenable GLA mutations
2020s	Trials testing gene therapy (e.g., ST-920-201, 4D-310, AMT191)	Next-generation approaches aiming for sustained enzyme production
2022	CRISPR/Cas9 preclinical studies initiated 576	Opened the door to gene-editing approaches
2023	Approval of pegunigalsidase alfa (PRX-102) in Europe and USA	ERT with extended half-life, potentially improving patient convenience and efficacy

The pathophysiology of cardiomyopathy in Fabry disease is complex and involves a multitude of biological mechanisms. Under physiological conditions, the glycosphingolipid Gb3 functions as a component of lipid raft microdomains within the cell membrane, and is hydrolyzed by the lysosomal enzyme GLA as part of its degradation process ³. However, in the absence of GLA, the cumulative buildup of Gb3 disrupts cellular homeostasis, inducing metabolic dysfunction, oxidative stress, and inflammatory responses that exacerbate cardiac injury. The progressive accumulation of Gb3 leads to structural changes in cardiac tissue, such as fibrosis, eventually resulting in functional impairment. Although the disease is caused by deficiency of GLA, patients with classic Fabry disease have <1% of enzymatic function and exhibit severe symptoms, whereas atypical have >1% enzymatic activity, exhibit phenotypes in a specific organ system, and are characterized by delayed onset of clinical symptoms⁴. Plasma levels of globotriaosylsphingosine (lysoGb3), a deacylated form of Gb3, represent a biomarker of diastolic dysfunction indicating cardiac involvement, and underscore the need for timely interventions in managing this condition ⁵.

When considering the diagnosis of Fabry disease, multiple facets come into play. Genetic testing and enzyme assays remain central to the diagnostic process, particularly as the heterogeneity of Fabry disease complicates clinical recognition⁶. Advances in cardiac imaging, notably echocardiography and cardiac magnetic resonance imaging (MRI), illustrate the importance of non-invasive techniques for assessing cardiac involvement, offering crucial insights into myocardium structure and function ⁷. These tools are essential for both diagnosing and monitoring patients throughout the progression of the disease.

The management of Fabry disease primarily revolves around enzyme replacement therapy (ERT). Prognostication in patients with Fabry disease cardiomyopathy remains challenging due to the inherent variability of clinical presentation, including the progressive nature of cardiac involvement, characterized by increasing LVH and diastolic dysfunction, and can improve with early and appropriate management. Although there have been significant advancements in developing additional approaches to restore GLA deficiency including oral chaperone therapy and gene therapy (Table 1), a holistic approach that includes psychosocial support is essential, as the disease imposes substantial psychological burdens in addition to physical health challenges ⁸.

A growing body of literature highlights a concerning underdiagnosis of Fabry disease within various patient populations, particularly in individuals presenting with unexplained cardiomyopathies ^9,10. Heightened awareness among clinicians about the potential cardiac manifestations of Fabry disease may assist in reducing the diagnostic delay, which has been reported to retard access to life-saving interventions by about 15 years ^11,12. Increasing access to genetic screening can further aid in identifying at-risk family members, fostering the potential for preemptive management strategies.

There is an urgent need for continued research into novel therapeutic avenues that target the underlying genetic and metabolic abnormalities associated with Fabry disease. Initiating multicenter studies to explore the long-term outcomes of treatment modalities, as well as the psychological impact of the disease, could provide invaluable data that informs best practices for patient care. As advancements in technology permit ongoing assessments of cardiac function and fibrosis with improved accuracy and sensitivity, these methods may become instrumental in developing more effective approaches to manage the disease.

Epidemiology

The global reported incidence of Fabry disease ranges from approximately 1 in 40,000 to 1 in 117,000 individuals ^4,13. However, these figures may likely underestimate the true prevalence due to underdiagnosis and variability in clinical presentations. Screening initiatives have suggested that the prevalence could be closer to 1 in 10,000 in cohorts undergoing comprehensive genetic testing ^14–18. A higher incidence, up to 1 in 3100 in Italy, and 1250 in Taiwan, has been recently reported by newborn screening surveys ^19–22, suggesting that both atypical and classic forms of Fabry disease are more prevalent than previously recognized. In Japan, the estimated prevalence of Fabry disease among dialysis patients is about 1 in 7,000 individuals, underscoring the importance of targeted screening in populations with chronic renal disorders ²³. Furthermore, the incidence of LVH in patients with Fabry disease is about 50% in males and 33% in females, highlighting the necessity for differential diagnostic considerations in cardiomyopathy cases ²⁴. These findings suggest that while Fabry disease is commonly categorized as rare, its actual prevalence in certain populations, particularly those with renal or cardiovascular conditions, may be substantially higher, and should be investigated during the line of treatment in addition to conditions such as hypertension and diabetes^25,26.

Screening and diagnostic challenges

Challenges in accurately characterizing the epidemiology of Fabry disease stem mainly from limited awareness and diagnostic capacity among healthcare providers. Studies focusing on patients with cryptogenic strokes have revealed undiagnosed Fabry disease in a notable percentage of those screened ^27,28, emphasizing the need for improved recognition of the disease’s clinical signs and symptoms. Newborn screening programs have been pivotal in identifying affected individuals pre-symptomatically; however, implementation remains inconsistent across different regions ²⁹.

Family screening is crucial: targeted genetic testing of family members relating to a diagnosed case of Fabry disease can reveal asymptomatic carriers, underlining the need for broader screening initiatives to identify at-risk individuals and initiate early intervention to reduce morbidity ^30–32.

Epidemiological studies report highly variable prevalence rates of Fabry disease, influenced by geographical location, study design, and the population studied. Bayesian models and systematic reviews indicate that while clinical databases often report a prevalence below 1 in 50,000, more recent community-based studies and newborn screenings suggest figures could exceed 1 in 7,000 in specific cohorts, especially among those with chronic conditions like kidney failure ^15,31,33.

Advancements in genetic screening and diagnostic methodologies, including enzyme activity assays and molecular analysis, add complexity to prevalence estimations, particularly as understanding of genotype-phenotype correlations evolves. Classical estimates may fail to capture the full spectrum of the disease, due to clinical symptoms which overlap with phenotypes arising from conditions such as hypertension and diabetes leading to misdiagnosis. These aspects are particularly observed in adult populations who present mild phenotypes ¹⁵ and exhibit variability in severity and progression of clinical symptoms and disease progression even amongst members of the same family, leading to challenges in surveillance and delays in initiation of therapy^15,19,34.

Given these complexities, future research must encompass a clearer understanding of the disease’s natural history, especially in identifying risk factors for earlier and more accurate diagnosis. Research initiatives leveraging machine learning and data analytics hold unexplored potential for identifying previously unrecognized cases, particularly among younger populations or those presenting unexplained conditions ^35–37.

Phenotypic variability and disease presentation

Fabry disease exhibits remarkable clinical heterogeneity, with symptoms varying significantly not only between males and females but also among individuals of the same sex ³⁸. Classic symptoms that typically present in childhood include acroparesthesia, angiokeratomas, and hypohidrosis, while renal failure, cardiac issues, and progressive neuropathy typically arise later; females often present with a milder phenotype, leading to underdiagnosis or misdiagnosis as carriers rather than affected individuals ^15,39,40.

The understanding of ’late-onset’ phenotypes ^41–44 has profound implications, as variants such as A143T can result in GLA mutations that do not substantially affect early enzyme activity, leading to symptoms manifesting in adulthood. These aspects alter the traditional expectations regarding disease penetrance and require careful monitoring in at-risk populations, particularly in families with a known history of Fabry disease ^33,45.

Pathophysiology of Fabry disease

GLA gene mutations

At its core, Fabry disease arises from mutations in the GLA gene located on the X chromosome. The different mutations range from missense changes to larger deletions, and their effects vary significantly, resulting in a spectrum of clinical manifestations (Table 2). For example, specific mutations such as R112H and A143T can exhibit unique phenotypic outcomes, contributing to late-onset manifestations; some patients might show only mild symptoms or may be asymptomatic carriers, highlighting the complexity of genotype-phenotype correlations within this disorder ^10,46–62.

Table 2.

Common Mutations in Fabry disease

Mutation	Nucleotide Change	Protein Change	Type	Prevalence / Notes	Major Clinical Features
R301Q	c.902G>A	p.Arg301Gln	Missense	Common in Fabry cardiomyopathy	Cardiac variant: LVH, residual enzyme activity, minimal renal/CNS symptoms
N215S	c.644A>G	p.Asn215Ser	Missense	Common late-onset variant in Europe and USA	Cardiac-only phenotype: LVH, minimal renal involvement
A143T	c.427G>A	p.Ala143Thr	Missense	Found in various populations, including Europe; uncertain pathogenicity	Often asymptomatic or mild; controversial pathogenicity; may have cardiac symptoms
L415P	c.1244T>C	p.Leu415Pro	Missense	Reported in classic Fabry patients; rare	Classic phenotype: early-onset, renal failure, cardiac and CNS involvement
IVS4+919G>A	Deep intronic variant	–	Splicesite	Common in East Asian males (Taiwan: >1/1500)	Cardiac variant: late-onset Fabry; LVH with pseudoexon inclusion
M290I	c.870G>A	p.Met290Ile	Missense	Observed in various regions; variable expressivity	Variable phenotype; some with classic involvement (renal/cardiac)
W340X	c.1020G>A	p.Trp340-	Nonsense	Associated with classic Fabry	No residual enzyme; multisystem disease starting in childhood
R112H	c.335G>A	p.Arg112His	Missense	Rare; identified in later-onset variants	Milder phenotype; cardiac involvement, residual enzyme activity

Accumulation of Gb3

The deficiency of GLA impedes the normal catabolism of Gb3 (Fig. 1), leading to its accumulation within lysosomes, which not only disrupts lysosomal function but also triggers cellular pathways that mediate inflammation and apoptosis ^63,64. With progressive accumulation, cellular dysfunction occurs, which is particularly detrimental in organs such as the heart and kidneys ^65,66. For instance, in the heart, Gb3 deposits can cause alterations to myocardial interstitial structure, resulting in fibrosis, LVH, and HF ^67,68.

The level of inflammation correlates with increased cytokine production and oxidative stress in cardiac tissue ⁴⁸. Elevated levels of lysoGb3 have been also implicated in pathogenic mechanisms leading to fibrosis ^51,69. Histological examination of cardiac tissues in Fabry patients reveals fibrosis and cellular degeneration, which can be exacerbated by concomitant renal dysfunction typical in the disease’s progression ⁷⁰.

Cardiovascular complications

The cardiovascular involvement in Fabry disease (Fig. 2) represents the primary causes of morbidity and mortality ⁷¹. Patients typically present symptoms including LVH, HF, and arrhythmias. Echocardiographic studies have shown that structural changes in the heart, coupled with functional decline, can begin well before overt symptoms appear, emphasizing the importance of early screening and treatment ^72,73.

Fig. 2.

Major cardiac manifestations of Fabry disease.

Myocardial involvement during Fabry disease leads to cardiomyopathy, which represents the most common organ-specific manifestation in Fabry disease. Enhanced fibrosis and activation of hypertrophic signaling pathways lead to decreased contractility and functional impairment of cardiomyocytes, often resulting in left ventricular hypertrophy (LVH).

Fabry nephropathy

The kidneys are significantly affected in Fabry disease due to the accumulation of Gb3 in podocytes and tubular cells ^74,75. At the molecular level, Gb3 has been associated with an interplay of inflammation, apoptosis, and fibrosis ^76,77 as well as a decreased mTOR activity in kidney podocytes ⁷⁸. Its deposition leads to renal fibrosis, functional impairment, and ultimately renal failure, a relatively common endpoint in untreated patients ^79–86. Pathologically, Fabry nephropathy is characterized by the presence of lipid-laden accumulation, mesangial expansion, and glomerulosclerosis ^87,88. Early intervention with enzyme replacement therapy can help ameliorate some of the renal damage by reducing Gb3 levels, potentially delaying end-stage renal disease ^89,90.

Neurological manifestations

The accumulation of Gb3 extends beyond cardiac tissues and kidney to the nervous system, contributing to neuropathic pain, which is one of the earliest presenting symptoms of Fabry disease ^91–100. This pain is most likely due to toxic effects from Gb3 accumulation in peripheral nerves ¹⁰¹. Patients may present with angiokeratomas—small, reddish-purple skin lesions—reflecting the disease’s systemic implications ^1,102,103. The involvement of the nervous system can further complicate the clinical picture, as it may manifest through cognitive impairments alongside classical symptoms of neuropathy ^104–106.

Molecular mechanisms of cardiac involvement

The hallmark of Fabry disease is the accumulation of Gb3 in various cell types due to deficient GLA activity. Gb3 accumulates in cardiomyocytes early in the disease progression, often preceding overt clinical symptoms such as LVH ^49,50. The impact of Gb3 accumulation is not limited to structural changes in cells but extends to functional disturbances and pathological signaling cascades. This lipid buildup modifies membrane dynamics, leading to dysregulation of various cellular functions, including impaired signaling pathways critical for cardiomyocyte health.

Oxidative stress and inflammation

Enhanced oxidative stress is another critical outcome of Gb3 accumulation and seems to be instrumental in the progression of cardiac pathology in Fabry disease. The buildup of Gb3 results in increased production of reactive oxygen species (ROS), causing oxidative damage to cardiomyocytes and cardiac fibroblasts ^107–110. Gb3 has been shown to stimulate the expression of pro-inflammatory cytokines, exacerbating oxidative stress and cellular injury ^111–124. For instance, GB3 has been proposed to bind the Toll-Like Receptor 4 (TLR4) in peripheral blood mononuclear cells (PBMC) ¹²⁵, which may trigger Notch1 signaling, in turn activating the nuclear factor kappa B (NF-κB) pathway ¹²⁶.

Pro-fibrotic cytokines and fibrosis

The involvement of pro-fibrotic cytokines in the pathogenesis of Fabry disease-related cardiac dysfunction has received growing attention. Cytokines such as Transforming growth factor-beta (TGF-β) and connective tissue growth factor (CTGF) are upregulated as a consequence of Gb3 accumulation, promoting fibrosis through the activation of cardiac fibroblasts ¹²⁷. TGF-β has been implicated in pro-fibrotic signaling pathways that result in cardiac fibrosis, contributing to adverse remodeling of the myocardium and impaired diastolic function ^128–134. The crosstalk between endothelial cells and cardiomyocytes in the setting of Gb3-induced dysfunction might also foster an environment conducive to fibrosis, eventually resulting in long-term detrimental consequences for heart function ^135,136. These processes highlight the multifactorial nature of cardiac involvement, wherein the accumulation of Gb3 directly and indirectly promotes pathological cardiac remodeling through fibrotic and hypertrophic pathways ^{76,77,137–151}.

Impaired autophagy and mitochondrial dysfunction

Our group has recently shown that mitochondrial dysfunction and impaired autophagy are key processes altered in Fabry disease, leading to reduced clearance of damaged organelles and proteins, which is critical for cellular homeostasis, particularly in energy-demanding tissues like the heart ^152,153. Autophagic dysfunction, classically associated with lysosomal storage disorders ^154–197, can further exacerbate oxidative stress due to the accumulation of toxic substrates, creating a vicious cycle. The impairment of autophagic processes has been associated with cardiac hypertrophy, and has also been linked with necroptosis in cardiomyocytes, which may contribute to cell death and exacerbate injury in the heart ¹¹³. Furthermore, Gb3 may engage with pathways related to apoptosis, causing a cascade of cardiac damage ¹¹⁴.

Microvascular dysfunction

Cardiac microvascular dysfunction in Fabry disease, most likely driven by oxidative stress and Gb3 deposition, may decrease oxygen supply to the heart, further aggravating myocardial hypertrophy and dysfunction. Microvascular ischemia has been linked to the accumulation of Gb3 in vascular smooth muscle and endothelial cells, resulting in impaired vasodilation and altered perfusion ^198–200 even in the absence of significant epicardial artery disease, complicating the clinical picture and contributing to symptoms such as angina and HF.

Early interventions aimed at restoring endothelial function and reducing Gb3 burden may therefore be critical in preventing the progression of cardiovascular manifestations in Fabry patients. The measurement of biomarkers such as Lyso-Gb3, which has been identified as an important indicator of cardiac involvement, can assist in monitoring disease progression and treatment responses ^57,201.

The molecular mechanisms underlying cardiac involvement in Fabry disease are multifaceted, encompassing Gb3 accumulation, oxidative stress, mitochondrial dysfunction, impaired autophagy, pro-fibrotic signaling, and microvascular dysfunction ^202–214. The interplay between these processes culminates in significant cardiac manifestations, including hypertrophy and HF.

A comprehensive understanding of these mechanisms will not only elucidate the pathophysiology of Fabry disease but also inform potential therapeutic strategies, emphasizing the need for early diagnosis and intervention to mitigate cardiac damage and improve patient outcomes.

Histological features of fabry cardiomyopathy

Histological examination of cardiac tissues in patients with Fabry disease reveals critical features that are vital for understanding the disease mechanisms and progression of cardiomyopathy. The primary histopathological findings in Fabry cardiomyopathy include interstitial fibrosis and myocyte vacuolization caused by accumulation of Gb3.

Interstitial fibrosis

Interstitial fibrosis is a key component of Fabry cardiomyopathy histopathology. The excessive accumulation of Gb3 leads not only to myocyte vacuolation but also activates fibrotic pathways. Myocardial fibrosis results from an imbalance between matrix degradation and synthesis, driven by the upregulation of pro-fibrotic cytokines such as TGF-β and connective tissue growth factor (CTGF) due to cellular stress from Gb3 accumulation ²¹⁵.

Histological analysis typically demonstrates varying degrees of fibrosis across the myocardium, correlating with the severity of clinical symptoms. Patients with extensive fibrosis are likely to exhibit greater structural and functional declines in diastolic function, and can predispose patients to arrhythmogenic events, further complicating the clinical picture ^216,217.

Myocyte vacuolization

One of the hallmark characteristics of Fabry disease is the deposition of Gb3 within myocytes and endothelial cells, often described as “lamellated zebra bodies” when observed under electron microscopy, ²¹⁸. These Gb3 deposits form intracellular vacuoles and disrupt cellular architecture and processes, eventually leading to functional abnormalities. Histological specimens of myocytes can often show intracellular vacuoles that reduce the effective contractile mass of the myocardium ^60,218,219. Given the systemic nature of the disease, similar deposits can be identified in other tissues, but the cardiac implications are particularly prominent due to the heart’s critical role in systemic health.

Clinical implications of histopathological findings

The histological features observed in Fabry cardiomyopathy have important clinical implications and can inform treatment strategies and prognostication. Biopsy results revealing significant myocyte vacuolation and Gb3 deposition can provide valuable diagnostic insights, particularly in patients presenting with unexplained hypertrophic cardiac conditions. Notably, Gb3 deposits, despite being generally detected within cardiac lysosomes, represent only a minimal percentage of the total cardiac mass in patients with Fabry disease ^220,221. Interstitial fibrosis can also serve as an important prognostic marker: increased fibrosis correlates with poorer outcomes and greater risk for adverse cardiovascular events ²²².

Early intervention is crucial since established fibrosis may not be fully reversible and can contribute significantly to long-term morbidity. Cross-sectional histopathologic studies of cardiac tissue in Fabry disease have become increasingly relevant, helping to establish associations between histological findings and clinical outcomes, guiding both surveillance and treatment approaches for affected patients.

Clinical presentation

In the classic form of Fabry disease, cardiac involvement generally begins around the third or fourth decade of life, marked by a range of symptoms that vary in severity among individuals ²²³. Exertional dyspnea is a prominent complaint linked to HF secondary to LVH. Patients might also experience atypical chest pain due to myocardial ischemia associated with decreased microvascular integrity ²²⁴. Palpitations and syncope may occur as a result of arrhythmias, which are notably more prevalent in males. Ventricular tachycardia and other rhythm disturbances are common, imposing vigilant monitoring ^17,225.

Quality of life

Patients with Fabry disease experience a significant reduction in quality of life, primarily due to chronic symptoms that often begin in childhood and progressively worsen over time ^226–232. Fatigue is one of the most prevalent and debilitating symptoms reported by both pediatric and adult patients, regardless of disease severity or treatment status ^233–240. It is frequently described as persistent and overwhelming, interfering with daily activities, work productivity, and social participation, and remains a central challenge in improving overall quality of life. Our work has shown that fatigue, often considered a mechanism dependent on the failure of other organs (particularly the heart), mainly results from alterations in muscle energy metabolism ¹⁵³.

In addition to fatigue, patients suffer from neuropathic pain, gastrointestinal disturbances, depression, and thermoregulatory abnormalities, all of which contribute to impaired physical and mental well-being. Health-related quality of life assessments consistently show that Fabry patients score lower than the general population across multiple domains, including vitality, emotional health, and physical functioning ^241–254. These impacts persist even in individuals receiving enzyme replacement therapy or chaperone therapy, underscoring the need for comprehensive symptom management and psychosocial support ²²⁷.

Natural history of cardiac involvement

The natural progression of Fabry disease is marked by the progressive accumulation of Gb3, which leads to multi-organ involvement and subsequent complications. Cardiac manifestations (Fig. 2) can become evident well before the onset of other complications, although patients are often asymptomatic until significant damage occurs ^255–257. Without treatment, these issues typically lead to detrimental outcomes, including HF, arrhythmias, and sudden cardiac death. The presence of LVH is a common predictor of adverse events ^52,258,259.

Fabry disease in Females

There are two main X-linked disorders involving deficiency of lysosomal enzymes: Fabry disease and Hunter syndrome ²⁶⁰. However, while Hunter is exceptionally rare in females ²⁶¹, females with Fabry disease are regarded as patients and not as carriers; according to some experts, Fabry disease should be considered an X-linked dominant disease ²⁶². Female patients with Fabry disease may exhibit a range of severe disease events ^{235,262–267} leading to a requirement for cardiac transplantation in some cases ²⁶⁵. The exact reasons behind these phenotypes in females are mostly unknown, and could involve a complex relationship linking X-inactivation, enzyme levels, and cardiac involvement ^268–272. Female patients with Fabry disease often experience delay in access to treatment which can be attributed to underdiagnosis due to the wide spectrum of phenotypes; therefore the actual number of clinically diagnosed female patients might be significantly higher than current estimates ²⁶⁷. This area remains of significant concern, since the mean age of death in female Fabry disease patients is 55.4 years ^{15, 270,273–281}.

Diagnosis

The diagnosis of Fabry disease relies on a combination of clinical assessment, enzymatic testing, genetic analysis, and biomarker evaluation. Classic clinical features—such as acroparesthesias, angiokeratomas, cornea verticillata (whorl-like pattern of golden-brown deposits in the cornea), and progressive involvement of the heart, kidneys, and brain—raise suspicion. In males, measurement of GLA enzyme activity in plasma or leukocytes is typically diagnostic, as levels are markedly reduced or absent. However, because heterozygous females may have normal or near-normal enzyme activity due to X-chromosome inactivation, molecular genetic testing for pathogenic variants in the GLA gene is required in both sexes to confirm the diagnosis. Biomarkers play a critical role: plasma and urinary levels of Gb3 and particularly its deacylated form, lyso-Gb3, are elevated in most patients with classic Fabry disease and are useful for diagnosis, disease monitoring, and assessing response to therapy (Fig. 3). Lyso-Gb3 is considered the most specific and sensitive biomarker and can be measured using mass spectrometry. Together, clinical findings, enzymatic assays, genetic testing, and biomarker evaluation form a comprehensive approach to accurately diagnosing Fabry disease.

Fig. 3.

Diagnosis of Fabry cardiomyopathy.

Diagnosis and assessment of cardiac function during Fabry disease can be performed by evaluating circulating levels of biomarkers of Fabry disease, including plasma LysoGb3, and GLA enzymatic activity in the blood. These assessments should be correlated with results from genetic testing for GLA mutations, along with levels of cardiac impairment markers such as high-sensitivity cardiac troponins (hs-cTn) and N-terminal pro b-type natriuretic peptide (NT-proBNP). This approach should be complemented with evaluation of cardiac function, including diastolic function using imaging modalities (please see Fig. 4). Standard echocardiography remains the first line of investigation to assess the extent of hypertrophy. Additionally, cardiac MRI and measurement of T1 mapping values can be used to obtain further insights into tissue structure for early diagnosis. Further investigation into subtle changes in cardiac function can be performed using advanced techniques such as Speckle Tracking Echocardiography (STE), which provides information about systolic function.

Cardiac imaging modalities can indicate myocardial structural and functional abnormalities such as hypertrophy, diastolic dysfunction and microvascular dysfunction even in the presence of mild phenotypes. Thus, they can be leveraged to monitor the progression of the disease and provide pivotal information to facilitate timely therapeutic intervention, consequently improving patient quality of life and prolonging survival²⁸². Echocardiography plays a pivotal role in the diagnosis, monitoring, and management of cardiac involvement in the disease (Fig. 4). Given that cardiac manifestations can lead to significant morbidity and mortality, non-invasive echocardiographic assessment provides valuable insights into cardiac structure and function ²⁸³.

Fig. 4.

Representative cardiac dysfunction in Fabry disease as demonstrated by cardiac imaging.

From top to bottom: Conventional 2D ultrasounds, Doppler echocardiography, tissue Doppler imaging, and bull’s eye myocardial strain.

Traditional echocardiographic features

Standard echocardiography is frequently the first-line imaging modality for assessing cardiac involvement in Fabry disease (Fig. 4). Key parameters evaluated include diastolic (dys)function, LVH, and atrial dimensions:

The assessment of diastolic function is critical, especially since Fabry disease often leads to diastolic dysfunction before the appearance of overt hypertrophy^{130–133,284}. Measurements such as the early-to-late diastolic transmitral flow velocity (E/A) ratio and the isovolumic relaxation time (IVRT) are routinely evaluated and serve as indicators of left ventricular (LV) compliance. As the disease progresses, impaired relaxation can be noted, demanding thorough evaluation of these parameters to improve management strategies ^285,286.

LVH is a common echocardiographic finding in affected individuals. As Gb3 accumulates within cardiomyocytes, it triggers hypertrophic signaling pathways, resulting in increased LV wall thickness, particularly in the inferolateral wall ^287,288. Measurements from M-mode and 2D echocardiography assess the extent of hypertrophy, which can also serve as a prognostic marker for adverse outcomes in patients with Fabry disease²⁸⁷.

Left atrial enlargement (LAE) is also often observed in Fabry patients with progressive cardiac involvement ²⁸⁹. Atrial enlargement is a consequence of diastolic dysfunction and can increase the risk of arrhythmias, including atrial fibrillation, which has implications for thromboembolic risk management in this population ^290–294.

Advanced echocardiographic techniques

Beyond standard echocardiography, advanced techniques, particularly speckle-tracking echocardiography, provide critical insights into subtle cardiac dysfunction that may not be detected through conventional imaging.

Speckle-Tracking Echocardiography (STE) enables the measurement of myocardial deformation parameters, including global longitudinal strain (GLS), which quantifies systolic function non-invasively ^284,295. Identifying these changes can allow for earlier therapeutic interventions, potentially altering the disease course. Indeed, systolic dysfunction is commonly detected only in the advanced stages of Fabry disease ^{142,149,296–304}.

Myocardial stiffness is an important feature in the assessment of diastolic function. Alterations in stiffness can lead to impaired relaxation and contribute to HF symptoms. The use of STE allows for the evaluation of local and global myocardial mechanics, offering a detailed view of how Fabry disease affects the heart ^{142,297,298,300–304}.

Recently, several studies have applied Artificial Intelligence (AI) and Machine Learning (ML) to measure parameters such as LV wall thickness, myocardial texture, and ejection fraction by echocardiography and cardiac MRI. Given the higher rates of sensitivity and accuracy of these approaches in diagnosing conditions such as LVH and amyloidosis ^305–307, there is significant interest in assessing the potential of these models in distinguishing cardiovascular complications arising from Fabry disease ^296,308.

Clinical implications of echocardiographic findings

The information gleaned from echocardiographic imaging (Fig. 4) provides not only diagnostic confirmation but also significant prognostic value ^{73,297,298,300–304,309–324}. Early indicators of myocardial structural and functional changes can manifest as LV diastolic dysfunction, hypertrophy, alterations in strain, and microvascular dysfunction. These parameters can guide follow-up protocols and therapeutic decisions even in the presence of mild phenotypes ³²⁵. Thus, cardiac imaging modalities can be leveraged to monitor the progression of the disease and provide pivotal information to facilitate timely therapeutic intervention, consequently improving patient quality of life and prolonging survival²⁸².

Routine echocardiographic evaluations enable the monitoring of disease progression and treatment response. Establishing standardized echocardiographic criteria for regular monitoring becomes essential, especially given the progressive nature of cardiac involvement in Fabry disease ^{285,298,303,304,326–328}.

Cardiac magnetic resonance imaging

Cardiac MRI has become an indispensable tool in the evaluation of Fabry disease, particularly concerning the identification and characterization of myocardial fibrosis ³²⁹. By employing advanced imaging techniques, MRI enables clinicians to assess the extent of myocardial alterations linked to this disorder, thereby facilitating an accurate diagnosis and ongoing management ^330–332.

Late gadolinium enhancement (LGE)

One of the defining features of cardiac imaging in Fabry disease is the presence of late gadolinium enhancement (LGE), which reflects myocardial fibrosis. LGE typically occurs in the mid-wall of the LV, primarily affecting the inferolateral wall, while sparing the subepicardial and subendocardial regions ^216,333. The LGE pattern is significant as it correlates with the degree of cardiac dysfunction, particularly as myocardial fibrosis progresses throughout the disease. The fibrotic process observed on MRI coincides with the histological findings of collagen deposition, which is primarily driven by the activation of profibrotic cytokines, such as TGF-β, in response to Gb3 accumulation ³³⁴.

In addition to its diagnostic utility, the identification of LGE improves prognostication. Elevated fibrosis, as demonstrated by LGE, is associated with arrhythmias, worsening heart function, and an increased risk of cardiovascular events. Regular monitoring using MRI to assess LGE can guide treatment interventions, including ERT, and help ascertain the therapeutic response over time ³³⁵.

T1 mapping

Another innovative application of MRI in the context of Fabry disease is the use of T1 mapping. This technique measures the native T1 values of cardiac tissue, serving as a biomarker for myocardial involvement before hypertrophy is detectable. T1 mapping can reveal the early stages of lipid accumulation, fibrosis and edema ultimately leading to alterations in myocardial tissue composition long before overt clinical signs of cardiomyopathy manifest ²⁵⁹.

Elevated T1 values obtained from tissue mapping may correlate with higher levels of Gb3 accumulation as well, thus presenting an early indicator of cardiomyopathy progression, which can assist in guiding early therapeutic interventions. ^326,336.

Distinctive imaging features

In patients with Fabry cardiomyopathy, MRI findings often reveal atypical patterns of myocardial involvement. For instance, asymmetrical LVH, predominantly affecting the inferolateral wall, is characteristic, and in a substantial number of cases, this hypertrophy can be misdiagnosed as hypertrophic cardiomyopathy (HCM) due to its overlapping presentation ^258,337,338. The differential diagnosis using MRI helps clarify these distinctions through the combination of LGE and measurement of LV dimensions.

Changes such as regional strain patterns observed through advanced imaging modalities, like STE, can complement MRI findings, providing a nuanced view of cardiac function and structure, particularly in identifying early modifications in myocardial mechanics before actual changes in wall thickness occur ³³⁹. These multi-modal imaging approaches enhance our understanding of Fabry disease’s impact on cardiac health and aid in developing comprehensive management plans.

The integration of MRI into clinical practice for patients with Fabry disease offers a non-invasive method to monitor disease progression and evaluate the effectiveness of therapies directly linked to cardiac health during follow-up ³²⁷. Continuous research into correlating imaging findings with clinical outcomes and biomarkers will further refine the use of MRI in Fabry disease, assisting in risk stratification and optimization of patient management.

Diagnostic criteria and differential diagnosis

The diagnosis of Fabry disease, especially concerning cardiac involvement, is a complex process (Fig. 5, Table 3) that includes clinical assessment, biochemical testing, genetic analyses, and advanced imaging techniques ^340–347.

Fig. 5.

Therapeutic strategies and management.

Treatment and management of Fabry disease cardiomyopathy include a combination of treatment regimens to decrease Gb3 load and medications to improve cardiac function. Gb3 levels can be decreased by using Enzyme Replacement Therapy (ERT) such as Fabrazyme, Replagal and Elfabrio, which restore GLA levels and facilitate its clearance. Another approach involves the intake of the oral chaperone therapy, migalastat which stabilizes the misfolded GLA and enhances its function. Substrate Reduction Therapy (SRT), including Lucerastat, Venglustat and Eliglustat, aims at reducing the biosynthesis of Gb3 by inhibiting the enzyme glucosyl-ceramide synthase (GCS), thereby decreasing Gb3 metabolic load. Current investigations into newer generation therapeutics are focused on determining the role of gene therapy-based approaches, including lentiviral vector AVR-RD-01, adenoviral vectors ST-920-201, 4D-310 and AMT191 to restore GLA expression. In addition to this approach, preliminary CRISPR-based screening studies to silence the expression of Gb3 synthase (A4GALT) have shown significant potential. Mitigation of cardiac-specific complications of Fabry disease can be achieved by angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers and diuretics depending on secondary conditions (hypertension, diabetes, renal complications) and stage of disease progression.

Table 3.

Main diagnostic criteria for Fabry disease, incorporating clinical, biochemical, genetic, and imaging findings.

Domain	Criteria	Notes
Clinical Presentation	Neuropathic pain (acroparesthesias) - Hypohidrosis - Angiokeratomas - Corneal verticillata - Tinnitus/hearing loss - Gastrointestinal symptoms - Cardiac hypertrophy or renal dysfunction	Often present in childhood or adolescence in males; variable in females due to X-inactivation
Family History	Known GLA mutation in family - X-linked inheritance pattern	Strong supporting evidence, especially in males with affected maternal lineage
Enzymatic Activity	Low or absent α-galactosidase A (GLA) activity in plasma, leukocytes, or dried blood spots	Diagnostic in males; normal levels may occur in heterozygous females
Genetic Testing	Pathogenic or likely pathogenic mutation in the GLA gene	Confirms diagnosis in males and females; variants of uncertain significance may require further testing
Biomarker Testing	Elevated plasma or urinary globotriaosylsphingosine (lyso-Gb3)	Correlates with disease severity; useful in both sexes and mutation types
Imaging Studies	Cardiac MRI showing late gadolinium enhancement (LGE) or LV hypertrophy - Brain MRI showing white matter lesions	Non-specific but supportive; common in patients with cardiac or cerebrovascular involvement
Histology	Renal or skin biopsy showing Gb3 accumulation in lysosomes (zebra bodies on EM)	Rarely needed if enzymatic and genetic testing are diagnostic

• -Clinical Assessment: The clinical presentation of Fabry disease often provides initial indications. Symptoms such as acroparesthesia, hypohidrosis, corneal deposits, and gastrointestinal issues may suggest Fabry disease’s presence. Cardiac symptoms, including exertional dyspnea, chest pain, palpitations, and syncope, frequently manifest, particularly in males, during the third or fourth decades of life ³⁴⁸.

• -Enzymatic Activity Measurement: A pivotal laboratory test for Fabry disease is the measurement of GLA activity in blood or dried blood spots. A significant reduction or absence of enzyme activity can confirm the diagnosis in male patients ^349–351. In females, where enzyme activity might be partially preserved due to random X-chromosome inactivation, genetic testing is generally necessary to identify pathogenic mutations in the GLA gene.

• -Genetic Testing: Genetic testing for mutations in the GLA gene is essential for confirming the diagnosis, especially in female carriers with potentially normal enzyme levels. Over 1,000 mutations have been cataloged, and identifying these mutations can aid in predicting disease severity and guiding family counseling ^352–357.

• -Cardiac Imaging: Advanced imaging techniques such as cardiac MRI play a vital role in assessing myocardial pathology associated with Fabry disease. The use of stress echocardiography and other imaging modalities (Fig. 4) can further delineate the structural and functional effects of Fabry disease on the heart ^{318,358–372}.

Differential diagnosis

Given the similarities in presentation between Fabry disease and other cardiac conditions, establishing a differential diagnosis (Table 4) is critical:

Table 4.

Differential diagnoses for Fabry disease cardiomyopathy, comparing key features to distinguish it from other conditions.

Condition	Key Features	Distinguishing from Fabry disease
Hypertrophic Cardiomyopathy (HCM)	Asymmetric septal hypertrophy, dynamic LV outflow tract obstruction, family history	Fabry cardiomyopathy is concentric; lacks sarcomeric gene mutations; often has systemic symptoms
Cardiac Amyloidosis	Diastolic dysfunction, thickened ventricular walls, low voltage on ECG, abnormal gadolinium enhancement	Fabry disease has low native T1 on MRI (vs high T1 in amyloidosis); amyloidosis lacks GLA deficiency
Sarcoidosis	Granulomatous inflammation, arrhythmias, conduction block, systemic findings (e.g. lung, skin, eye)	Sarcoidosis has elevated ACE, non-caseating granulomas, and patchy enhancement on MRI
Anderson-Tawil Syndrome	Periodic paralysis, dysmorphic features, ventricular arrhythmias	No GLA deficiency; genetic mutation in KCNJ2 gene
Danon disease	X-linked, early-onset cardiomyopathy, mental retardation, skeletal myopathy	Fabry disease has GLA deficiency; Danon has LAMP2 mutations and high CK levels
PRKAG2 Syndrome	Glycogen storage cardiomyopathy, ventricular pre-excitation (WPW pattern)	Fabry disease lacks glycogen accumulation and WPW; PRKAG2 gene mutation present
Hypertensive heart disease	Concentric LVH, long-standing hypertension	Fabry disease can mimic this aspect, but younger age of onset and extra-cardiac manifestations suggest Fabry disease
Aortic stenosis (AS)	Systolic murmur, valve calcification, pressure overload LVH	Echocardiography shows valvular lesion; Fabry disease lacks obstructive valvular pathology
Chronic kidney disease (CKD)	LVH secondary to volume/pressure overload, uremic symptoms	Fabry-associated renal involvement precedes or parallels cardiac features; lyso-Gb3 elevated

• -Hypertrophic Cardiomyopathy (HCM): HCM, the most common genetic cardiomyopathy, can present similarly to Fabry cardiomyopathy, especially with symptoms like exertional dyspnea and syncope. In HCM, asymmetric LVH is typically present. Diagnosis often involves genetic testing for mutations in genes encoding sarcomeric proteins ^373–375. MRI can help distinguish between structural changes unique to Fabry disease and those seen in primary HCM ³⁶¹.

• -Amyloidosis: Cardiac amyloidosis may also present with LVH and HF features. In this condition, amyloid fibrils infiltrate cardiac tissue, often leading to restrictive cardiomyopathy. Biopsy and imaging can help differentiate amyloidosis from Fabry disease, with cardiac MRI revealing distinct patterns of LGE ^{292,361,376–378}. Increased uptake of tracers such as 99mTc-DPD during scintigraphy can confirm amyloidosis, distinguishing it from Fabry-related hypertrophy ³⁷⁹.

• -Hypertensive Heart Disease: Essential hypertension can induce cardiac morphological changes analogous to Fabry cardiomyopathy, primarily LVH ^380,381. Careful history taking, ECG findings, and imaging results can often clarify the origin of hypertrophy. A family history suggesting genetic cardiomyopathy or specific features such as diastolic dysfunction can further guide examination towards Fabry disease.

• -Mid-Ventricular Hypertrophic Obstructive Cardiomyopathy: This rare variant poses diagnostic challenges due to overlapping features with both HCM and Fabry cardiomyopathy ^382–386. The differential diagnosis relies on advanced imaging and may require invasive procedures to assess the relationship of outflow obstruction with muscle hypertrophy.

• -Other Infiltrative Cardiomyopathies: Less common conditions, such as Danon disease ^387–390 and late-onset Pompe disease ^391–394, can also mimic hypertrophic features by causing myocardial hypertrophy and dysfunction. Evaluating the patient’s family history, biopsy results, and predisposition to other genetic syndromes can help refine the diagnosis.

Biomarkers in Fabry cardiomyopathy

The identification and utilization of biomarkers in Fabry disease, particularly in the realm of cardiac pathology, have gained attention as vital tools for diagnosis, monitoring disease progression, and assessing treatment response.

Lyso-Gb3 as a biomarker

Lyso-Gb3, the deacylated form of Gb3 that accumulates within cells, is recognized as the most prevalent biomarker for Fabry disease due to its direct association with disease severity and progression (Fig. 3). Elevated levels of lyso-Gb3 in plasma correlate strongly with the burden of disease and can indicate the presence of affected organ systems, including the heart and kidneys ³⁹⁵. Unlike traditional markers, such as enzyme activity measurements, lyso-Gb3 levels can remain elevated even in patients with late-onset manifestations, making it a sensitive marker for early diagnosis and ongoing monitoring of Fabry disease, and can be used to inform clinicians regarding the treatment response and the effectiveness of interventions ^395–398. Of note, elevated levels of lysoGb3 have been established as predictors of myocardial involvement and complications, reinforcing its role as a critical biomarker in Fabry cardiomyopathy assessment ^399–401. Given its specificity to Fabry disease, the clinical utility of LysoGb3 as a screening biomarker in LVH is applicable only to patients with Fabry disease, LVH may still arise due to conditions such as hypertension and aortic stenosis.

Other cardiac biomarkers

In addition to lyso-Gb3, several biomarkers have been explored for their potential to reflect cardiac involvement in Fabry disease. N-terminal pro b-type natriuretic peptide (NT-proBNP) is a well-documented marker indicating cardiac stress and ventricular overload. Elevated NT-proBNP levels in patients with Fabry disease have been associated with LVH and serve as indicators of HF risk ^402,403. Sensitivity to changes in NT-proBNP can aid in the early detection of evolving heart conditions and facilitate timely therapeutic interventions.

High-sensitivity cardiac troponins (hs-cTn) are also increasingly being recognized as valuable biomarkers in this population. Elevated levels of hs-cTn indicate myocardial injury and correlate with the severity of cardiac impairment in Fabry disease ^404–407. As such, these biomarkers offer helpful clinical insights into cardiac condition and may guide treatment decisions.

Emerging biomarkers

Ongoing research into novel biomarkers is broadening the potential for early detection and monitoring of Fabry disease. For example, microRNAs and inflammatory mediators are gaining interest due to their roles in the disease’s pathology and potential as predictive markers ¹⁵². MicroRNAs, particularly those involved in cardiovascular pathways, might provide insights into the underlying mechanisms of cardiac damage and serve as non-invasive biomarkers for monitoring disease progression ¹⁵². We recently demonstrated that miR-17 is a major player in the regulation of Warburg effect in the skeletal muscle of patients with Fabry disease ¹⁵³. The variability of disease manifestations in Fabry patients has led to the exploration of additional metabolites produced during lipid metabolism as mediators to provide insights into disease variability ⁴⁰⁸. In conjunction with established biomarkers like lyso-Gb3, the analysis of these and other biomarkers ^{75,358,370,409–445} could result in a more comprehensive profile, enabling tailored therapeutic approaches.

Therapeutic strategies

The management of Fabry disease, particularly concerning its cardiac manifestations, involves a range of therapeutic strategies designed to improve patient outcomes by restoring enzymatic function, decreasing intracellular Gb3 load and mitigating organ damage (Table 5). ERT is at the forefront of treatment, and recent advancements have introduced new modalities such as chaperone therapy and adjunctive pharmacologic interventions. The overarching goal of these strategies is to address both the primary metabolic defect and the secondary complications arising from the disease (Fig. 5).

Table 5.

Current therapies for Fabry disease cardiomyopathy.

Therapy Type	Drug/Approach	Mechanism of Action	Clinical Application	Limitations
Enzyme Replacement Therapy (ERT)	Agalsidase beta (Fabrazyme) Agalsidase alfa (Replagal)	Replaces deficient GLA enzyme to reduce Gb3 accumulation Same as above	First-line therapy for classic Fabry disease, including cardiomyopathy Approved in some countries (EU)	Requires biweekly IV infusions; potential antibody formation Not available in the US; similar issues as agalsidase beta
	Pegunigalsidase alfa (PRX-102; Elfabrio)	PEGylated, same as above	Approved for biweekly IV infusions	Potential for anaphylactic and Infusion associated reactions
Pharmacological Chaperones	Migalastat	Stabilizes and enhances residual GLA activity in amenable mutations	For patients with amenable GLA mutations	Not effective in non-amenable mutations
Substrate Reduction Therapy	Lucerastat (investigational) Venglustat (investigational)	Inhibits glycosphingolipid synthesis to reduce Gb3 buildup Similar to lucerastat	Under clinical investigation Under clinical investigation	Not yet approved Limited cardiac efficacy data
Gene Therapy	ST-920, FLT190, 4D-310 (in trials)	AAV or lentiviral vector delivery of functional GLA gene	Aimed at one-time correction of enzyme deficiency	Long-term efficacy and safety under investigation
Adjunctive Cardiac Therapy	ACE inhibitors / ARBs	Afterload reduction, proteinuria reduction	For cardiomyopathy and nephropathy	Does not address underlying disease mechanism
	Beta-blockers, diuretics Implantable cardiac devices	Symptom control in HF Prevents arrhythmic sudden cardiac death	Supportive therapy In advanced disease with conduction abnormalities	No disease-modifying effects Invasive; does not modify disease progression

Enzyme replacement therapy (ERT)

ERT using agalsidase alpha (Fabrazyme) or agalsidase beta (Replagal) has been a cornerstone of treatment for Fabry disease^446–455. ERT aims to replenish the deficient GLA enzyme, promoting the catabolism of Gb3 and reducing its accumulation ^456,457, and is typically administered by intravenous infusion once every 2 weeks.

Unfortunately, ERT has serious adverse effects arising from the high immunogenicity of the recombinant enzyme which leads to development of anti-drug antibodies (ADA) in patients ^458–460, resistance of cardiac cell responsiveness to available therapies which limits its effectiveness on HF patients ^{212,461–469}, and high financial expenditures (>$200k/year per patient) ^{470 469,471–476}. In fact, histological data from a study in patients with Fabry disease who had received ERT for at least 18 months, revealed that ERT treatment was associated with cardiomyocyte disarray, severe vacuolization, cell death, and fibrosis ⁴⁶⁷. In line with these observations, a very recent meta-analysis of 11 clinical studies examining the heart via MRI has demonstrated that ERT treatment augmented LGE, indicating increased myocardial fibrosis ³⁵⁹. This aspect is critical because heart disease is the most common cause of death in Fabry disease ^477,478.

Recently, a newer generation ERT named Elfabrio (pegunigalsidase alfa) consisting of GLA conjugated with polyethylene glycol (PEG) moieties has also been approved for patient use⁴⁷⁹. One of the key advantages of Elfabrio is its extended half-life and elevated activity despite minor inhibitory effects of preexisting ADAs and anti-PEG antibodies. Current trials are focused on assessing the efficacy of biweekly versus monthly dosing frequency and long-term effects (Table 6).

Table 6.

Ongoing clinical trials for Fabry disease.

Drug	Intervention	Phase & Status	Key Focus
Pegunigalsidase alfa – Japan (RISE study)	Enzyme replacement (PEGylated)	Phase 2/3, recruiting in Japan	Evaluating PK/PD and clinical efficacy in Japanese patients
Venglustat (GZ/SAR402671)	Oral substrate-reduction therapy	Phase 3, randomized, comparing to standard care	LV mass and neuropathic/abdominal pain endpoints
Migalastat HCl	Oral pharmacological chaperone	Phase 4, open-label PK/PD in renal impairment; NCT04020055	Safety and pharmacokinetics in severe renal disease
Fabagal® (Agalsidase beta) – ISU ABXIS	Enzyme replacement	Phase 3, safety/efficacy against agalsidase beta	Comparing new enzyme to standard therapy
Lucerastat	Oral substrate-reduction (iminosugar)	Long-term safety and tolerability; recruitment closed	Including kidney Gb3 histology sub-study
4D-310 Gene Therapy (4D Molecular Therapeutics)	AAV-mediated GLA gene delivery	Phase 1/2, open-label, enrolling or in-progress	Assessing safety, tolerability, and pharmacodynamics
ST-920-201 (STAAR, Sangamo Therapeutics)	AAV-mediated GLA gene delivery	Phase 1/2 completed	Assessing safety, tolerability, and pharmacodynamics
AMT-191	IV alpha-Gal A variant	Phase 1/2, open-label, dose-escalation	Safety and biomarker efficacy in classic male Fabry
AL01211	Novel therapeutic (GCS inhibitor)	Phase 2, safety/tolerability in treatment-naïve males	Early efficacy in classic Fabry disease

Early diagnosis and intervention are crucial, as progression to established fibrosis can further limit therapeutic outcomes. Moreover, while ERT may compensate for the underlying enzymatic deficiency, it does not completely reverse fibrotic changes or restore normal cardiac function in patients with advanced disease. These issues, combined with the lifelong physical burden of therapy, and development of ADA in patients, have prompted the development of alternative therapeutic approaches to treat the disease, including chaperone and substrate reduction therapy, and new-generation approaches such as gene therapy and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based approaches ⁴⁸⁰.

Chaperone therapy

Recent advancements have introduced oral chaperone therapy (migalastat), which is specifically indicated for patients with amenable GLA mutations, defined as mutations that allow for sufficient residual enzyme activity when augmented by the chaperone ^481,482. Migalastat functions as a competitive inhibitor of misfolded GLA, and stabilizes the misfolded enzyme, thereby enhancing its function and facilitating Gb3 clearance. This therapy offers an alternative for patients who may not tolerate ERT or prefer an oral option. Migalastat can effectively reduce substrate levels and improve patient-reported outcomes, potentially alleviating some of the disease’s debilitating symptoms ^{274,483–520}. The advantages of migalastat include elevated bioavailability, high immunologic tolerance, and it has been shown to favorable outcomes in cardiorenal parameters even in patients with classical Fabry disease. However its effectiveness is limited to patients with the misfolded mutant forms of GLA and to patients in early and mid-stages of the disease. ⁵¹¹

Substrate reduction therapy (SRT)

SRT aims to reduce the accumulation of Gb3 and lyso-Gb3 by limiting their biosynthesis, thereby alleviating cellular stress. Lucerastat, the most advanced oral SRT for Fabry disease, inhibits glucosylceramide synthase (GCS) to reduce the biosynthesis of glycosphingolipids^521–526. Other examples in this class include Venglustat ^527–539 and Eliglustat (currently approved for Gaucher disease type 1, another glycosphingolipidosis ^540–551). SRT has been shown to efficaciously cross the blood-brain barrier to positively impact neurological symptoms arising from the disease. However, since the treatment focuses on decreasing Gb3 load to facilitate residual clearance, it is not effective on patients with low levels of residual enzyme activity ^523,552.

Emerging combination and adjunctive therapies

The landscape of Fabry disease management is evolving, with ongoing research exploring combination therapies that may further enhance treatment outcomes, and emphasize the need for a multidisciplinary approach toward managing Fabry disease, with close collaboration between cardiologists, geneticists, and primary care providers. The main ongoing clinical trials are reported in Table 6. Patients with classic Fabry disease are recommended to initiate treatment before reaching adulthood irrespective of clinical presentation of symptoms, and should be regularly screened and monitored for organ assessment, particularly cardiac, renal, and neurological. In patients diagnosed with atypical forms, regular screening of patients using biochemical and imaging tests along with biopsy screening is essential, and treatment should be initiated when there is evidence of maladaptive response of the cardiac, renal or neurological system before any overt clinical symptoms appear. Appropriate management of Fabry disease involves a multidisciplinary approach toward managing Fabry disease, with close collaboration between cardiologists, geneticists, and primary care providers to provide symptomatic relief, organ-specific therapy and psychosocial support ⁵⁵³.

Emerging adjunctive therapies, including standard HF medications, have shown promise in managing arrhythmias and mitigating HF symptoms in Fabry patients receiving ERT; medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics are commonly utilized to optimize cardiac function and quality of life for these individuals ⁴⁶². The risk of sudden cardiac death in patients with cardiac complications compels ongoing monitoring and proactive management of arrhythmias, emphasizing the importance of a multidisciplinary approach in the care of affected individuals ⁵⁵⁴. For those experiencing severe arrhythmias or other significant cardiac events, the use of implantable cardioverter-defibrillators (ICDs) may be warranted ⁵⁵⁵.

Dedicated studies are investigating the potential of using novel biomarkers to enhance the monitoring of treatment responses and disease progression. For example, the combination of lyso-Gb3 measurements with traditional cardiac markers may provide a comprehensive profile that allows for better assessment of disease status and therapy effectiveness in real-time. Therapeutic approaches involving gene therapy, such as Lentiviral and Adeno-associated Virus (AAV), as well as CRISPR-based approaches are gaining traction, with preliminary data suggesting that these methods may provide long-lasting solutions to address the root cause of Fabry disease at the genetic level ^{459,556–574}. One study performed autologous transplantation of CD34+ hematopoietic stem cells (HSC) transduced with a lentiviral vector expressing α-galactosidase A (AVR-RD-01) into patients with classical Fabry disease. Initially the patients showed increased restoration of enzymatic levels of α-galactosidase A and decreased levels of plasma Gb3, however these differences were not statistically significant after 5 years of followup. However, expression of LV-transduced cells was observed up to 18 months post transplant, with no evidence of leukemogenic transformation of cells, and minimum side effects throughout the course of the study ^556,566,575. Further, four AAV serotype investigational studies (ST-920-201, FLT190, 4D-310, AMT191) have also been initiated to restore α-galactosidase in patients with Fabry disease. Preliminary results have shown that patients have significantly decreased Gb3 and elevated GLA, albeit with a few patients experiencing side effects such as atypical hemolytic uremic syndrome ⁵⁷⁵. Observational studies are underway to evaluate the long-term impact of these therapies. Furthermore, two CRISPR based screening strategies to silence the expression of the gene alpha 1,4-galactosyltransferase (A4GALT) encoding Gb3 synthase suggest that downregulation of A4GALT rescues the nephropathic phenotype of Induced Pluripotent Stem Cells (iPSC)-derived kidney organoids ⁵⁷⁶, and the vasculopathy phenotype and angiogenic ability of iPSC-derived endothelial cells from patients with Fabry disease ⁵⁷⁷. Thus, gene therapy and CRISPR based approaches show significant potential for the development of more effective therapies to treat Fabry disease⁵⁷⁵.

Animal models of Fabry disease

The main impediment which restricts the identification and testing of new therapies for Fabry disease is the lack of animal models which can fully recapitulate the pathological features of human Fabry disease cardiomyopathy (Table 7). GLA-KO rodents ^578–583 obtained simply ablating the endogenous GLA gene but not replacing it with a mutated form, do not have any evident cardiac phenotype. The probable reason for the lack of phenotype is a compensatory upregulation of other enzymes, including α-galactosidase B (a.k.a. NAGA or GALB) and galactosidase Beta 1 (GLB1), which can metabolize Gb3 ^584–586.

Table 7.

Currently available animal models of Fabry disease.

Model	Genetic Manipulation	Cardiac GLA Activity	Cardiac phenotype	Resemblance to human disease
GLA KO mouse 578–582 & rat 583	-Deletion of GLA	Not detectable	NO	The total absence of GLA is very rare in patients with Fabry disease; GLA KO triggers a compensatory upregulation of other enzymes like NAGA and GLB1.
TgM/KO mouse 587	-Deletion of GLA -Insertion of Tg mutated R301Q GLA under the chicken β-Actin promoter	16.4-fold increased (!) (due to β -Actin promoter)	NO	No phenotype (Compensatory effect of Tg overexpression); No Gb3 accumulation.
TgG3S mouse 588	-Transgenic Gb3 Synthase under the hybrid CMV enhancer / chicken β-Actin promoter	Similar to WT	NO	Gb3 Synthase is not overexpressed nor hyperactive in human Fabry disease; No phenotype (Compensatory effect of Tg overexpression); Gb3 increased in kidney; trend to reduction (!) in the heart at 15w.
G3Stg/GLA-KO mouse 589–591	-Deletion of GLA -Transgenic Gb3 Synthase under the hybrid CMV enhancer / chicken β-Actin promoter (obtained crossing GLA KO with TgG3S)	Reported to be reduced (however, no actual data vs WT are shown)	NO	Gb3 Synthase is not overexpressed nor hyperactive in human Fabry disease; Despite being called “symptomatic” mouse, the phenotype is observed only in the kidney (increased blood urea nitrogen at 15 weeks); Gb3 increased in kidney (>70 μg/mg at 25w); Gb3 in heart: ~30 μg/mg; Heart weight NOT increased.
FD-Tgmut/KO mouse153	-Deletion of GLA -Insertion of human hR301Q Tg under the human α-GAL-A promoter	10-fold reduced compared to WT	YES	Reduced GLA activity, increased Gb3 in the heart; Diastolic dysfunction; Cardiac fibrosis and hypertrophy.

Other models include transgenic animals overexpressing a mutated GLA ⁵⁸⁷ or Gb3 synthase ^588–591 under a strong ubiquitous promoter (i.e. the chicken β-actin) harness genetic manipulations that do not reproduce the pathophysiology of human Fabry disease (indeed, Gb3 Synthase is not overexpressed nor hyperactive in Fabry disease) and therefore these mice do not exhibit any phenotype within the heart.

Conclusions

Fabry disease remains a complex multisystem disorder with significant cardiac implications that contribute substantially to morbidity and mortality. Advances in diagnostic tools—particularly genetic testing, enzyme assays, and cardiac imaging—have improved the ability to detect and monitor Fabry cardiomyopathy, yet underdiagnosis remains a critical challenge. Regular follow-up with echocardiography, cardiac MRI, and biomarker measurements, including lyso-Gb3 and NT-proBNP, may aid in assessing the disease’s progression and patient response to therapy.

In addition to cardiac manifestations, patients often experience a variety of additional systemic symptoms, including neuropathic pain, gastrointestinal disturbances, and renal impairment, thereby necessitating the development of comprehensive management strategies that consider both the systemic and interconnected nature of the disease.

Future research should focus on novel therapies that more directly target the underlying genetic and metabolic mechanisms, as well as longitudinal studies that assess treatment efficacy and quality of life. A holistic and multidisciplinary approach that involves early screening, timely treatment, and psychosocial support can ultimately improve patient quality of life, prolong survival and improve long-term patient outcomes.