Fabry Disease: An Update Based on Evidence and ExperienceAbstract
Fabry disease is an X-linked genetic disorder caused by GLA gene variants, resulting in a lysosomal enzyme deficiency of the acid hydrolase α-galactosidase A, with a progressive accumulation of globotriaosylceramide that mainly affects the cardiovascular, renal, and nervous systems. In September 2023, a local group of physicians, experts in Fabry disease patient management, convened in a face-to-face meeting to discuss and review some controversial aspects, based on their experience and the updated literature. This study aims to report the results of the review. A non-exhaustive literature search was conducted using the Embase and PubMed databases. The review highlighted that early initiation of treatment in children with “classic” forms has been associated with better outcomes, based on the reduction in biomarkers, improvement in symptoms, and stabilization of renal and cardiovascular function. Although the dose of enzyme replacement therapy has been a controversial issue, the personal experience of the authors, long-term data, and new therapeutic guidelines suggest that a dose of 1 mg/kg every other week should be considered the first-line treatment for males with the “classic” phenotype.
Keywords:
Fabry disease phenotype; Fabry treatment criteria; monitoring Fabry disease; enzyme replacement therapy
Keywords:
Fabry disease phenotype; Fabry treatment criteria; monitoring Fabry disease; enzyme replacement therapy
Keywords:
Fabry disease phenotype; Fabry treatment criteria; monitoring Fabry disease; enzyme replacement therapy
Introduction
Fabry disease (FD) is an X-linked genetic disorder caused by GLA gene variants, leading to a lysosomal deficiency of the acid hydrolase α-galactosidase A enzyme (α-Gal A). This results in the accumulation of the substrate globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3) in many tissues, causing a systemic disease that mainly affects the cardiovascular, renal, and nervous systems [1].
The spectrum of FD varies from the severe “classic” form (mainly in male patients) to a seemingly asymptomatic course on occasions observed in females, in part due to X-chromosome inactivation [1]. In 1995, an atypical FD variant in males with left ventricular hypertrophy (LVH) was described [2]. Then, the sub-categorizations “cardiac variant” and “renal variant” were established, according to the predominant organic involvement [2,3].
In September 2023, a local group of physicians, experts in FD patient management, convened in a face-to-face meeting to discuss and review some controversial aspects of FD, based on their experience and the updated literature. This study aims to report the results of the review.
Methods
For this review, a non-systematic literature search was performed using Embase and PubMed databases. Outcomes selected for analysis included: phenotype characterization, treatment criteria, prognosis value of biomarkers, efficacy of the available therapeutic options, monitoring treatment response, and the role of antibodies anti-agalsidase.
Phenotype Characterization
Currently, more than a thousand genetic variants of the GLA gene have been described [4]. However, analysing these results is a challenging task for bioinformatics professionals, and many genetic variants may remain of unknown significance. In such cases, a thorough multidisciplinary analysis is essential to determine the significance of the variant. This analysis should include a functional assessment of the variant’s effect on the protein, biochemical testing, and clinical studies [5].
In the field of FD, conflicting or discordant interpretations of multiple GLA variants have been reported in the literature. While there is consensus on the non-pathogenicity of many benign variants, some reports still suggest these variants have pathogenic effects [6,7].
The clinical picture and course of the disease in each patient are diverse and associated not only with specific genetic variants but also with other factors such as environmental, cardiovascular risk factors, or epigenetics. However, there is a genotype-phenotype correlation. So, in those cases in which the GLA variant has been previously reported, the patient's phenotype can be predicted [5]. As described in the introduction, the severity of clinical expression in women with “classic” phenotypes carrying nonfunctional gene variants can be mild or moderate, depending on the pattern of X-chromosome inactivation [1].
The literature analysis allows us to conclude that it is possible to distinguish the FD phenotypes through “the use of 6 tools”: age of symptoms onset, age of Fabry-associated clinical events (FACEs) onset, endothelial involvement in tissue biopsy, residual enzyme activity, Lyso-Gb3 values in plasma and/or dried blood spot (DBS), and a genetic variant evaluation. FACEs were defined as myocardial infarction, new symptomatic arrhythmia requiring medication or interventional procedure, unstable angina, congestive heart failure, stroke, TIA, doubling of serum creatinine from baseline, end-stage renal disease or death [8].
“Classic” male patients usually experienced the onset of symptoms at an earlier age (mean age of 6 years), compared with 9 years between females [9]. The most frequent symptoms in childhood are abdominal pain, diarrhea, heat intolerance, and neuropathic pain in the hands and feet. Laney et al. reported that manifestations can occur during early childhood, with cases as early as 2-3 years [10]. In “late-onset” forms (also known as attenuated variant), symptoms such as neuropathic pain, gastrointestinal (GI), dermatological, and ophthalmological involvement are not described. When they have been reported, other differential diagnoses could explain these early manifestations (irritable bowel syndrome, fibromyalgia, diabetic neuropathy, etc.) [11-13]. The incidence of first cardiac events was higher in the most common cardiac variant (N215S genotype) male patients than in “classic” males (31% vs. 21%); although events happened later in life (52.3 vs. 43.3 years respectively) [13]. Cerebrovascular events were more frequent between “classic” males than N215S male patients and occurred earlier in life. In women, the “classic” variant has more cerebrovascular events in comparison to N215S patients and these occurred at a younger age [12]. In summary, cardiac, renal, and cerebrovascular events occur 10 to 15 years earlier in the “classic” than “late-onset” phenotype.
Tissue biopsies of FD “cardiac” variants have demonstrated Gb3 deposit in cardiomyocytes but not in cardiac endothelial cells [14,15], suggesting that residual α-Gal A enzyme can limit Gb3 accumulation at this level. The lack of Gb3 deposition in the endothelial cells was also reported for the renal variant [16], thereby the presence of Gb3 inclusions at the endothelial level can be considered as another tool for the phenotype classification.
Substrate accumulation in male patients begins once α-Gal A activity drops below 20%-25% of normal values [1]. In the "classic" phenotype, α-Gal A levels are less than 1-3%, and in "late-onset" FD patients, a range of 3-25% enzyme activity has been described. Even though reduced α-Gal A activity in female patients is an indicator of pathogenicity, its diagnostic significance is diminished depending on X-chromosome inactivation [5].
Serum Lyso-Gb3 values are significantly higher in FD patients than in healthy controls. More relevantly, Lyso-Gb3 values were significantly higher in the “classic” than in the “late-onset” variant and in male vs. female Fabry patients. A significant correlation between Lyso-Gb3 levels and genotype severity enables the functional characterization of GLA variants and phenotype differentiation [17]. Even though there may be slight differences from the cut-off values, most publications show the following plasma reference values about phenotype and gender: males with “classic” variants: 45-150, females with “classic” variants: 1.5-41.5, males with “late-onset” variants: 1.3-35.7, and females with “late-onset” variants: 0.5-2.0 (normal levels for plasma Lyso-Gb3: ≤0.6 nmol/L) [18-20]. The analysis of Lyso-Gb3 levels in DBS and plasma shows strong correlation, with the model explaining over 97% of data variability and demonstrating that plasma values can be estimated from DBS samples [21,22]. It is important to note that normal values and units of measurement may vary across different laboratories.
Regarding molecular genetic analysis, some variants are predicted to have a high probability of causing a “classic” phenotype because they create a premature stop codon (nonsense or frame-shift variants) with the subsequent loss of α-Gal A protein sequence. Other sequence changes resulting in a catalytically inactive enzyme, for example, missense variants affecting one of the 15 residues in the enzyme active site, may be related to a "classic" or "late-onset" phenotype; when this is the case, the use of other "tools" is recommended [5].
Treatment Criteria
The criteria for starting treatment in pediatric patients initially require a correct phenotype distinction, since to date there is no evidence to treat pediatric FD patients with a “late-onset”
phenotype. In 2016, the management and treatment guidelines for pediatric patients in the US recommended that treatment should be considered for patients with Fabry-related symptoms, regardless of age or gender. In asymptomatic pediatric patients, starting enzyme replacement therapy (ERT) should be considered around the age of 8-10 years in boys with “classic” FD [23].
Recently, a consensus recommendation of pediatric FD patients in France reinforced that ERT should be considered for symptomatic boys and girls with acroparesthesias, abnormal albuminuria, severe gastrointestinal involvement, and abdominal pain or cardiac compromise. This group also concluded that asymptomatic boys may benefit from earlier treatment initiation based on the following criteria: i) the presence of a pathogenic “classic” variant, ii) family background of severe FD in male patients, iii) undetectable α-Gal A activity and, iv) plasmatic Lyso-Gb3 >20 nmol/L [24].
The inclusion of Lyso-Gb3 levels as a criterion for starting treatment was reported in other publications during the same year. Kritzer et al. reported two FD male patients with a predicted “classic” phenotype who started therapy at the age of three and five respectively, and who evidenced sustained biomarkers normalization within one year of ERT [25]. The latter results were relevant since we know that treatment initiation after the second decade of life has not shown normalization of Lyso-Gb3 levels to date [26,27].
A study of 24 pediatric patients treated with agalsidase beta aged 2 to <8 years at ERT initiation and with elevated plasma Gb3 values at baseline, showed that plasma Gb3 levels descended within the normal range in 91%, 95%, and 92% of patients at 6, 12, and 24 months, respectively. Based on this study, agalsidase beta prescribing information was updated in March 2021, reporting that agalsidase beta is indicated for adult and pediatric FD patients 2 years of age and older in the US [28]. In clinical practice, particularly for asymptomatic patients, many young children experience significant stress. Therefore, in most cases, the timing of treatment initiation is determined through shared decision-making with parents.
In adult males with a “classic” phenotype, ERT should be considered and is appropriate in all patients at any presentation age. Migalastat prescription is restricted to patients with “amenable” variants and an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2. Females with “classic” FD, can be classified into two groups: symptomatic and asymptomatic. Symptomatic patients should initiate treatment in the presence of neuropathic pain, GI compromise, proteinuria/albuminuria, cardiac manifestations, and stroke/transient ischemic attack (TIA). In asymptomatic females, treatment should be considered if there is laboratory, histologic, or imaging evidence of organic damage. Finally for adult males and females with a “late-onset” phenotype treatment should be considered if there is laboratory, histologic, or imaging evidence of organic compromise [29, 30,31]. In case of kidney biopsy, the presence of podocyte foot process effacement, glomerulosclerosis, or moderate/severe Gb3 inclusions may be sufficient evidence of cell damage, after excluding other causes such as treatment with chloroquine, amiodarone, etc.
Prognosis Value of Biomarkers
Previous publications had questioned the validity of Lyso-Gb3 as a prognostic marker of FD. The inclusion of males and females with “classic” and “late-onset” phenotypes in the same group may explain inconclusive results. It is currently known that high values of Lyso-Gb3 are associated with a worse prognosis for the appearance of serious typical FD events. Rombach et al. reported that Lyso-Gb3 was an independent risk factor for the development of cerebrovascular white matter lesions in male and LVH in female patients and reported a correlation between disease severity and exposure to plasma Lyso-Gb3 [32]. In 2018, two different publications concluded that plasma Lyso-Gb3 values were more suitable indicators of overall disease severity in males compared to other parameters (enzyme activity, age, serum creatinine) [17,33]. A median follow-up time of 68 months in males and females with “classic” and “late-onset” phenotypes was published. In this study, severe events occurred in 29% of the patients and Lyso-Gb3 level pretreatment exposure was significantly associated with adverse outcomes [34]. Recently, these results have been replicated by the Dutch group, concluding that Lyso-Gb3 level in untreated patients was associated with almost all Fabry-specific disease manifestations in both men and women [35].
Lavalle et al. analysed the effect of plasma Lyso-Gb3 and its prognostic value in late-onset variants (N215S FD patients). In this study, a statistically significant correlation was found between clinical manifestations and time exposure to Lyso-Gb3. This result suggests that prolonged exposure contributes to disease progression [12]. Similar findings were reported one year before, in patients carrying the “late-onset” IVS4+919G>A cardiac variant, where plasma and urinary Lyso-Gb3 were positively associated with the Mainz Severity Score Index [36].
Available Treatments and Efficacy
The goal of specific treatment in FD is to prevent irreversible organ damage and, when administered in the early stages, to reverse certain pathophysiological processes that lead to cell death. In our country, the available specific treatments include ERT with agalsidase alpha (0.2 mg/kg every other week [EOW]) and agalsidase beta (1 mg/kg EOW), as well as the oral pharmacological chaperone migalastat. The choice of therapy is determined through a comprehensive evaluation of disease severity, genetic variants, organ involvement, and individual patient characteristics.
Regarding ERT, various studies have evaluated biomarkers, tissue characteristics, and clinical outcomes of switching between agalsidase beta and agalsidase alpha [37,38]. A study of systematic kidney biopsies evaluated the efficacy of ERT on early renal histological features in young patients with “classic” variants. This study demonstrated that treatment with agalsidase alpha or beta can lead to complete Gb3 clearance in mesangial and glomerular endothelial cells. However, no effect on podocyte inclusions was observed in the low-dose group, whereas substantial clearance was seen in patients receiving higher doses [37]. A correlation between podocyte substrate clearance and cumulative dose has been observed in FD patients with a median age of 21 years who had a longer duration of ERT with different dosing regimens [38].
A series of investigations with a three-year follow-up period provided evidence showing that agalsidase beta was associated with eGFR stabilization, whereas a reduction in the beta dose and/or a switch to alpha led to a decline in eGFR. MSSI scores and the frequency of neuropathic and GI pain significantly increased when patients switched to alpha or when the beta dose was reduced [39-41]. This increase in neuropathic pain intensity following a significant dose reduction was reported in a multidisciplinary study involving patients with “classic” FD and the same variant. The study concluded that improvements and stabilization in neuropathic pain, cardiac and renal function, and brain magnetic resonance imaging findings were primarily observed in patients receiving ERT with agalsidase beta rather than agalsidase alpha [42].
A retrospective study compared biochemical and clinical outcomes among FD patients receiving different agalsidase formulations. The study found no difference in the rate of clinical events between FD patients treated with agalsidase beta and those treated with agalsidase alpha. However, among patients with the “classic” FD phenotype, a significant reduction in plasma Lyso-Gb3 and left ventricular mass index (LVMi) was observed with agalsidase beta compared to agalsidase alpha, despite the presence of neutralizing antibodies. These findings suggest that agalsidase beta has a greater pharmacodynamic effect on plasma Lyso-Gb3 than agalsidase alpha [43]. In 2017, El Dib et al. published a review on ERT, including 77 cohort studies with a total of 15,305 participants. The study concluded that agalsidase beta was associated with a lower incidence of cerebrovascular, cardiac, and renal events compared to untreated patients, as well as a significantly lower incidence of cerebrovascular events compared to agalsidase alpha [44].
Migalastat, an oral pharmacological chaperone administered at a dose of 123 mg every other day, is available for the treatment of patients older than 12 years with “amenable” variants of the GLA gene and an eGFR greater than 30 mL/min/m² [8]. In the Phase III ATTRACT trial, 42 patients were treated with ERT (agalsidase alpha or beta) or migalastat for 18 months. After this period, “amenable” patients on ERT were switched to migalastat for an additional 12 months. The pharmacological chaperone migalastat and ERT showed similar effects on kidney function, while cardiac assessments revealed that LVMi decreased with migalastat, whereas there was no significant change in patients on ERT. Plasma Lyso-Gb3 levels remained low and stable in patients who switched from ERT to migalastat during both the primary study and the 12-month extension period [45,46]. It is important to note that in the ATTRACT study, due to the randomization ratio (1.5:1), there were hypothetically fewer patients in the ERT group, which may have limited the analysis of changes in LVMi.
Recently, an expert consensus on the management of patients with "classic" FD was published. The authors conducted a critical analysis of the results presented in the Phase III ATTRACT trial. Even though the results showed that ERT with agalsidase alpha and beta, as well as migalastat, had comparable effects on kidney function, the outcomes were less favourable for both drugs when the measured GFR was analysed. Additionally, in the included patient population, the mean baseline eGFR was normal at a median age of 49 years, and most patients received agalsidase alpha. Germain et al. pointed out that the population was not representative of “classic” FD patients, who, in the absence of specific therapy, have been shown to require renal replacement therapy because eGFR falls below 10 mL/min/1.73m2 at a median age of 38 years. Moreover, 40% of the variants in the study were associated with "late-onset" phenotypes, while others are currently considered non-pathogenic [31]. Recent studies have demonstrated that, for certain GLA variants, in vitro amenability does not necessarily correspond to in vivo amenability in migalastat-treated patients. [47]. Although other studies have shown benefits in “classic” male FD patients receiving migalastat [48], in our opinion, more studies are needed to confirm the true "treatability" of male patients affected by the “classic” FD phenotype.
Lyso-Gb3 for Monitoring Treatment Response
The 2018 European expert consensus on therapeutic goals for FD suggested reducing plasma Lyso-Gb3 values as much as possible. If this biomarker remains elevated or does not reach near-normal values, it may be necessary to increase ERT and assess the presence of anti-drug IgG antibodies [49]. This statement is primarily applicable to males with the “classic” phenotype, where Lyso-Gb3 levels are consistently elevated. In some females, even those with a “classic” variant, Lyso-Gb3 levels may be only slightly increased due to random X-chromosome inactivation. Additionally, in individuals with "late-onset" variants, Lyso-Gb3 levels may fall within the normal range [17-19].
In 2011, van Breemen et al. analysed the effects of ERT in “classic” FD patients using agalsidase alpha (0.2 mg/kg) and agalsidase beta (0.2 mg/kg or 1.0 mg/kg) on Lyso-Gb3 levels. All regimens significantly reduced plasma Lyso-Gb3 in Fabry males within three months, with stabilization thereafter. However, the decrease in plasma Lyso-Gb3 was significantly greater in patients receiving agalsidase beta at 1.0 mg/kg compared to those on agalsidase alpha or beta at 0.2 mg/kg. Antibody development, particularly in agalsidase beta-treated males, was associated with smaller Lyso-Gb3 reductions, though high-dose beta treatment mitigated this effect [50]. This dose-dependent response of Lyso-Gb3 has been replicated in other studies [51]. A worldwide shortage of agalsidase beta in 2009, caused by contamination at the production facility, resulted in dose reductions (from 1 mg/kg EOW to 0.5 mg/kg/month) or a switch to agalsidase alpha (0.2 mg/kg EOW). Findings showed a significant increase in Lyso-Gb3 levels in males (p = 0.001) after one year, irrespective of dose adjustment or enzyme substitution. No clear association was observed between changes in Lyso-Gb3 and antibody status, treatment duration, or clinical events [52].
A multicenter study assessed changes in plasma Lyso-Gb3 levels in 15 male Fabry patients who switched from agalsidase alpha (0.2 mg/kg EOW for at least 12 months) to agalsidase beta (1.0 mg/kg EOW). Within two months, plasma Lyso-Gb3 levels decreased significantly, with further reductions observed through six months (p < 0.001). No differences were detected in IgG antidrug antibody titers, and the switch was well tolerated [53]. Finally, in 2018, an international multicenter retrospective cohort study compared the effects of both ERTs at their registered doses, adjusting for phenotype and sex. Among 387 patients (192 women), 248 received agalsidase alpha. Agalsidase beta led to a greater reduction in plasma Lyso-Gb3, particularly in men with “classic” FD (p < 0.001), even in the presence of antibodies [54]. These findings suggest that agalsidase beta has a more significant pharmacodynamic impact on glycosphingolipid biomarkers, supporting its use at 1.0 mg/kg EOW.
In migalastat-treated patients, Bichet et al. concluded that Lyso-Gb3 may not be appropriate as a biomarker for monitoring the therapeutic response [55]. The author's conclusion is probably controversial because the analysis was conducted in a population that included mostly women and “late-onset” patients. Another recent analysis demonstrated that plasma Lyso-Gb3 values do not correlate with the progression of kidney damage among FD patients treated with migalastat [56].
Anti-Drug Antibodies
Male patients with “classic” FD and without cross-reactive immunologic material (i.e., a lack of endogenous α-Gal A enzyme) are at risk of generating neutralizing antidrug antibodies (ADAs), which reduces the efficacy of ERT [57]. In about 50% of males with “classic” FD, the formed ADAs are capable of inhibiting α-Gal A activity (iADAs) in vitro as well as inhibiting cellular enzyme uptake [58]. The development of iADAs negatively affects the biochemical response to ERT, resulting in a consequent decline in kidney function [59].
Complete cross-reactivity of these antibodies suggests that it is unlikely that the switch from one recombinant product to the other prevents antibody formation [57]. Germain et al. recommended IgG testing before the first ERT infusion, every 3-6 months for the first 18 months, and then every 6-12 months until two consecutive negative results are confirmed [31]. Recently, a logistic regression model was developed to determine iADA risk before ERT initiation. This helps decide which patients may require adjusted treatment and/or immunomodulatory regimens [60].
Lenders et al. developed an advanced inhibition assay using purified IgGs from patients’ serum to determine individual ADAs. They demonstrated that the amount of circulating anti-GLA ADAs decreased in each patient during ERT infusions [61]. This group further reported a better biochemical response in patients whose ADA titers were saturated during ERT [62].
Conclusions
The distinction between phenotypes should be considered the first step after diagnosis, as the timing of treatment initiation, monitoring, and therapeutic options can be adjusted for each variant. Early initiation of treatment in children with “classic” forms has been associated with better outcomes, based on the reduction of biomarkers, improvement of symptoms, and stabilization of renal and cardiovascular function. Although the dose of ERT has been a controversial issue, long-term data and new therapeutic guidelines suggest that the use of a 1 mg/kg EOW dose of ERT should be considered the first line of treatment in males with the “classic” phenotype.
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Funding
This research received no external funding for publication. This face-to-face meeting was organized by Sanofi Argentina; however, Sanofi had no role in the design, execution, interpretation, or writing of the manuscript. The authors were responsible for all content and editorial decisions and did not receive honoraria related to the development of this publication.
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Data Availability
In this review, data supporting the findings and discussions are available from the corresponding author upon reasonable request.
Data availability
In this review, data supporting the findings and discussions are available from the corresponding author upon reasonable request.
Data citations
4. The Human Gene Mutation Database. https://products.sanofi.us/Fabrazyme/Fabrazyme.pdf Accessed May 10, 2025.
Publication Dates
-
Publication in this collection
16 June 2025 -
Date of issue
2025
History
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Received
13 Nov 2024 -
Accepted
16 May 2025
