Version May 2024
INTRODUCTION — Fabry disease, also called Anderson-Fabry disease, is the second most prevalent lysosomal disease after Gaucher disease. It is an X-linked inborn error of the glycosphingolipid metabolic pathway. This results in accumulation of globotriaosylceramide (Gb3) primarily within lysosomes in a wide variety of cells, thereby leading to the protean manifestations of the disease.
There is no cure for Fabry disease. Treatment options include both Fabry-specific and non-Fabry-specific therapies. Available Fabry-specific therapies include recombinant alpha-galactosidase A (alpha-Gal A), the enzyme that is deficient in patients with Fabry disease, and migalastat hydrochloride, an oral pharmacologic chaperone that corrects folding of mutated alpha-Gal A in patients with Fabry disease and amenable alpha-Gal A mutations. The impact of these therapies on mortality is unknown. Non-Fabry-specific therapies include adjunctive therapies for complications such as chronic kidney disease (CKD), cardiac disease, neurologic disease, gastrointestinal disease, and other clinical manifestations.
The treatment and prognosis of Fabry disease are presented here. Other aspects of this disease are discussed separately:
●(See "Fabry disease: Clinical features and diagnosis".)
●(See "Fabry disease: Cardiovascular disease".)
●(See "Fabry disease: Neurologic manifestations".)
●(See "Fabry disease: Kidney manifestations".)
PRETREATMENT CONSIDERATIONS
Clinical phenotypes — Patients with Fabry disease can generally be categorized into the following three clinical phenotypes, which guide the approach to therapy:
●Classic Fabry disease – The classic form of Fabry disease is the most severe clinical phenotype. Males with classic Fabry disease have little or no functional alpha-galactosidase A (alpha-Gal A) enzyme activity (<1 percent of the normal mean). These patients have a childhood or adolescent onset of disease, followed by progressive multiorgan failure and, ultimately, premature death. (See "Fabry disease: Clinical features and diagnosis", section on 'Classic Fabry disease'.)
●Heterozygous females – Clinical manifestations in heterozygous females with classic mutations can vary widely from no apparent clinical disease to a severe phenotype that resembles that observed in males with classic Fabry disease. This phenotypic variation may be due, at least in part, to skewed (nonrandom) X-chromosome inactivation, which results in a higher percentage of X chromosome with the disease mutation being expressed in affected organs. Heterozygous females may exhibit any or all of the symptoms and signs of Fabry disease. (See "Fabry disease: Clinical features and diagnosis", section on 'Heterozygous females'.)
●Patients with later-onset and cardiac variants – Males and females with atypical, "later-onset" variants of Fabry disease usually present later in life (fourth to seventh decades of life) than those with the classic form of the disease. They have residual alpha-Gal A activity (between 2 and 30 percent of the normal mean). Many do not display the classical features of Fabry disease, and their disease may sometimes be dominated by a particular organ system, such as the heart or kidney. Patients with cardiac variants have clinical disease limited to the heart. (See "Fabry disease: Clinical features and diagnosis", section on 'Atypical (later-onset) variants'.)
Goals of therapy — The overall goals of therapy in patients with Fabry disease are to slow down or prevent progression to irreversible tissue damage, organ failure, and premature death, and to improve quality of life. Treatment generally consists of Fabry-specific therapy (such as enzyme replacement therapy [ERT] or chaperone therapy [migalastat]) for those with an indication for treatment, as well as adjunctive therapies for complications such as chronic kidney disease (CKD), cardiac disease, neurologic disease, gastrointestinal disease, and other clinical manifestations. (See 'Fabry-specific therapy' below and 'Supportive care' below.)
Since the manifestations of Fabry disease vary among individual patients, therapeutic goals should be individualized depending upon the extent of organ involvement. Organ-specific goals include the following [1,2]:
●Kidney – Fabry disease is associated with progressive CKD and proteinuria that can ultimately progress to end-stage kidney disease (ESKD). Therapeutic goals for Fabry-related kidney disease are to stabilize and prevent the progressive decline in kidney function and to reduce proteinuria to less than 500 mg/day. These goals can be primarily achieved only if therapy is introduced at early stages of CKD. (See "Fabry disease: Kidney manifestations".)
●Cardiac – Fabry disease is associated with significant cardiac complications, which are the leading cause of death in males and females with Fabry disease [3,4]. Therapeutic cardiac goals include preventing the development or progression of left ventricular hypertrophy, the development of myocardial fibrosis, as well as the development of heart failure [5]. In patients with heart failure symptoms, additional goals include improving exercise tolerance, normal daily activities, and quality of life. Other goals are the prevention of life-threatening arrhythmias including heart block, severe bradyarrhythmias, and malignant ventricular arrhythmias. (See "Fabry disease: Cardiovascular disease".)
●Neurologic – Patients with classic Fabry disease commonly have a small fiber peripheral neuropathy that contributes to neuropathic pain, impaired sweating, and other sensory deficits. In addition, the development of chronic white matter hyperintensities in the central nervous system, likely representing cerebral vasculopathy or arrhythmia-induced ischemic events, contributes to an increased risk of ischemic and hemorrhagic cerebrovascular events [6]. Therapeutic goals include management of acute and chronic neuropathic pain and prevention of ischemic stroke and transient ischemic attacks (TIAs). (See "Fabry disease: Neurologic manifestations".)
●Gastrointestinal – Gastrointestinal symptoms are common in patients with classic Fabry disease and include abdominal pain, diarrhea, constipation, nausea, and vomiting. In patients who have symptoms of gastrointestinal involvement, the goals of therapy are to reduce these symptoms to improve quality of life. (See "Fabry disease: Clinical features and diagnosis", section on 'Classic Fabry disease'.)
●Other manifestations – Other clinical manifestations of Fabry disease include dermatologic, ophthalmologic, bone [7], and pulmonary manifestations [8], as well as hearing loss, tinnitus, Raynaud phenomena, lymphedema, and neuropsychiatric complaints. Goals of therapy for these manifestations should focus on management of symptoms with the use of adjunctive therapies. (See 'Other clinical manifestations' below.)
FABRY-SPECIFIC THERAPY
Overview — Available Fabry-specific therapies include enzyme replacement therapy (ERT) and pharmacologic chaperone therapy (ie, migalastat hydrochloride).
●ERT – ERT consists of providing affected patients with the deficient enzyme, alpha-galactosidase A (alpha-Gal A). Three formulations of recombinant human alpha-Gal A are available: agalsidase alfa (Replagal), agalsidase beta (Fabrazyme), and pegunigalsidase alfa-iwxj (Elfabrio). Agalsidase alfa is not approved by the US Food and Drug Administration but is available in other countries. Pegunigalsidase alfa is a novel pegylated recombinant alpha-Gal A that was designed to provide a prolonged plasma half-life and potentially reduce the incidence of anti-drug antibodies [9,10]. Agalsidase alfa is generally prescribed at 20 percent of the dose of agalsidase beta. The overall efficacy of the two available agalsidases has not been directly compared in long-term randomized trials [11]. Pegunigalsidase alfa was found to be noninferior to agalsidase beta in slowing the decline of kidney function in a randomized controlled trial [10]. (See 'Enzyme replacement therapy' below.)
●Migalastat – Migalastat is an oral pharmacologic chaperone that binds to and stabilizes specific mutant forms of alpha-galactosidase, thereby facilitating proper trafficking of the enzyme to lysosomes and increasing enzyme activity [12]. Migalastat has been approved in the United States, Canada, and Europe for use as first-line therapy in patients with Fabry disease who have amenable galactosidase alpha (GLA) gene variants. Migalastat should not be used in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. (See 'Chaperone therapy (migalastat)' below.)
The estimated retail cost of therapy with agalsidase beta for one year is approximately USD $300,000 in the United States and Europe. By comparison, the price of migalastat is USD $315,000 per year. Insurance coverage for these therapies as well as patient assistance programs is available.
Indications and timing of therapy — Although expert guidelines are available [2,13-18], there are no uniform recommendations for the use of Fabry-specific therapy. Clinical practice may vary significantly among different countries. Our recommendations are largely consistent with contemporary guidelines and are guided by the patient's clinical phenotype and genetics. Whenever possible, treatment should be guided by an expert in the management of Fabry disease. (See 'Clinical phenotypes' above.)
Males with classic Fabry disease — For all males with classic Fabry disease (ie, with very low or undetectable levels of alpha-Gal A), we suggest Fabry-specific therapy plus supportive care, rather than supportive care alone. We typically initiate Fabry-specific therapy as soon as possible after the diagnosis is established in adults. In patients who are very young, the timing of initiation of therapy must be weighed against the burdens and possible complications of therapy [17]. The choice of Fabry-specific therapy is discussed below. (See 'Choice of therapy' below.)
Evidence in support of Fabry-specific therapy in males with classic Fabry disease comes from a few randomized, placebo-controlled trials and several observational studies that have examined the efficacy and safety of ERT (agalsidase alfa or beta); data for migalastat are more limited. Studies in adults have shown that ERT reduces tissue deposition of globotriaosylceramide (Gb3) and may slow the decline of glomerular filtration rate (GFR), reduce left ventricular wall thickness and/or mass, and possibly reduce neuropathic pain [19]. Studies in children have also shown benefits with ERT, including reduction in tissue Gb3 accumulation [20] and potentially reduced pain, improved gastrointestinal symptoms, and increased quality of life [20]. ERT has not been clearly shown in randomized trials to improve patient survival or reduce important clinical endpoints (ie, end-stage kidney disease [ESKD], cardiovascular events, and stroke). However, observational data suggest that the incidence of these clinical endpoints decreases after the first six months of ERT and remains stable thereafter [21,22]. Patients with late manifestations of disease (such as advanced cardiac fibrosis or significant clinical kidney manifestations) at the time of initiation of ERT do not appear to benefit to the same extent as those who initiate ERT at earlier stages of disease [23-28]. Outcomes for different organ systems are summarized below:
●Kidney outcomes – The efficacy of ERT on Fabry-related kidney disease in males with classic Fabry disease has been evaluated by several studies, which have collectively reported the following outcomes:
•Observational studies in adult males have shown that long-term treatment with ERT can result in complete clearance of Gb3 deposits from mesangial and glomerular endothelial cells and can reduce podocyte Gb3 deposits in a dose-dependent manner [24,25].
•Short-term clinical trials and long-term observational studies suggest that ERT may slow progressive decline of kidney function and attenuate the early development of albuminuria [26,29-33]. As an example, in a retrospective analysis that compared outcomes of 740 patients who received agalsidase alfa for a median of five years with those of untreated historical controls, males with a baseline of eGFR <60 mL/min/1.73 m2 had a mean annualized change in eGFR of -2.9 mL/min/1.73 m2 compared with -6.8 mL/min/1.73 m2 in the untreated cohort [32]. Another observational study that followed 151 male patients for 24 months found that early treatment with agalsidase beta was associated with a reduced slope of eGFR decline [26]. One randomized trial found comparable rates of GFR loss (expressed as mean annualized eGFR slope decline) over two years with pegunigalsidase alfa compared with agalsidase beta [10]. In general, patients with less kidney involvement at the time of initiating ERT appear to benefit more from therapy than those who have more advanced kidney disease [23,26,34,35].
•There is no high-quality evidence showing that ERT reduces the risk of ESKD. Such studies are difficult to perform given the rare nature of the disease, phenotypic variation, and variability in the age of initiation of therapy. In long-term observational studies that followed male patients on ERT for up to 10 years, rates of ESKD have ranged from 7 to 10 percent [23,28,36]. By comparison, in one study, prior to the institution of ERT, ESKD developed in 18 percent of males over a median of 12 years [37]. In another pre-ERT-era study, the incidence of ESKD among males with likely classic Fabry disease exceeded 50 percent by age 50 years and was 100 percent in those surviving to age 60 years [38]. However, assessing the impact of ERT on ESKD based upon these studies is difficult given the changing nature of inclusion criteria and differences in sex, clinical phenotype, and duration of follow-up between the studies. (See 'Prognosis' below.)
Data for migalastat are more limited. In a trial that randomly assigned 50 patients with confirmed amenable GLA variants to oral migalastat or placebo every other day for six months, followed by open-label migalastat for up to an additional 18 months, those treated with migalastat had a greater reduction in Gb3 inclusions per kidney peritubular capillary at six months than those receiving placebo [39]. There were no differences in the change in estimated or measured GFR from baseline to month 6 in either treatment group. Over 24 months, the mean annualized change from baseline in estimated and measured GFR were -0.30 and -1.51 mL/min/1.73 m2, respectively. An analysis of paired kidney biopsies of eight males in the trial at baseline and after six months of migalastat found a reduction in podocyte Gb3 inclusions that correlated with a reduction in podocyte foot process width [40].
Observational studies have also reported long-term stability of kidney function for up to nine years of migalastat treatment [41,42]. However, the degree to which the specific type of GLA variant, the point in the natural history when treatment was started, sex, and other potential variables impact the stability of kidney function cannot be discerned. No comparative data were presented in these studies.
●Cardiac outcomes – Data from one small randomized, placebo-controlled trial and observational studies have shown that long-term ERT or migalastat treatment can reduce left ventricular wall thickness and stabilize or improve left ventricular mass [27,43,44]. However, patients who already have advanced cardiac fibrosis at the time of initiating ERT may not benefit to the same degree [44,45]. The impact of ERT on the risk of cardiovascular events (such as heart failure or myocardial infarction) remains unclear.
In the randomized trial comparing migalastat with placebo cited above, among patients in both placebo and migalastat groups who received migalastat for up to 18 to 24 months in the open-label extension, there was a significant improvement in left ventricular mass index compared with baseline [39].
●Neurologic outcomes – Data are mixed regarding the effect of ERT on neuropathic pain, with some, but not all, studies showing that ERT decreases pain symptoms [11,46]. The effects of ERT on the risk of stroke or transient ischemic attack (TIA) are unclear [47]. In long-term observational studies that followed male patients on ERT for up to 10 years, rates of stroke have ranged from 5 to 10 percent [23,28,36]; by comparison, in one study, prior to the institution of ERT, 11 percent of males developed a stroke over a median of 12 years [37]. Another study found that ERT institution before rather than after severe Fabry-related events was associated with fewer on-ERT strokes [36]. However, assessing the impact of ERT on stroke based upon these studies is limited by the changing nature of how studies in patients with Fabry disease were performed, as well as by differences in clinical phenotype and methods used to reduce stroke risk between the studies.
●Gastrointestinal outcomes – Data from observational studies suggest that ERT may partially relieve Fabry-associated gastrointestinal symptoms in males [48-52]. As an example, in one study, sustained treatment with agalsidase beta was associated with a reduction in the prevalence of self-reported abdominal pain (41 versus 56 percent at baseline) and diarrhea (47 versus 57 percent at baseline) over a median of 4.7 years and 5.5 years, respectively [52].
In the randomized trial comparing migalastat with placebo cited above, patients in both placebo and migalastat groups who received migalastat for up to 18 to 24 months in the open-label extension experienced a reduction in gastrointestinal symptoms including diarrhea, reflux, and indigestion [39].
●Quality of life – Some [51,53-55], but not all [56,57], studies have shown that ERT may improve quality of life measures among males with classic Fabry disease.
Female heterozygotes — For female heterozygotes who have clinical symptoms or signs of major organ involvement (ie, kidney, cardiac, neurologic, gastrointestinal), we suggest Fabry-specific therapy plus supportive care, rather than supportive care alone. For asymptomatic female heterozygotes with laboratory, histologic, functional, or radiologic evidence of major organ injury, we suggest Fabry-specific therapy plus supportive care, rather than supportive care alone. In asymptomatic females whose baseline evaluation does not reveal evidence of major organ injury, some experts perform a kidney biopsy to determine the extent of histologic involvement and treat with Fabry-specific therapy if substantial Gb3 accumulation is observed. Truly asymptomatic females generally do not receive Fabry-specific therapy but should be monitored every two to three years for the development of new symptoms or signs of Fabry disease. If decisions regarding initiation of Fabry-specific therapy are unclear, testing for skewed X-chromosome inactivation, which has been associated with greater risks for adverse clinical outcomes in females with Fabry disease, can also be considered although this testing is not widely available [58]. The choice of Fabry-specific therapy is discussed below. (See 'Choice of therapy' below.)
Evidence in support of Fabry-specific therapy in symptomatic females with Fabry disease comes primarily from observational studies examining the efficacy and safety of ERT. The randomized trials evaluating ERT enrolled primarily males with classic Fabry disease, and it is uncertain if these results can be broadly extrapolated to females, given their varied phenotypes. Studies in females have shown that ERT reduces plasma and urine Gb3 in those with elevated pretreatment levels and may reduce left ventricular mass and improve quality of life [59]. As with males with Fabry disease, there are no randomized trials showing that ERT improves patient survival or reduces the risk of other important clinical endpoints (ie, ESKD, cardiovascular events, and stroke). However, observational data suggest that the incidence rate of these clinical endpoints decreases after the first six months of ERT and remains stable thereafter [21]. Even more than in males, females with a history of pre-ERT clinical events have been shown to have higher incidence rates of on-ERT clinical events compared with those without pre-ERT events [36]. Outcomes for different organ systems are summarized below:
●Kidney outcomes – Data on kidney outcomes in females are provided by a few single-arm clinical trials and multiple observational studies and case reports, which have collectively shown that long-term treatment with ERT may stabilize eGFR but does not appear to have an effect on proteinuria [26,27,31,51,60-62]. ERT also reduces Gb3 deposits within the kidney in females [25].
There are no data from randomized trials showing that ERT reduces the risk of ESKD in females, and it appears unlikely that this outcome will be evaluated in future clinical trials in females with Fabry disease [63]. In one long-term observational study that followed 442 females for a median of 3.2 years, 2 percent developed ESKD [36]; by comparison, in a study of 168 females prior to the initiation of ERT, 5 percent developed ESKD over a median of 12 years [37]. However, there may be some bias in these studies since females who are initiated on ERT generally have more severe disease.
●Cardiac outcomes – Observational studies in females receiving ERT have found that ERT can stabilize or improve left ventricular mass [31,51,60,61,64]. However, the impact of ERT on the risk of cardiovascular events (such as heart failure or myocardial infarction) remains uncertain.
●Neurologic outcomes – Data are mixed regarding the effect of ERT on neuropathic pain, with some [61,65], but not all [51], studies showing that ERT decreases pain symptoms in females. The effects of ERT on the risk of stroke or TIA in females are unclear [47]. In one long-term observational study that followed 442 female patients on ERT for up to 3.2 years, the rate of stroke was 3 percent [36]. By comparison, prior to the institution of ERT, one study reported that 8 percent of females developed a stroke over a median of 12 years [37].
●Gastrointestinal outcomes – ERT may improve gastrointestinal symptoms in some females with Fabry disease. In an analysis of 168 female patients enrolled in the Fabry Registry who were treated with agalsidase beta for a median of 5.7 years, the proportion of patients reporting abdominal pain decreased from 45 percent at baseline to 31 percent, and the proportion of patients reporting diarrhea decreased from 39 percent at baseline to 27 percent [66].
●Quality of life – Some [55,60], but not all [51,56,57], studies have shown that ERT may improve quality of life measures among females with Fabry disease.
Patients with later-onset variants — For males or females with later-onset variants who have symptoms or signs of major organ involvement (ie, kidney, cardiac, neurologic, gastrointestinal), we suggest Fabry-specific therapy plus supportive care, rather than supportive care alone. The choice of Fabry-specific therapy is discussed below. (See 'Choice of therapy' below.)
There are no randomized trials evaluating the efficacy of Fabry-specific therapy in patients with later-onset variants of Fabry disease. Available data are limited to mostly small observational studies evaluating the effects of ERT [19,67-71]. Collectively, these studies suggest that ERT may improve certain cardiac parameters and stabilize kidney function. It should be noted, however, that the majority of patients with later-onset variants will not develop ESKD if untreated [72]. The impact of ERT on survival and other important clinical endpoints such as ESKD and cardiovascular events is not known. In a study that included 37 males with later-onset disease, ERT with agalsidase alfa or beta was associated with a reduction in left ventricular mass index [70].
Patients with ESKD — Some patients develop end-stage kidney disease (ESKD) and require dialysis or kidney transplantation before they are diagnosed with Fabry disease or before Fabry-specific therapy is initiated. Such patients may be considered for ERT on an individual basis, particularly if they experience quality-of-life issues such as neuropathic pain or bothersome gastrointestinal symptoms [13,19]. However, the potential benefits of ERT in this patient population are supported by very limited evidence, and initiating treatment with ERT should be weighed against the cost and burden of long-term therapy. Migalastat is contraindicated in patients with an eGFR <30 mL/min/1.73 m2.
Limited evidence suggests that patients with Fabry disease on dialysis may also benefit from treatment. These reported benefits are based on subjective improvement in self-reported symptoms such as heat intolerance, gastrointestinal symptoms, abdominal pain, pain medication usage, and acroparesthesias [73,74]. In addition, studies on the effects of ERT on neuropathic pain in patients on dialysis may be confounded by the presence of uremic polyneuropathy in these patients. (See "Uremic polyneuropathy".)
Similarly, ERT may benefit patients with Fabry disease who have undergone kidney transplantation. One study found slower rates of GFR decline among transplant recipients treated with ERT compared with those not treated with ERT [75]. Other studies have observed a slower increase in left ventricular mass index in transplanted patients receiving ERT [75,76].
Choice of therapy — Available Fabry-specific therapies include ERT (agalsidase alfa, agalsidase beta, or pegunigalsidase alfa) and pharmacologic chaperone therapy (migalastat hydrochloride). For patients who have an indication for Fabry-specific therapy, the choice between ERT and migalastat is influenced by factors such as the amenability of the patient's GLA variant to migalastat, patient age, baseline kidney function, and patient and clinician preference (algorithm 1).
●Patients who do not have an amenable GLA gene variant, whose baseline eGFR is <30 mL/min/1.73 m2, or who are <18 years old (or <12 years old if living in the European Union) should receive ERT (agalsidase alfa or beta). Those who are >18 years old may be treated with pegunigalsidase alfa. The choice of ERT is frequently dictated by insurance coverage and cost. Migalastat should not be used in patients without an amenable GLA gene variant or with an eGFR <30 mL/min/1.73 m2. Migalastat is not yet approved in the United States for individuals <18 years old but is approved in the European Union for children ≥12 years old.
●In patients who have an amenable GLA gene variant, whose baseline eGFR is ≥30 mL/min/1.73 m2, and who are ≥18 years old (or ≥12 years old if living in the European Union), both ERT and migalastat are potential treatment options.
•In patients who are initiating Fabry-specific therapy for the first time, we engage in shared decision-making regarding the choice between ERT and migalastat. Patients who are already receiving treatment with ERT can be offered the option of switching to migalastat if desired. We inform patients that there is much more long-term clinical experience with ERT than with migalastat, and data directly comparing these two therapies are limited. Migalastat offers the convenience of oral dosing, compared with biweekly infusions with ERT, and is not impacted by antibody formation as may occur with ERT. In addition, migalastat is a small molecule that, unlike ERT, has a wide organ and cellular penetration and therefore may have the potential for a better metabolic correction [77]. However, treatment adherence with migalastat must be monitored. (See 'Anti-agalsidase antibodies' below.)
•If the patient is interested in migalastat therapy, we first test the patient's alpha-Gal A leukocyte activity at baseline to confirm that the GLA gene variant is associated with deficient enzyme activity (ie, ≤35 percent of the mean normal).
Once it has been confirmed that the patient has true enzyme deficiency, we assess if the patient's GLA gene variant is likely to result in a substantial increase in enzyme level (ie, increase in alpha-Gal A leukocyte activity close to or above the 35 percent disease threshold) with migalastat therapy. This can be determined by reviewing a published set of known genetic variants that have been tested for their response to migalastat in vitro [78] or accessing an online website that is updated with amenability data. Patients with a GLA gene variant that is likely to result in a substantial increase in enzyme level can be treated with migalastat instead of ERT. Patients with a GLA gene variant that is not likely to result in a substantial increase in enzyme level (eg, an increase from 1 to 6 percent of the mean normal) may not benefit from migalastat. In such patients, we treat with ERT.
In vitro amenability testing does not always predict in vivo clinical responses in migalastat-treated patients [79]. Thus, in patients started on migalastat, clinical and biochemical evidence of amenability (ie, increased alpha-Gal A leukocyte activity and/or decreased plasma globotriaosylsphingosine [lysoGb3] levels) should be confirmed again after 4 to 12 weeks of therapy [79]. If there is no significant improvement in these parameters, the patient can be given the option of switching to ERT.
The efficacy and safety of ERT and migalastat in patients with different clinical phenotypes are presented elsewhere in this topic. (See 'Indications and timing of therapy' above.)
There are few studies that have directly compared the efficacy of agalsidase alfa and agalsidase beta with respect to clinical outcomes. In a multicenter retrospective study of 387 patients with Fabry disease (192 females; 248 on agalsidase alfa and 139 on agalsidase beta), rates of clinical events (defined as stage 5 chronic kidney disease [CKD], kidney transplantation or dialysis, implantation of an implantable cardiac defibrillator or pacemaker, stroke or TIA, or death) over a mean of 4.9 years were similar among patients receiving agalsidase alfa and those receiving agalsidase beta (26 and 27 percent, respectively) [80]. However, treatment with agalsidase beta was associated with a larger decrease in lysoGb3 concentrations compared with agalsidase alfa. Among patients with baseline left ventricular hypertrophy, a higher proportion had a decrease in left ventricular mass index after one year of treatment with agalsidase beta than with agalsidase alfa (79 versus 62 percent). Pegunigalsidase alfa has been shown to have similar rates of eGFR decline and plasma lyso-Gb3 concentrations as agalsidase beta [10].
Data directly comparing ERT with migalastat are also limited. In one trial, 57 adults with Fabry disease who were previously treated with ERT (37 with agalsidase alfa, 19 with agalsidase beta) were randomly assigned to receive 18 months of migalastat or continued treatment with ERT [81]. More than one-half (56 percent) of the patients were female, and most (88 percent) had multiorgan disease at baseline; the average duration of ERT prior to the start of the trial was approximately three years. Nearly two-thirds of the patients who received ERT before and during the trial received low-dose ERT (0.2 mg/kg every two weeks). At 18 months, migalastat and ERT had comparable effects on kidney function (mean annualized change in eGFR -0.40 versus -1.03 mL/min per 1.73 m2, respectively). Left ventricular mass index decreased from baseline in patients on migalastat but did not change significantly in those on ERT. There was no significant difference in the rate of kidney, cardiac, or cerebrovascular events or treatment-related adverse events between the two groups, but the power was limited to detect differences given the small sample size. Studies comparing migalastat with agalsidase beta at 1 mg/kg every 2 weeks are still needed.
Enzyme replacement therapy — ERT consists of providing affected patients with the deficient enzyme, alpha-Gal A. Three formulations of recombinant human alpha-Gal A are available: agalsidase alfa (Replagal), agalsidase beta (Fabrazyme), and pegunigalsidase alfa (Elfabrio).
Dosing and administration
●Dosing – ERT doses are as follows:
•Agalsidase alfa (Replagal) – 0.2 mg/kg or 0.4 mg/kg as an intravenous infusion every two weeks
•Agalsidase beta (Fabrazyme) – 1 mg/kg as an intravenous infusion every two weeks
•Pegunigalsidase alfa (Elfabrio) – 1 mg/kg as an intravenous infusion every two weeks
Therapy should be continued at these doses indefinitely, if possible, for the following reasons:
•Gb3 clearance from tissues, once achieved, may not be maintained in patients who are switched to a lower dose. In one study, for example, standard-dose agalsidase beta for six months cleared Gb3 from the kidney endothelium and skin of 21 patients with Fabry disease [82]. Following a dose reduction (0.3 mg/kg every two weeks) that was administered for the subsequent 18 months, kidney endothelial and skin clearance was maintained in only 70 to 90 percent of patients, suggesting that the lower dose may not be adequate in all patients.
•Due to a shortage of agalsidase beta in 2009, 67 of 105 stable patients receiving 1 mg/kg every two weeks either switched to agalsidase alfa (38 patients) or had their agalsidase beta dose reduced to 0.3 to 0.5 mg/kg every two weeks (29 patients) [83]. After one year, both lower-dose ERT groups developed more frequent and more severe pain attacks. There was also a greater increase in albuminuria in the group switched to agalsidase alfa and a faster decline in kidney function in the group with reduced agalsidase beta dose, as compared with those who remained on higher doses of agalsidase beta.
●Administration – Given that infusion reactions may occur, ERT should be given slowly, and some, but not all, clinicians routinely administer pretreatment with antipyretics (acetaminophen 650 mg, 30 minutes prior to infusion). In the original ERT trials, agalsidase alfa was given over 40 minutes [29], and agalsidase beta was ultimately given over a mean of 2 to 2.5 hours (approximately 10 percent of patients required a slower infusion) [84]. With agalsidase beta, the initial infusion rate should not exceed 15 mg/hour. If the patient tolerates the initial infusion, the infusion rate can be progressively increased by 3 to 5 mg/hour with each subsequent infusion until the minimum infusion time of 1.5 hours is reached or the patient develops an infusion reaction. Since infusion reactions only rarely occur in females, some experts choose to initiate ERT in females at a faster infusion rate. (See 'Infusion reactions' below.)
With pegunigalsidase alfa, the recommended infusion rate for the initial four to six infusions is based on actual body weight depending on whether the patient is ERT-experienced or ERT-naïve [85]. If a patient tolerates the initial four to six infusions, the duration of every third infusion may be decreased in decrements of 30 minutes as tolerated. The minimum recommended infusion duration is 1.5 hours.
●Home therapy – ERT is initially administered in a clinical setting. However, home therapy with ERT is the preferred option for many patients who have uneventful infusions. Transitioning to home therapy is usually done after a minimum of four to six infusions, but timing may vary and may be dictated by insurance regulations.
The safety and feasibility of long-term home infusions was examined in a study of 36 (17 males) carefully selected patients with Fabry disease in the Netherlands [86]. Patients were treated with either agalsidase alfa or beta at a dose of 0.2 mg/kg, which they self-administered without medical supervision via a butterfly needle. Only six adverse events (chills or fever) occurred in six of these patients out of a total of over 1400 infusions, only three of which were at home. Hypotension or anaphylactoid events were not reported. Those who had a reaction were able to resume therapy with oral dexamethasone premedication without further adverse events. This low rate of adverse events may be due to the fact that the dose of agalsidase beta in this study was substantially lower than in previous studies (0.2 versus 1 mg/kg). Another study of 79 patients (41 males) found that even patients with anti-agalsidase antibodies could be safely infused at home after 13 infusions in a center [87]. However, adverse events can occur in antibody-positive patients following increases in the speed of infusion; in such patients, the speed of infusion should be decreased. (See 'Anti-agalsidase antibodies' below.)
Adverse effects — Common side effects with ERT include infusion reactions and seroconversion (ie, the development of antibodies to either agalsidase alfa or agalsidase beta). Anaphylactic reactions are rare.
Infusion reactions — In the initial ERT trials, over 60 percent of participants (mainly males with the classic phenotype) developed rigors, fevers, or other infusion reactions, which tended to diminish over time and were readily controlled with premedication [29,84].
Infusion reactions were less frequent in some later studies of agalsidase alfa and beta (reported to occur in <20 percent), perhaps due to slower infusion rates and the use of pretreatment medications [88,89]. In these later studies, infusion reactions were generally mild and did not preclude resumption of treatment [89].
If the patient develops an infusion reaction, which is usually manifested by fever, tachycardia, rigors, hyper- or hypotension, and dyspnea, we proceed in the following way:
●Stop the infusion.
●Administer intravenous (IV) diphenhydramine, 0.5 to 1 mg/kg, not to exceed 50 mg.
●If the reaction is severe, we also administer IV hydrocortisone, 1 to 2 mg/kg (not to exceed 100 mg), or IV methylprednisolone 125 mg.
●If the reaction resolves and the patient has normal vital signs, we restart the infusion at a slower rate (usually by 50 to 100 percent of the originally planned infusion duration; eg, 80 minutes for agalsidase alfa and four hours for agalsidase beta).
In patients who have had a mild infusion reaction, pretreatment with both oral acetaminophen and diphenhydramine should be given prior to subsequent doses. In patients who have had moderate to severe infusion reactions, pretreatment with oral diphenhydramine (0.5 to 1 mg/kg, maximum dose 50 mg), famotidine (40 mg), and prednisone (2 mg/kg or 50 to 60 mg) should be given the night before and two hours prior to therapy; alternatively, IV methylprednisolone 125 mg can be given at the time of infusion. In addition, all patients with prior infusion reactions should receive ERT more slowly, with durations 50 to 100 percent longer than the duration in patients without infusion reactions.
If subsequent infusions are well tolerated, we continue the described pretreatment regimen for six months. Infusion reactions tend to diminish with longer duration of ERT. Thus, if no subsequent infusion reactions occur, we begin to slowly titrate off premedications. If no complications occur, we then begin to gradually shorten the duration of the infusion.
If infusion reactions continue despite these pretreatment regimens, other options include the addition of H1 antihistamines (eg, loratadine, cetirizine) or, in severe cases that specifically involve dermatologic manifestations, cromolyn. Tolerization protocols have also been used with some success in patients with Fabry disease [90].
Although the foregoing approach describes our practice in most patients, highly individualized regimens may be required to prevent infusion reactions in some patients. However, once induced, antidrug antibodies are difficult to reduce.
Anti-agalsidase antibodies — Antibodies to recombinant agalsidase alfa and agalsidase beta have been found to develop in 64 to 88 percent of patients receiving ERT in clinical trials [29,84,91]. In one open-label extension study, three patients were withdrawn for positive serum immunoglobulin E (IgE) or skin tests [88]. However, all later successfully resumed therapy, and none developed anaphylaxis.
Although earlier studies suggested that there was no correlation between the production of anti-agalsidase antibodies and clinical events [92], subsequent studies have found that the presence of such neutralizing antibodies may lower the efficacy of ERT [93,94]. As an example, an analysis of 168 patients with Fabry disease treated with ERT found that agalsidase inhibition (present in 40 percent) was associated with higher lysoGb3 levels, worse disease severity scores, greater left ventricular mass, and substantially lower GFR compared with no agalsidase inhibition [93]. In addition, agalsidase inhibition was associated with more Fabry disease symptoms, including worse diarrhea, fatigue, and neuropathic pain. Only higher ERT doses can compensate for these neutralizing antibodies [94,95]. However, increased immunosuppression was associated with lower antibody titers and reduced ERT inhibition in a group of male Fabry disease kidney and heart transplant recipients [96]. Further prospective studies are required to assess the long-term clinical impact of the seroconversion and to determine whether those with high antibody titers will require different dosing schedules.
An alloimmune form of membranous nephropathy (MN) has been documented in rare patients receiving ERT with recombinant human acid alglucosidase alfa for lysosomal acid alpha-glucosidase deficiency (Pompe disease) and with recombinant aryl-sulfatase B for mucopolysaccharidosis type VI. In both cases, the recombinant enzyme was detected and colocalized with immunoglobulin G (IgG) in the glomerular immune deposits. Although MN has not yet been reported in patients with Fabry disease receiving ERT, clinicians should be aware of the possibility of developing alloimmune MN due to an immunologic reaction to ERT in such patients. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Enzyme replacement therapy'.)
Monitoring for anti-agalsidase antibodies is discussed below. (See 'Monitoring' below.)
Discontinuation of ERT — A consensus statement from the European Fabry Working Group has recommended that discontinuation of ERT be considered in patients with the following [14]:
●Noncompliance with >50 percent of treatments
●Failure to regularly attend follow-up visits
●Persistent life-threatening or severe infusion reactions that do not respond to prophylaxis (eg, anaphylaxis)
●ESKD, without an option for kidney transplantation, in combination with advanced heart failure (New York Heart Association class IV)
●End-stage Fabry disease or other comorbidities with a life expectancy of <1 year
●Severe cognitive decline of any cause
●Lack of treatment response for one year, when the primary indication for ERT is neuropathic pain while receiving maximum supportive care
The discontinuation of ERT was evaluated in a retrospective study of 75 patients with Fabry disease treated with ERT, of which 21 patients stopped treatment [97]. Compared with patients who remained on ERT, patients who stopped ERT were older at the initiation of treatment, more likely to have had cardiac complications or stroke prior to ERT, and more likely to have an eGFR of <60 mL/min per 1.73 m2. The primary reasons for discontinuing ERT were patient request (eight patients), death or terminal illness (seven patients), and treatment failure (five patients). Although death occurred in 12 of the 21 patients, some patients remained stable at one year after treatment cessation.
Chaperone therapy (migalastat) — Migalastat is an oral pharmacologic chaperone that binds to and stabilizes specific mutant forms of alpha-galactosidase, thereby facilitating proper trafficking of the enzyme to lysosomes and increasing enzyme activity. In preclinical studies, migalastat was shown to increase alpha-Gal A activity and decrease accumulation of Gb3 in cultured human Fabry disease cell lines and in animal models of Fabry disease [12]. Migalastat has been approved in the United States, Canada, and Europe for use as first-line therapy in adult Fabry patients with amenable GLA gene variants. It is approved in the European Union for children ages 12 and above. (See 'Choice of therapy' above.)
●Dosing and administration – Migalastat is administered at a dose of 123 mg (equivalent to 150 mg of migalastat hydrochloride) orally once every other day. It should be taken without consuming food or caffeine two hours before and two hours after each dose to give a minimum four hour fast.
●Adverse effects – Migalastat is generally well tolerated among patients with Fabry disease [98]. The most commonly reported adverse effects include headache (25 to 35 percent), nasopharyngitis (18 to 33 percent), urinary tract infection (15 percent), nausea (12 percent), and pyrexia (12 percent) [39,81].
Investigational therapies — Other Fabry-specific therapies that are under investigation include moss-aGalactosidase A (NCT02995993) [99]; substrate reduction therapy such as venglustat and lucerastat [100,101]; and gene therapy [102].
SUPPORTIVE CARE — All patients with Fabry disease should receive supportive care as indicated to manage the kidney, cardiac, neurologic, and other complications of Fabry disease.
Kidney disease — Patients with Fabry disease are at high risk for progressive kidney failure. Hypertensive patients and/or those with urine protein excretion >500 mg/day should receive an inhibitor of the renin-angiotensin system (RAS), such as an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Whether RAS blockade is beneficial for patients with Fabry disease who are normotensive or have urine protein excretion less than 500 mg/day is unclear. In addition, patients should receive standard care for complications of chronic kidney disease (CKD), and, when required, dialysis and/or transplantation. (See "Overview of the management of chronic kidney disease in adults".)
ACE inhibitors and ARBs — Patients with Fabry disease who are hypertensive or who have proteinuria >500 mg/day should receive an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to lower the blood pressure and reduce proteinuria. This approach is similar to that for adult patients with CKD due to other causes who have hypertension and/or proteinuria. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)
Patients with Fabry disease who continue to have >500 mg/day of proteinuria despite maximal doses of an ACE inhibitor or ARB or who have CKD may benefit from treatment with a sodium-glucose cotransporter 2 inhibitor although there are no data specifically in patients with Fabry disease. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)
Blood pressure goals in patients with Fabry disease and nephropathy are similar to those in patients with other forms of kidney disease. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
Data are limited on the use of RAS inhibitors in addition to Fabry-specific therapy in patients with Fabry disease [103-105]. As examples:
●A small series of 11 patients treated with RAS inhibitors suggested that these drugs are associated with a reduction in proteinuria and stabilization of the estimated glomerular filtration rate (eGFR) [103]. Similarly, another study found that patients achieving proteinuria reduction to or below 0.5 g/g creatinine with RAS inhibitors had slower rates of eGFR decline; however, these patients still had more than three times the expected rate of eGFR loss [105].
●However, a larger study compared the decline in eGFR and proteinuria in 84 patients treated with RAS inhibitors with 124 patients not treated with RAS inhibitors; all patients received enzyme replacement therapy (ERT) [104]. After more than five years, eGFR decline and proteinuria were nonsignificantly worse (not better) in patients treated with RAS inhibitors. Baseline information was not given about those treated and not treated with RAS inhibitors, and it is possible that RAS inhibitors appeared ineffective because the patients who received them had more advanced kidney disease at the start. On the other hand, ERT may mitigate the beneficial effects of RAS inhibitors by directly inhibiting the angiotensin-converting enzyme [106].
Dialysis — Patients with Fabry disease who develop end-stage kidney disease (ESKD) may require maintenance dialysis. Both hemodialysis and peritoneal dialysis are potential modalities, and there is no evidence to support the use of one dialysis modality over the other.
In general, patients with Fabry disease fare worse with maintenance dialysis than other patients with ESKD. Overall survival is lower among patients with Fabry disease than in non-Fabry controls:
●In a study of 42 patients who initiated dialysis between 1995 and 1997, 64 and 34 percent were treated with hemodialysis and peritoneal dialysis, respectively, with one patient being preemptively transplanted [107]. Three-year survival was slightly lower among these patients compared with control patients with nondiabetic ESKD (70 and 76 percent, respectively).
●In a European Renal Association-European Dialysis and Transplant Association report that described patients initiating kidney replacement therapy between 1975 and 1993, five-year survival on dialysis was lower among patients with Fabry disease compared with the general dialysis population (41 versus 68 percent) [108].
Among patients with Fabry disease, the need to initiate kidney replacement therapy has been associated with a reduced quality of life [109]. Whether ERT affects the survival of patients with Fabry disease who are on dialysis is unknown. In addition, survival of patients with Fabry disease who are on dialysis as a bridge to transplantation is also unknown.
Transplantation — Patients with Fabry disease who develop ESKD are potential candidates for kidney transplantation. The evaluation of the potential kidney transplant recipient is discussed elsewhere. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
Graft and patient outcomes among transplant recipients with Fabry disease appear to be comparable with those of recipients who have ESKD due to other causes [76,110-112]. The following studies illustrate the range of findings:
●In one study that compared 93 transplant recipients with ESKD due to Fabry disease with a matched cohort of 186 recipients transplanted for ESKD due to other causes, five-year patient and graft survival were similar in patients with and without Fabry disease (83 and 75 percent versus 82 and 67 percent, respectively) [111].
●In another study of 17 kidney transplant recipients with Fabry disease who were followed for a median of 11.5 years (range, 0.8 to 25.5 years), graft survival was similar to that of matched controls without Fabry disease [76]. Patient survival among those with Fabry disease was 100 percent at 10 years, 67 percent at 15 years, and 25 percent at 20 years. Most deaths were attributed to cardiac events.
●However, one study that compared 197 kidney recipients with Fabry disease with a matched cohort of 1970 transplant recipients with other causes of ESKD found lower five-year patient survival among those with Fabry disease (81 versus 90 percent) [112]. Five-year graft survival was similar between the two groups. Cardiovascular complications were the leading cause of death in both Fabry and non-Fabry study populations. It should be noted that most patients in this study were followed during the pre-ERT era.
In general, clinically significant Fabry kidney disease does not recur in the transplanted kidney, although some recipients may develop endothelial cell globotriaosylceramide (Gb3) deposition that does not compromise graft function. As an example, the examination of kidney allograft tissue obtained six and eight months after transplantation has shown Fabry inclusions in vascular endothelial cells [113], possibly of recipient origin [114,115].
Cardiovascular disease — Patients with Fabry disease with cardiac manifestations should generally receive standard therapies for heart disease, including antianginal medication for angina, standard antiarrhythmic therapy (including preventive implantation of cardioverter-defibrillators in some patients with advanced cardiomyopathy), and guideline-directed therapy for heart failure. Heart transplantation is also feasible in patients with Fabry disease [116]. These issues are discussed in more detail elsewhere. (See "Fabry disease: Cardiovascular disease", section on 'Management'.)
Neurologic disease — Patients with chronic neuropathic pain may benefit from treatment with carbamazepine, gabapentin, or other anticonvulsants, as discussed separately. (See "Fabry disease: Neurologic manifestations", section on 'Pain relief'.)
Patients with Fabry disease should receive standard measures for primary or secondary prevention of ischemic stroke, as discussed elsewhere. (See "Fabry disease: Neurologic manifestations", section on 'Stroke prevention'.)
Other clinical manifestations — Patients with Fabry disease may require treatment for other clinical manifestations, including gastrointestinal symptoms, lower extremity lymphedema, depression or anxiety, telangiectasias and angiokeratomas, erectile dysfunction, and hearing loss (see "Fabry disease: Clinical features and diagnosis", section on 'Clinical presentation'):
●Gastrointestinal symptoms – Gastrointestinal symptoms, such as abdominal pain, recurrent nausea and vomiting, and either diarrhea or constipation, occur commonly among Fabry disease patients. We treat patients with such symptoms with an approach similar to that used in patients with irritable bowel syndrome who have functional gastrointestinal symptoms, as discussed elsewhere. In one case series, treatment with oral alpha-galactosidase as a dietary supplement (600 units three times daily) resulted in an improvement of gastrointestinal symptoms (mostly abdominal pain and diarrhea) [117]. (See "Approach to functional gastrointestinal symptoms in adults with inflammatory bowel disease" and "Treatment of irritable bowel syndrome in adults".)
●Lymphedema – In patients with Fabry disease, it is important that peripheral lymphedema not be confused with fluid retention from kidney or cardiac causes as this could lead to inappropriate fluid and salt restriction and diuresis. The management of peripheral lymphedema is discussed elsewhere. (See "Lower extremity lymphedema", section on 'Conservative care' and "Clinical staging and conservative management of peripheral lymphedema", section on 'Overview of management'.)
●Depression and anxiety – Depression and anxiety are common in Fabry disease, often overlooked, and consequently often left untreated despite their substantial contribution to decreased quality of life. The diagnosis and treatment of depression are discussed elsewhere. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)
●Dermatologic manifestations – Dermatologic manifestations of Fabry disease (telangiectasias and angiokeratomas) are generally treated in collaboration with a dermatologist. Cosmetic treatment of these skin manifestations and sometimes bleeding complications frequently involves laser therapy, as discussed in more detail elsewhere. (See "Laser and light therapy for cutaneous vascular lesions" and "Laser and light therapy of lower extremity telangiectasias, reticular veins, and small varicose veins".)
●Erectile dysfunction – The treatment of erectile dysfunction is discussed elsewhere. (See "Treatment of male sexual dysfunction", section on 'Erectile dysfunction'.)
●Hearing loss and vertigo – The treatment of hearing loss and vertigo in Fabry disease patients is similar to that in non-Fabry disease patients and is discussed elsewhere. (See "Hearing amplification in adults" and "Treatment of vertigo".)
Sudden deafness can occur in male and female patients with classic Fabry disease [118,119] and should be treated as for patients with idiopathic sudden sensorineural hearing loss. (See "Sudden sensorineural hearing loss in adults: Evaluation and management".)
MONITORING — All patients with Fabry disease should have continued monitoring regardless of whether or not they are receiving therapy [2]. The extent and timing of evaluations should take into consideration a patient's disease manifestations, disease severity, and side effects of therapy.
In all patients who are treated with Fabry-specific therapy, clinical monitoring is as follows:
●We perform a clinical evaluation and obtain routine blood chemistries (including serum creatinine concentration) and a complete blood count every 6 to 12 months.
●We obtain an estimation of the glomerular filtration rate (eGFR) and a urine protein-to-creatinine ratio every three to six months. We use serial measurements of eGFR over time to calculate an eGFR slope and determine the patient's rate of annual kidney function decline; the goal of therapy is to limit the eGFR decline to the normal age-related decline of glomerular filtration rate (GFR). (See 'Goals of therapy' above.)
●In patients with cardiac involvement, we obtain an electrocardiogram every 6 to 12 months. In addition, we obtain an echocardiogram (including measurement of global longitudinal strain) once yearly and/or cardiac magnetic resonance imaging once every three to five years using a Fabry disease-specific protocol [2]. A 48-hour Holter recorder or an event recorder may be considered to detect possible arrhythmias.
●In patients receiving enzyme replacement therapy (ERT), we routinely test for anti-agalsidase antibodies prior to initiation of ERT, then at six months after ERT initiation, and yearly thereafter. Testing for anti-agalsidase antibodies is not required in patients treated with migalastat. (See 'Anti-agalsidase antibodies' above.)
●We measure plasma globotriaosylsphingosine (lysoGb3) levels at least once yearly in patients receiving ERT or migalastat [120]. One study suggested that an increase in plasma lysoGb3 levels while a patient is receiving ERT may indicate the development of anti-agalsidase antibodies, but these findings require further validation in larger studies [93].
Clinical monitoring of patients with Fabry disease who are not receiving Fabry-specific therapy is discussed elsewhere. (See "Fabry disease: Clinical features and diagnosis", section on 'Follow-up assessment'.)
PROGNOSIS — Survival is substantially reduced in untreated males with classic Fabry disease [3]. Median cumulative survival is approximately 50 years, with very few individuals alive after the age of 60 years [38,121]. Most deaths are due to cardiovascular disease (including stroke, myocardial infarction, and heart failure) although deaths from kidney failure, sepsis, and suicide have also been reported [38,121]. Whether Fabry-specific therapy (enzyme replacement therapy [ERT] or migalastat) impacts survival remains unclear.
Data on other long-term clinical outcomes are provided by studies of the natural history of Fabry disease in patients prior to ERT:
●In a retrospective study of 447 patients (279 males, 168 females) followed for a median of 12 years, end-stage kidney disease (ESKD) developed in 18 percent of males and 5 percent of females at a median age of 39 and 42 years, respectively [37]. Myocardial infarction occurred in 3 percent of males and 2 percent of females, and heart failure developed in 4 percent of males and 1 percent of females. Stroke occurred in 11 percent of males and 8 percent of females. The mean age for first stroke was 42 and 45 years, respectively.
●In a study of the natural history of 2869 patients (1424 males, 1445 females) in the Fabry Registry prior to the institution of ERT, 6 percent of males and 4 percent of females experienced major cardiovascular events (myocardial infarction, heart failure, or cardiac-related death) [122]. Among those with a cardiovascular event, 30 percent of males and 6 percent of females also experienced a kidney event (kidney transplant or chronic dialysis), and 11 percent of males and 13 percent of females also experienced stroke.
●In a study of 499 adult patients before ERT treatment, males with classical Fabry disease had a higher risk of clinical events (kidney, cardiac, or cerebral) than males with nonclassical disease or females with either phenotype [72]. Females with classical Fabry disease were also more likely to develop complications than those with nonclassical disease.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease" and "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – The overall goals of therapy in patients with Fabry disease are to prevent progression to irreversible tissue damage, organ failure, and premature death, and to improve quality of life. Treatment generally consists of Fabry-specific therapy (such as enzyme replacement therapy [ERT] or chaperone therapy [migalastat]) for those with indications, as well as adjunctive therapies for Fabry disease complications. Since disease manifestations vary among individual patients, therapeutic goals should be individualized based upon the extent of organ involvement. (See 'Goals of therapy' above.)
●Fabry-specific therapy – Available Fabry-specific therapies include ERT and chaperone therapy (ie, migalastat). ERT consists of providing affected patients with the deficient enzyme, alpha-galactosidase A (alpha-Gal A). Migalastat is an oral pharmacologic chaperone that binds to and stabilizes specific mutant forms of alpha-Gal A, thereby facilitating proper trafficking of the enzyme to lysosomes and increasing enzyme activity. (See 'Overview' above.)
•Indications – For the following patients with Fabry disease, we suggest Fabry-specific therapy plus supportive care, rather than supportive care alone (Grade 2C):
-All males with classic Fabry disease. (See 'Males with classic Fabry disease' above.)
-Female heterozygotes who have clinical symptoms or signs of major organ involvement (ie, kidney, cardiac, neurologic, gastrointestinal) or asymptomatic female heterozygotes with laboratory, histologic, functional, or radiologic evidence of major organ injury. (See 'Female heterozygotes' above.)
-Males or females with later-onset variants who have clinical symptoms or signs of major organ involvement (ie, kidney, cardiac, neurologic, gastrointestinal). (See 'Patients with later-onset variants' above.)
Patients with end-stage kidney disease (ESKD) due to Fabry disease may be considered for ERT on an individual basis. (See 'Patients with ESKD' above.)
•Choice of therapy – The choice between ERT and migalastat is influenced by factors such as the amenability of the patient's GLA variant to migalastat, patient age, baseline kidney function, and patient and clinician preference (algorithm 1) (see 'Choice of therapy' above):
-Patients who do not have an amenable GLA gene variant, whose baseline estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m2, or who are <18 years old (or <12 years old if living in the European Union) should receive ERT (agalsidase alfa or beta or pegunigalsidase alfa). Agalsidase alfa is not approved for use in the United States. Migalastat should not be used in patients without an amenable GLA gene variant or with an eGFR is <30 mL/min/1.73 m2.
-In patients who have an amenable GLA gene variant, whose baseline eGFR is ≥30 mL/min/1.73 m2, and who are ≥18 years old (or ≥12 years old if living in the European Union), both ERT and migalastat are potential options. We engage in shared decision-making regarding the choice between ERT and migalastat.
Dosing, administration, and adverse effects of ERT and migalastat are discussed above. (See 'Enzyme replacement therapy' above and 'Chaperone therapy (migalastat)' above.)
●Supportive care – All patients with Fabry disease should receive supportive care as indicated to manage the kidney, cardiac, neurologic, and other complications of disease. (See 'Kidney disease' above and 'Cardiovascular disease' above and 'Neurologic disease' above and 'Other clinical manifestations' above.)
●Monitoring – All patients with Fabry disease should have continued monitoring whether or not they are receiving therapy. The extent and timing of evaluations should take into consideration a patient’s disease manifestations, disease severity, and side effects of therapy. (See 'Monitoring' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jeffrey B Kopp, MD, who contributed to earlier versions of this topic review.
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