Genetics of Fabry Disease

Updated: Aug 23, 2018
Author: Robert J Desnick, MD, PhD; Chief Editor: Maria Descartes, MD 



Fabry disease is an X-linked lysosomal storage disease that is caused by deficient activity of lysosomal enzyme α-galactosidase A (α-Gal A). Most males with no α-Gal A activity develop the classic phenotype of Fabry disease, which affects multiple organ systems. The first clinical manifestations of the disease, which consist of episodes of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma), develop in childhood.[1] See the images below.

Angiokeratoma is the small punctate reddish-to-blu Angiokeratoma is the small punctate reddish-to-bluish angiectases on the umbilicus.
Angiokeratomas are commonly observed as dense clus Angiokeratomas are commonly observed as dense cluster of lesions on the flank and private areas.
Corneal verticillata, commonly seen in patients wi Corneal verticillata, commonly seen in patients with Fabry disease, detectable by slit lamp examination.

The rate of disease progression and specific organ damage demonstrate intrafamilial and interfamilial variability. Renal failure, cardiovascular disease, and stroke are the major causes of morbidity and mortality, occurring in the fourth or fifth decade of life.


Glycosphingolipids, predominantly globotriaosylceramide (GL-3) and galabiosylceramide, accumulate in the lysosomes of various cells (eg, in the vascular endothelium of multiple organs) owing to α-Gal A deficiency. The accumulation of GL-3 in the lysosomes causes lysosomal and cellular dysfunction; this, in turn, triggers the cascade of cells and tissue ischemia and fibrosis.



United States

Fabry disease is one of the more common lysosomal storage disorders, affecting approximately 1 in 40,000-60,000 males.


Prior to the availability of renal transplant, dialysis, and, more recently, enzyme replacement therapy (ERT), the average age at death in men with classic Fabry disease was 41 years. Renal failure, heart failure and/or myocardial infarction, and stroke were among the most likely causes of death.


Although most patients with Fabry disease are white, the disorder has been described in patients in many ethnic groups, including those with Hispanic, African, Asian, and Middle Eastern ancestry.


As is expected in X-linked disorders, males with deleterious mutations have little to no residual α-Gal A activity. Therefore, these patients experience the full spectrum of disease symptoms. Because of random X inactivation (lyonization), the disease presentation in female carriers is more variable and depends on the normal-to-mutant ratio of α-Gal A in the different tissues. A significant number of female carriers may develop Fabry disease–related symptoms, including acroparesthesias, GI symptoms, renal and cardiac disease, and/or stroke.


Most males with classic Fabry disease first manifest symptoms in childhood or early adolescence. The earliest manifestations include acroparesthesias, angiokeratomas, hypohidrosis, and lenticular and corneal changes. Proteinuria usually becomes evident in the second decade of life, and renal insufficiency is typically present in the third decade of life. Cardiovascular and cerebrovascular diseases usually develop in the fourth decade of life.

Individuals with atypical renal or cardiac variants usually do not have signs or symptoms in childhood. Many of these patients remain asymptomatic well into adulthood, when patients with classic symptoms are severely affected or have died from the disease.




Fabry disease should be considered in patients with the isolated features detailed below or in those who show signs of multisystemic involvement in a pattern consistent with renal, cardiac, and cerebrovascular involvement. A detailed and complete medical and family history and thorough physical examination are necessary.

A detailed medical and family history should be obtained, with emphasis on the following:

  • Presence, location, and density of skin rash (angiokeratoma)

  • Characteristics, frequency, and intensity of pain (acroparesthesia)

  • Bowel habits, abdominal cramping, vomiting, nausea, and food intolerance

  • History of abnormal sweating

  • Heat, cold, and exercise intolerance and easy fatigability

  • Family history of kidney failure, heart disease, stroke, or other signs or symptoms of Fabry disease in X-linked pattern of segregation

Classic Fabry Disease

Patients with classic Fabry disease typically have α-Gal A activity of less than 1% and often demonstrate the full spectrum of symptoms. The 2 categories of classic disease manifestation are as follows:

Early manifestations

Early manifestations generally begin in childhood or adolescence and include the characteristic corneal and lenticular opacities, skin lesions (angiokeratoma), pain in the extremities (acroparesthesia), and decreased ability to sweat (hypohidrosis). In addition, patients may have chronic abdominal pain and diarrhea. Some patients may experience spontaneous relief of these early symptoms during adulthood (eg, symptomatic improvement of acroparesthesias).

The earliest reported symptom of Fabry disease is often intermittent or chronic acroparesthesias. These pain episodes are described as burning, tingling, and numbness and are thought to be related to the involvement of the vascular supply and small fibers of the peripheral nervous system. Pain, especially in the hands and feet, may occur daily and may vary in severity. These episodes may occur in both sexes and may begin as early as age 2 years. Pain may be triggered by a body temperature increase due to exercise, fever, emotional stress, or environmental temperature changes. Extreme pain attacks, referred to as Fabry pain crises, usually affect male patients and are described as severe episodes that last several hours to days. These episodes may be accompanied by low-grade fever, body pains, and fatigue.

GI manifestations of Fabry disease are common and are believed to be caused by the deposition of GL-3 in the small vessels and the autonomic ganglia of the intestine. GI symptoms often begin in adolescence and may worsen with age. Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety. Symptoms are generally more frequent and appear earlier in life in males compared with female carriers.

Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis). Weakening of the capillary wall and vascular ectasia within the epidermis and dermis causes angiokeratomas. They usually manifest at age 5-13 years and initially appear as small, slightly raised, purplish-red, nonblanching angiectases. The number and size of these lesions progressively increase with age. Anhidrosis or hypohidrosis is also frequently reported and is thought to be secondary to lipid accumulation in the eccrine cells of the sweat glands and dysfunction of the autonomic nervous system.

Corneal manifestations are reported in more than 70-90% of patients. The best-known ocular symptom is a pattern of whitish spiral streaks in the corneal epithelium known as cornea verticillata.

Some patients may have recurrent fevers with no obvious source. Pain usually accompanies the fevers, and an elevated erythrocyte sedimentation rate may be present.

Disease symptoms and implications may affect the patient's school performance, level of activity, and mental health.

Late and serious clinical manifestations of Fabry disease

During the late stage of the disease, the progressive deterioration of renal, cardiac, and nervous system function ultimately results in significant morbidity and mortality.

Kidney involvement is a prominent feature and is the main cause of premature death in classic Fabry disease. It develops as a result of the progressive accumulation of GL-3 in the renal endothelium and other kidney cell types. Microalbuminuria, proteinuria, and isosthenuria may be apparent in adolescence and early adulthood. Progressive kidney disease is marked by the progression of proteinuria, an increase in serum creatinine levels, and the reduction of the glomerular filtration rate (GFR) during the third decade of life. Long-term hemodialysis is often required, and renal transplantation is usually successful.[2]

Fabry-related cardiovascular disease is a key cause of premature death. Early signs of cardiac involvement include interventricular septal and left ventricular hypertrophy (LVH) associated with valvular regurgitation.

Clinical signs of congestive heart failure may accompany the progressive concentric LVH and diastolic dysfunction observed in advanced stages of the disease. Mitral valve prolapse and thickening may also be observed.

Common initial electrocardiographic abnormalities include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval.

Conduction system involvement may be observed as early as the second decade of life, and, as it progresses, the risk of lethal arrhythmias and sudden death increases.

Permanent cardiac pacing is needed in approximately 10-20% of patients.

Damage to the coronary vascular bed may lead to angina pectoris, variant angina, and myocardial infarction.

Predominant involvement of small, penetrating vessels has been reported. This involvement does not necessarily follow the typical patterns observed in atherosclerosis.

CNS involvement may be observed on brain MRI as white matter changes. This involvement may be noted as early as the second or third decade of life, typically occurring earlier in males than in females. The primary ischemic-hypoxic damage in CNS results from prothrombotic and occlusive abnormalities, in addition to large-vessel ectasias. Patients may present with transient ischemic attacks, vascular thromboses, seizures, or hemorrhagic or ischemic stroke.

Paroxysmal attacks of severe rotational vertigo occur in many patients. Although these episodes are usually brief, some prolonged severe attacks require cessation of activities for several days. Megadolichobasilar compression of the vestibulocochlear nerve has been suggested as a likely cause for these episodes.

Sensorineural hearing loss has been frequently documented in patients with Fabry disease and most likely reflects vascular pathology of the inner ear.

Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. The progressive loss of temperature and pain sensation should be assessed during the physical examination.

Lymphedema of the legs is a poorly described and a less common manifestation. Often asymmetric, the symptom may start as a transient seasonal event with a tendency to become more severe and extensive over time. This manifestation presumably reflects the progressive GL-3 deposition in the lymphatic vessels and lymph nodes, compromising the lymphatic circulation.

Obstructive and constrictive lung diseases have both been documented in a subgroup of patients, often presenting as wheezing, dyspnea, or bronchitis.

Priapism has been associated with Fabry disease.

Mild anemia is probably due to decreased RBC survival.

Poor heat and exercise tolerance is commonly observed in patients. It may start at the early stages of the disease and is reported by both males and females. This poor tolerance is typically attributed to hypohidrosis and acroparesthesias and may become more pronounced in the presence of pulmonary disease or cardiomyopathy in later stages of the disease. Patients may report lack of energy and fatigue.

Atypical Fabry Disease

In atypical cases, individuals with residual enzyme activity demonstrate symptoms later in life, and the symptoms are usually limited to one or a few organs. For example, individuals with atypical cardiac variants usually do not have any signs or symptoms in childhood and present mainly with cardiac disease later in adulthood. In various surveys, approximately 3-12% of patients with unexplained LVH have been diagnosed with the cardiac variant of Fabry disease.

Clinical manifestations in female carriers vary greatly because of random X-chromosome inactivation. Although carriers commonly remain asymptomatic throughout life, many demonstrate clinical symptoms as variable and severe as those of affected males. Affected females may experience early manifestations of the disease, such as acroparesthesia and GI discomfort. Their symptoms may also be as severe and progressive as those seen in males (ie, they may develop renal failure). Females who are asymptomatic at the time of initial assessment should be closely and regularly monitored for any evidence of disease manifestation.


Skin symptoms

Angiokeratoma, small punctate reddish-to-bluish angiectases, may be either flat or slightly raised and may blanch with pressure. These are commonly observed as dense clusters of lesions on the umbilicus, flanks, thighs, penis, and scrotum.

Lesions in the oral mucosa and conjunctiva are observed in some patients.

Hypohidrosis and anhidrosis may be observed.

Visual symptoms

Vision is not usually impaired.

A slit-lamp examination reveals cornea verticillata, which manifests as whirl-like white-to–golden-brown opacities that extend from the center to the periphery of the cornea. Cornea verticillata is often prominent in female carriers and may play an important role in the early recognition of Fabry disease. Therefore, in females with either a positive family history or symptoms suggestive of Fabry disease, a slit-lamp examination can be very helpful.

Other possible ocular findings include lens, retinal and conjunctival changes.

Neurological symptoms

Peripheral neuropathy, specifically loss of temperature and pain sensation, has been reported.

Hearing deficit may be observed.

Lymphedema symptoms

Asymmetric involvement of the lower extremities with pitting edema has been reported in the absence of significant renal or cardiac disease.

Other symptoms

Characteristic facial appearance, such as coarse facial features, have been described by some authors.


GLA, the gene that encodes α-Gal A, has been isolated and sequenced, and more than 245 different mutations (missense, nonsense, splice, deletion, and insertion errors) have been reported. Attempts to correlate genotype with clinical presentation have been confounded by the fact that very few recurrent mutations have been reported.

The typical interfamilial variability of the disease phenotype may be due to other modifying factors, which may be genetically or environmentally derived.

A study of the p.E66Q variant of GLA suggested that this variant is not involved in the progression of chronic kidney disease (CKD) in Fabry disease. In the study, Watanabe et al determined the frequency with which the p.E66Q allele occurred in patients with CKD, including 1651 who were on chronic hemodialysis and 941 who were not on hemodialysis. They found that the frequency did not significantly differ between the dialysis and nondialysis groups. Moreover, in the nondialysis patients, no significant difference was found for the estimated GFR between those with the p.E66Q allele and those with the wild-type allele.[3]



Laboratory Studies

The following studies are indicated in Fabry disease:

α-Gal A

α-Gal A activity may be measured in plasma, serum, and leukocytes. Tissue biopsies and cultured skin fibroblasts may also be used to measure a-Gal A activity.

In males with the classic or variant phenotype, the disease is readily diagnosed based on low α-Gal A activity.

Female carriers may have α-Gal A activity that ranges from zero to within the reference range. Thus, enzyme assays are rarely helpful in determining female carrier status.

DNA analysis

DNA isolated from blood or biopsy specimens can be used for analysis of the α-Gal A gene sequence to identify the disease-causing mutation. DNA testing is the preferred method for identifying and confirming the carrier status of females in whom enzyme activity is within or near the reference range.

Laboratory tests after diagnosis

After the diagnosis has been confirmed using enzyme assays, DNA testing, or both, carefully assess the patient. A recommended minimum assessment schedule has been developed by the Fabry Board of Advisors[4] and other experts in the field.[5] The recommended assessment frequency depends on patient age and previous findings. Females and males should undergo the same degree of assessment and monitoring. The following recommended laboratory assessments should be obtained at baseline and at appropriate intervals:

CBC count, serum electrolyte level measurement, and lipid profile

Obtain at baseline and appropriate intervals.

Renal evaluation

Serum BUN and creatinine levels and 24-hour urine or spot urine measurement for total protein/creatinine, albumin/creatinine, sodium, creatinine, and urinary GL-3 (optional) levels.[6]

Renal biopsy (This may be warranted in atypical cases to exclude any other causes of renal disease.)

Imaging Studies

CNS evaluation

MRI is used to document evidence of brain ischemic disease.

Magnetic resonance angiography (MRA) may be indicated to assess cerebral vasculopathy.

Peripheral nerves should be periodically assessed using a detailed neurological examination.

Other Tests

Cardiac evaluation

Ventricular hypertrophy and septal thickening can be demonstrated using echocardiography. If left ventricular hypertrophy (LVH) is present, a cardiac MRI with contrast can be performed to evaluate the presence of scarring.

Abnormal ECG findings include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval. Evidence of LVH and previous ischemic injury may also be present.

Holter monitoring in selected patients may provide important information.

Psychosocial evaluation

All health care professionals who treat patients with Fabry disease should be sensitive to the psychosocial burden of a chronic, rare, and progressive disease. In these families, denial, guilt, and anger frequently play a significant role in intrafamilial dynamics. Pay special attention to the history and signs of anxiety disorders, clinical depression, suicidal ideation or attempts, and substance abuse.

Pulmonary evaluation

Perform induced sputum analysis, lung biopsy, or both if severe pulmonary involvement is present (to exclude an intercurrent disease process).

Visual evaluation

Perform slit-lamp microscopy to identify the typical Fabry disease–specific changes in the cornea, lens, retina, and conjunctiva.



Medical Care

Fabry disease management strategies should be tailored to the individual according to patient age and disease stage. These strategies include the use of medication to alleviate the symptoms, disease-specific treatment to delay and prevent possible serious organ damage, and adherence to standard health care measures and a healthy lifestyle.

Pain management

Daily prophylactic doses of neuropathic pain agents (eg, phenytoin, carbamazepine, gabapentin, or a combination of these agents) provide some degree of relief. They are effective in decreasing the frequency and severity of pain episodes or pain crises in most patients.

Some patients may require more potent analgesics (eg, opioids) for pain management.

Management of GI symptoms

No specific treatment has been found to control GI symptoms in Fabry disease. However, pancrelipase, metoclopramide, H2 blockers, loperamide, and hydrochloride can ameliorate GI symptoms in some patients.

Patients with abdominal symptoms often benefit from a change in eating habits that includes frequent small meals.

Management of skin symptoms

The results of various laser methods used to treat angiokeratomas in patients with Fabry disease have not been promising for patients who are not receiving enzyme replacement therapy (ERT).

Lesions that are more pedunculated may be treated with a series of liquid nitrogen treatments prior to laser therapy.

Management of visual symptoms

Ocular symptoms in patients with Fabry disease rarely, if ever, cause significant impairment of vision and, as a rule, do not require treatment.

Management of other symptoms

Symptomatic treatment of renal, cardiovascular, and cerebrovascular complications is warranted.

Enzyme replacement therapy (ERT)

ERT provides the patient with the biologically functional protein. The infused enzyme is taken up into lysosomes through specific receptors located on the surface of the target cells. Reversal of the metabolic and pathologic abnormalities in the cells and tissues are the key therapeutic goals of ERT. These changes should, in turn, result in improvement of symptoms and prevention of disease complications.

Multiple clinical trials with recombinant α-Gal A (agalsidase β [Fabrazyme]: Genzyme Corporation, Cambridge, Mass; agalsidase alfa [Replagal]: TKT Corporation, Cambridge, Mass) have been performed to investigate the safety and efficacy of ERT in patients with Fabry disease. The outcomes of these clinical studies were the basis for approval of Fabrazyme and Replagal in most European countries in 2001 and for the approval of Fabrazyme in the United States in 2003. The enzyme is administered intravenously. Replagal is intravenously administered at a dose of 0.2 mg/kg every 2 weeks, and Fabrazyme is intravenously administered at a dose of 1 mg/kg every 2 weeks.

West et al summarized the effects of agalsidase alfa on kidney function from 3 prospective, randomized, placebo-controlled trials (n=108).[7] Treatment with agalsidase alfa did not affect proteinuria and glomerular filtration rate (GFR) category at baseline was predictive of the rate of GFR decline. Patients treated with agalsidase had a lower annualized rate of GFR decline compared with those in the placebo group. These data represent the largest group of patients with Fabry disease taking enzyme replacement therapy evaluated for effects on kidney function. Agalsidase may help stabilize kidney function in Fabry disease.[8]

Initial clinical studies with recombinant α-Gal A showed that ERT is safe and well tolerated, except for mild-to-moderate infusion–associated reactions, which have been managed conservatively. During the phase 3 clinical study, Fabrazyme was shown to clear GL-3 from the plasma and capillary endothelium of the major sites of pathology, such as the kidney, heart, and skin.

The clinical benefits of ERT using α-Gal A in patients with advanced Fabry disease were examined in a phase 4 clinical study, which had a double-blind, placebo-controlled design. The rate of progression of renal, cardiac, and cerebrovascular complications and death among patients who received active drug was reduced compared with the placebo group. Therefore, starting ERT immediately after diagnosis to prevent irreversible organ damage is reasonable.

A literature review by Spada et al indicated that in pediatric patients with Fabry disease, ERT can significantly diminish plasma and urine levels of GL-3, relieve pain, and improve gastrointestinal symptoms and quality of life. The investigators reported that agalsidase’s impact on GL-3 clearance from podocytes seems to be dose dependent.[9]

The commercial availability of Replagal and Fabrazyme has allowed treatment for many patients around the world. This increased use has enabled further assessment of the effect of ERT on various clinical manifestations of Fabry disease. A growing body of evidence suggests that ERT is beneficial in improving most disease symptoms. However, the response to ERT may vary, depending in part on tissue-specific differences in drug delivery and disease stage. A summary of the effect of ERT on various manifestations as reported by the authors and others is as follows:

  • Improved acroparesthesias

  • Improved GI symptoms

  • Improvement of hypohidrosis and anhidrosis

  • Improvement in the function of C-, –Ad-, and Ab-nerve fibers

  • Stabilization of deteriorating renal function

  • Improved cardiac function

  • Improved lymphedema

  • Improved vertigo

  • Stabilization and occasional improvement in hearing

  • Reduction in stroke frequency

Current recommendations suggest that ERT should be initiated as early as possible in all males with Fabry disease (including those with end-stage renal disease). Symptomatic female carriers with serious organ system involvement should also be assessed for ERT administration.

The following signs and symptoms suggest serious implications of Fabry disease in females that warrant ERT:

  • Uncontrolled pain at any age that requires alteration of lifestyle and interferes with quality of life

  • Presence of and a progressive increase in proteinuria, exceeding 300 mg per 24 hours or renal biopsy findings that suggest significant renal involvement

  • Patients on dialysis or who have undergone transplantation

  • Ischemic heart disease with or without cardiac dysfunction

  • Moderate-to-severe heart enlargement (ie, LVH)

  • Heart rhythm abnormalities

  • Significant brain involvement or MRI changes

  • Frequent severe vertigo episodes

  • Severe fatigue

A study by Trimarchi et al found that patients with Fabry disease who were undergoing enzyme therapy exhibited significantly lower podocyturia than did Fabry disease patients who were not being treated, although it was also found that the untreated patients displayed lower proteinuria and better renal function than did the treated patients. The investigators suggested that podocyturia precedes the development of proteinuria in Fabry disease and that enzyme therapy discourages podocyte loss.[10]

Alpha-galactosidase A stabilizers

In August 2018, the US Food and Drug Administration (FDA) approved migalastat (Galafold) for the treatment of adults in whom a diagnosis of Fabry disease has been confirmed and who possess an amenable galactosidase-α gene (GLA) variant (as determined through in vitro assay data). Binding to and stabilizing endogenous α-galactosidase A (α-Gal A), migalastat chaperones the enzyme from the endoplasmic reticulum to lysosomes, where α-Gal A can degrade the accumulated glycolipid (globotriaosylceramide [GL-3]) and globotriaosylsphingosine (lyso-Gb3).

The efficacy of migalastat therapy is supported by the FACETS and ATTRACT clinical trials. The FACETS trial showed that after 6 months, the improvement rate for diarrhea was significantly greater in Fabry disease patients with an amenable mutation who received migalastat than in those treated with placebo (43% vs 11%).[11]

Results from the ATTRACT trial revealed the impact on renal function by migalastat and ERT to be similar. In addition, patients on migalastat showed a significant decrease in the left ventricular mass index (-6.6 g/m2), while those treated with ERT demonstrated no significant index change. Twenty-nine percent of migalastat patients experienced renal, cardiac, or cerebrovascular events during 18 months of treatment, compared with 44% in the ERT group. When patients were switched from ERT to migalastat, plasma globotriaosylsphingosine levels remained low and stable.[12]

Adjunctive therapies and preventive measures

Use of ACE inhibitors and/or blockers in patients with proteinuria is the criterion standard. The dose should be optimized by a nephrologist.

Control of hypertension is essential.

Dyslipidemia (most commonly, hypercholesterolemia) should be treated.

Prophylaxis with antiplatelet or anticoagulant medication can be important in patients who have had transient ischemic attacks or a stroke.

Permanent cardiac pacing should be considered in high-risk patients.

Hearing loss can be treated with hearing aids. Patients should avoid excessive noise exposure.

Patients should be encouraged to maintain a healthy lifestyle, such as avoiding smoking.

Surgical Care

In patients who have undergone renal transplantation, engrafted kidneys from unaffected and noncarrier individuals correct kidney function and remain free of GL-3 storage because the transplanted kidney is capable of producing normal levels of α-Gal A. However, other organ system damage continues unabated in patients who have undergone kidney transplantation.

In particular, vascular disease of the heart and brain may continue to progress. Thus, these patients should receive or continue to receive ERT.


A multidisciplinary team is essential. Emotional support and family counseling should be an integral part of patient care. In addition, providing patients with the resources to learn about Fabry disease and to contact other patients and families struggling with similar issues may help ameliorate feelings of isolation. Consultations should include the following:

  • Medical geneticist

  • Nephrologist

  • Cardiologist

  • Ophthalmologist

  • Pain specialist

  • Neurologist


A "renal diet" is recommended for patients with proteinuria and renal failure.

A nutritionist should supervise a low-protein and low-sodium diet.

Patients are advised to monitor their activity level in order to avoid factors that precipitate symptoms. For example, adequate hydration prior to any physical activity and avoidance of exposure to extreme temperatures are recommended to avoid pain.



Guidelines Summary

International panels of Fabry disease experts released recommendations for the management and treatment of Fabry disease in adult patients. The recommendations, published in 2018, include the following[13] :

  • In adult male and female patients with later-onset Fabry mutations or missense GLA variants of unknown significant (VUS), ERT should be considered and is appropriate once there is biochemical, histologic, or imaging evidence of injury to the kidney, heart, or central nervous system (CNS) attributable to Fabry disease, even in the absence of other typical Fabry symptoms
  • Individuals with later-onset Fabry mutations or missense GLA VUS who have well-characterized benign GLA polymorphisms should not be treated with ERT
  • In individuals with later-onset Fabry mutations or missense GLA VUS who have no demonstrable Fabry disease–related tissue pathology or clinical symptoms, ERT may not be appropriate, particularly in heterozygous female patients; these patients should be monitored regularly by a multidisciplinary care team
  • Patients with poor clinical outcome on ERT should be tested for agalsidase inhibition; the higher agalsidase formulation of 1.0 mg/kg every 2 weeks may be necessary to overcome the impact of immunoglobulin G (IgG) anti-agalsidase antibodies in patients with greater disease severity
  • Treatment with ERT should be combined with supportive interventions, if indicated, to clinically manage the renal, cardiac, neurologic, and other complications of Fabry disease–induced chronic tissue injury
  • A standard management approach is recommended for chronic kidney disease
  • Regarding cardiac complications, consider angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs); beta blockers should be used with caution and amiodarone avoided in patients receiving ERT
  • Delayed gastric emptying and dyspepsia symptoms may be successfully treated with metoclopramide and H2 blockers, respectively; dysmotility and diarrhea may be treatable with dietary changes (increased fiber intake, more frequent and smaller meals) and pharmacotherapy


Medication Summary

Neuropathic pain agents, enzyme replacement therapy (ERT), or α-galactosidase A (α-Gal A) stabilizers may be indicated.


Class Summary

These agents are used to relieve neuropathic pain. Phenytoin and carbamazepine are 2 medications used to treat acroparesthesias in patients with Fabry disease. Either drug may be used, although some patients benefit from a combination.

Phenytoin (Dilantin)

Used for analgesia for acroparesthesia. May act in the motor cortex, where it may inhibit spread of seizure activity. Activity of the brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Individualize dose. Administer larger dose before bedtime if dose cannot be equally divided.

Carbamazepine (Tegretol)

Indicated for complex partial seizures and trigeminal neuralgia. May block posttetanic potentiation by reducing summation of temporal stimulation. May reduce polysynaptic responses and block posttetanic potentiation. Following therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 mo. Doses are typically lower than those used to treat seizures and are administered once daily.

Gabapentin (Neurontin)

FDA-approved PO medication for management of postherpetic neuralgia. Also FDA approved for the treatment of partial seizures in adults and children. Chemical structure similar to the inhibitory neurotransmitter GABA. Appears to work by raising GABA levels by some effect on a GABA transporter protein. Also decreases activity of voltage-gated calcium channels via binding to a secondary protein. Approved for epilepsy in children. Available as tab, cap, and liquid dosage forms.

Enzyme Replacement Therapy

Class Summary

α-Gal A deficiency leads to the accumulation of GSLs with terminal α-galactosyl residues. Clinical manifestations of Fabry disease are reflected in the tissue target sites of lipid storage. The recombinantly produced enzyme α-Gal A is available in Europe and United States.

Agalsidase alfa (Fabrazyme, Replagal)

Recombinant form of the human enzyme α-Gal A, which is deficient in patients with Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduction or relief of neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells. Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.

Alpha-Galactosidase A Stabilizers

Class Summary

Binding to and stabilizing endogenous α-galactosidase A (α-Gal A), migalastat chaperones the enzyme from the endoplasmic reticulum to lysosomes, where α-Gal A can degrade the accumulated glycolipid (globotriaosylceramide [GL-3]) and globotriaosylsphingosine (lyso-Gb3).

Migalastat (Galafold)

Indicated for adults in whom a diagnosis of Fabry disease has been confirmed and who possess an amenable galactosidase-α gene (GLA) variant (as determined through in vitro assay data).



Further Outpatient Care

Genetic counseling is necessary for the proband, and a careful pedigree should be obtained to identify all family members potentially affected by Fabry disease.

Because Fabry disease is an X-linked recessive trait, all daughters of affected males are carriers, and no sons of affected males have the gene for Fabry disease. Typically, mothers of probands are obligate carriers, and their siblings should be considered at risk.

Inpatient & Outpatient Medications

See Treatment.


Transfer to a center with specialists familiar with Fabry disease may be indicated.


Prenatal testing can be performed in women who are pregnant and are carriers of the gene to identify fetuses affected with Fabry disease. A karyotype should be obtained first to identify if the fetus is male. Enzyme activity can then be measured, using either chorionic villus sampling (CVS) or amniotic fluid samples.

If the mutation carried in the family is known, DNA can be isolated from CVS or amniotic fluid samples, and genotyping can be performed.


As with all chronic illnesses, patients are at risk for anxiety disorders, depression, or both.


Prognosis for patients with Fabry disease has improved with the more widespread use of advanced medical techniques, such as hemodialysis and renal transplant.

Enzyme replacement therapy (ERT) has demonstrated favorable results in modifying long-term complications of Fabry disease. Early treatment with ERT to prevent irreversible damage to the organs seems reasonable.