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Clinical Presentation and Progression
Signs and Symptoms
Ophthalmologic Findings
Cardiac Dysfunction
Gastrointestinal Manifestations
Genetics and inheritance of Fabry disease
Diagnosis of Fabry Disease
Current Treatments in Fabry Disease
The Fabry Registry - A Collective Resource to Optimize Outcomes
Fabry Support and Resources
Fabry Articles
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Fabry Disease - Description

Fabry disease was first described independently by Drs. William Anderson in England and Johann Fabry in Germany in 1898. Fabry disease is a rare, X-linked recessive lysosomal storage disorder, seen in all ethnic groups, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-GAL). Partial or complete deficiency of alpha-GAL leads to progressive accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in visceral tissues and the vascular endothelium throughout the body.

The inability to breakdown GL-3 leads to progressive damage to the kidney, heart, and nervous system. The clinical course of Fabry disease is usually marked by chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke, and cardiac complications. As the disease progresses, complications may become life-threatening.

Since Fabry is X-linked, the disease predominantly affects males (hemizygotes), who have little if any endogenous alpha-GAL. Although an X-linked recessive disease, females with Fabry often experience varying degrees of disease manifestations. It is believed that X-chromosomal inactivation (lyonization), which can block expression of the functional alpha-GAL gene in all or some parts of the body, is responsible for disease onset in females. Although the prevalence of female carriers who develop overt clinical manifestations is not definitiely known, recent studies indicate that manifestations in carrier females are more common than previously thought.


Clinical presentation and progression

Classical Fabry disease usually presents in childhood (with pain, fever, hypohidrosis, fatigue, and exercise intolerance) but diagnosis may not be confirmed until there has been considerable accumulation of GL-3. The average age of diagnosis is approximately 30 years. Delayed diagnosis may be due in part to under-recognition of the disease and/or misattribution of Fabry disease symptoms to other disorders.

Progressive organ and tissue damage associated with Fabry disease may result in substantially decreased life expectancy. Before the availability of renal dialysis or transplantation, the average age of death among patients with classical Fabry disease was 41 years; today, average life expectancy is still only 50 years.

Atypical Variant

Growing evidence indicates there may be a significant number of "atypical variants" - hemizygotes who have few or none of the hallmark symptoms of classical Fabry disease. Atypical variants have residual plasma alpha-GAL levels (1% to 30% of normal) and present much later in life than patients with classical Fabry disease. They are often identified by chance, and usually have manifestations predominately in one organ system.

Signs & Symptoms of Fabry Disease

The cardinal presenting features of Fabry disease are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas, hypohidrosis, heat and cold intolerance, and a characteristic "whorled" corneal opacity that does not affect vision. Progressive accumulation of GL-3 in the vascular endothelium and other tissues leads to life-threatening manifestations in adulthood involving the heart, kidneys, central and peripheral nervous system, and cerebrovascular system.

The list below provides an overview of the signs and symptoms of Fabry disease that may be seen at different stages of life. Both male and female patients may experience some or all of these manifestations to varying degrees.




Signs & Symptoms

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Angiokeratomas are the most visibly recognizable clinical feature of Fabry disease. These dark red or purple skin lesions (ranging in size from pinpoint to several millimeters in diameter) do not blanch with pressure and are usually distributed on the buttocks, groin, umbilicus, and upper thighs (bathing trunk distribution). Lesions generally appear in adolescence or young adulthood. Angiokeratomas are almost universal in male hemizygotes; they occur in approximately 30% of heterozygous females. Because angiokeratomas may be concealed by undergarments, their presence can be missed during routine physical examinations.


There are two types of pain common to Fabry disease:

  1. Acroparesthesia

    Acroparesthesias occur in the majority of hemizygotes, and in many of the heterozygotes. These sensory symptoms are characterized by tingling, burning pain and discomfort in the palms of the hands and the soles of the feet. The accumulation of GL-3 in the walls of blood vessels in skin tissue leads to nerve fiber degeneration. Degeneration of small myelinated and unmyelinated fibers and/or loss of small peripheral sensory neurons in the dorsal root ganglia and the resultant small fiber dysfunction are thought to contribute to the characteristic acroparesthesias in Fabry disease.

  2. Fabry pain crises

Fabry pain crises are episodes of acute agonizing pain, typically beginning in the extremities and radiating inward, lasting from several minutes to several days, and are often induced by emotional stress, changes in temperature, exercise, and/or fatigue.

Pain crises are often one of the first symptoms experienced in Fabry disease and may lead a child to his/her first Fabry-related physician visit. Because the pain is often accompanied by fever and elevated erythrocyte sedimentation rates, it may be erroneously identified as rheumatic in origin.


Impaired sweating, either hypohidrosis or anhidrosis, usually presents in childhood or adolescence and has been attributed to selective peripheral nerve damage or to intracytoplasmic lipid deposits in the small blood vessels surrounding sweat glands. This may result in dry skin and heat and exercise intolerance. In approximately 40% of Fabry disease patients, production of tears and saliva is also reduced.

Heat and Cold Intolerance

Temperature sensitivity is common in Fabry disease. It presumably results from lipid deposition in small vessel walls, perineural cells, and unmyelinated or myelinated nerve cells resulting in small fiber neuropathy. Hypohydrosis and androsis may also contribute to heat intolerance.

Renal Disease

Progressive glycosphingolipid (particularly GL-3) accumulation may lead to irreversible and potentially life-threatening clinical sequelae in the kidney.

While GL-3 deposits are primarily found in the lysosomes of the vascular endothelium, renal biopsy studies of young hemizygotes show diffuse lipid accumulation in the glomerular, vascular, and interstitial cells, and tubular involvement primarily in distal convoluted tubules and loops of Henle. With age, intimal thickening and degenerative glomerular and tubular changes are apparent.

Proteinuria, isosthenuria, and azotemia

Most patients with classical Fabry disease develop proteinuria in late adolescence, which progresses to isosthenuria and alterations of tubular reabsorption, secretion, and excretion. Azotemia usually occurs by the third to fifth decade of life, although renal failure has also been reported in patients as young as 16 years old. Renal complications tend to be less evident in female carriers than in hemizygotes.

Urinalysis is also characterized by hematuria and lipiduria, often beginning in childhood. Polarization microscopy of free urine or urinary sediment reveals birefringent lipid globules with characteristic "Maltese crosses."

Cerebrovascular Complications

Strokes and transient ischemic attacks are associated with Fabry disease. Thrombosis of small arteries thickened by the vascular accumulation of GL-3 lipids makes Fabry patients vulnerable to early ischemic stroke. Thrombus formation may also be enhanced in Fabry disease due to adhesion of neutrophils and monocytes to endothelial cell walls. Hypertension associated with renal dysfunction may also increase the risk for hemorrhagic stroke. Co-morbid prothrombotic genetic risk may influence stroke risk.

Other Fabry-related cerebrovascular signs and symptoms associated with Fabry disease may include:

  • Hemiparesis
  • Vertigo
  • Diplopia
  • Seizures
  • Basilar artery ischema and aneurism
  • Labyrinthine disorders
  • Cerebral hemorrhage

Ophthalmologic Findings
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Common ophthalmologic findings in Fabry disease include:

Corneal opacities

Corneal opacities, beginning with a diffuse haziness and progressing to a characteristic "whorled" or "spoke-like" pattern, are found almost universally among classically affected hemizygotes and in a high proportion of heterozygous females (estimated to be approximately 70%). This finding can be visualized through slit lamp microscopy. Corneal opacities do not impair vision.

Lenticular opacities

Two types of lens opacities have been noted in Fabry patients: cream-colored anterior capsular deposits in the lens (sometimes distributed like a propeller), and whitish, granular spoke-like deposits on the posterior lens (referred to as Fabry cataracts). Fabry cataracts are more commonly observed than capsular deposits; they can be visualized by retroillumination.

Eye Vascular Findings

Conjunctival and retinal vascular lesions resulting from the generalized disease process are common. Lesions may appear to be sausage-like, with markedly dilated vessels. The presence of several lesions of this type, which do not affect vision, may be pathognomonic for Fabry disease.

Cardiac Dysfunction
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There is considerable clinical variability in regards to cardiac involvement in Fabry disease. Cardiac manifestations generally develop in patients older than 30 years of age.

Cardiac-related signs and symptoms of Fabry disease may include:

  • Left ventricular hypertrophy
  • Valvular disease (especially mitral valve prolapse and/or regurgitation)
  • Premature coronary artery disease
  • Angina
  • Myocardial infarction
  • Conduction abnormalities
  • Arrhythmias
  • Congestive heart failure

Left ventricular hypertrophy

Progressive GL-3 accumulation in myocardial cells may lead to significant enlargement of the heart, particularly the left ventricle. The main determinants of left ventricular mass appear to be age and alpha-GAL activity.

Electrocardiographic and Echocardiographic findings

Characteristic electrocardiographic findings include AV conduction abnormalities (short P-R intervals or AV block), signs of left ventricular hypertrophy, and repolarization abnormalities (ST-T wave changes). Supraventricular arrhythmias may also be noted.

Echocardiographic findings may include aortic root dilatation, enlarged ventricular mass, and valvular disease (especially of the mitral valve). Left ventricular enlargement tends to increase with disease severity and age.

Cardiac variant

Cardiac variants are the most widely recognized and studied of these subtypes. In cardiac variants, disease manifestations typically present later in life and are limited to the heart. The vascular endothelium is generally not affected.

A recent study in Japan suggests that the cardiac variants of Fabry disease may be under-recognized. Among the 230 unselected males with left ventricular hypertrophy, 3% were found to have low alpha-GAL activity (4-14% of normal). None of these men exhibited signs and symptoms considered typical of Fabry disease, such as angiokeratomas, acroparesthesias, corneal opacities, or hypohidrosis. An additional study of 79 men with late-onset hypertrophic cardiomyopathy found 6.3% of the hemizygotes to have low alpha-GAL levels.

Gastrointestinal Manifestations
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Gastrointestinal symptoms are thought to be due to the deposition of glycosphingolipids in mesenteric blood vessels and autonomic ganglia. Up to two thirds of affected males and about half of symptomatic females may experience gastrointestinal symptoms associated with Fabry disease. Gastrointestinal symptoms may include:

  • Postprandial bloating
  • Abdominal cramping and pain
  • Early satiety
  • Diarrhea
  • Constipation
  • Nausea
  • Vomiting

Genetics and inheritance of Fabry disease
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The alpha-GAL gene

The alpha-GAL gene is localized to the long arm of the X chromosome (locus Xq22.1). [1] The gene, which encodes a 429 amino acid polypeptide; including a 31 amino acid signal peptide, is 12 kilobases long and contains 7 exons. [2] The defect that causes Fabry disease is heterogeneous - to date, over 200 mutations of the alpha-GAL gene have been recorded. Moreover, most families have "private" mutations (found only in that family) [3] that may explain variations in the clinical presentation of Fabry disease.


Fabry is an X-linked recessive disease. It is inherited through the mother who, with each conception, has a 50% chance of passing the defective gene on to all offspring. Her sons who inherit the gene will have Fabry disease. Daughters who inherit the mutated Fabry gene will be carriers. Because of X-chromosomal inactivation, some female carriers develop symptoms of mild, moderate, or classical Fabry disease.

Males with Fabry disease pass on the defective gene to none of their sons and all of their daughters.

Although a positive family history is a strong indicator for Fabry disease, de novo or spontaneous mutations have been documented. Thus, absence of a family history does not rule out a diagnosis of Fabry disease.

Diagnosis of  Fabry Disease
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Clinical heterogeneity and the rarity of Fabry disease makes the diagnosis of Fabry disease a challenge. The age of presentation, presenting symptoms, and clinical course vary from individual to individual. Although symptoms generally appear in childhood, they may go unrecognized until adulthood when organ system damage has already occurred. Greater recognition of Fabry disease symptoms may lead to earlier suspicion and diagnosis, which in turn may result in more effective disease management.

Presumptive diagnosis

The following signs and symptoms are characteristic of Fabry disease and may lead to a presumptive clinical diagnosis:

One confounding factor in diagnosis is the fact that many common signs and symptoms of Fabry disease are common in other conditions.

Definitive diagnosis

Once a presumptive diagnosis of Fabry disease has been made based on clinical signs and symptoms, definitive diagnosis can be made by testing for deficient alpha-GAL enzyme activity in plasma, leukocytes, tears, or biopsied tissue.

DNA mutational analysis is clinically available and can be an important tool in family genetic risk assessment particularly in females.

Diagnosis in women

Although females carrying the Fabry gene may be asymptomatic or present with mild clinical manifestations, definitive identification of carriers is important. Diagnosis allows practitioners to monitor for new or worsening symptoms, and can help with identifying other family members with the disease.

Affected females may be able to be diagnosed with Fabry disease when they have very low or absent alpha-GAL activity and/or by lipid deposition in biopsied tissues or urinary sediment. Many female carriers (with or without symptoms) have below-normal levels of alpha-GAL activity and/or the characteristic corneal opacities. However, this is not true for all carriers - some have alpha-GAL activity in the low normal range. In families with an identified mutation, mutation analysis is the definitive way to clarify diagnosis in potential carrier females. In families for whom a specific mutation is not documented, linkage analysis if possible, may establish carrier status.

Prenatal diagnosis

Fabry disease can be diagnosed prenatally via cultured amniotic fluid cells and by chorionic villus sampling (at 9-10 weeks) and amniocentesis (at approximately 15 weeks).

Current Treatments in Fabry Disease
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Disease management strategies may include medications and lifestyle approaches to symptom relief and interventions to delay serious sequelae due to organ damage (eg, kidney transplantation, cardiac pacemaker insertion).

Symptom Management

Treatment of Fabry disease includes management of symptoms and of life threatening complications. Because the disease affects multiple organ systems, a multidisciplinary team approach (geneticist, genetic counselor, gastroenterologist, nephrologist, neurologist, dermatologist, ophthalmologist, cardiologist, pediatrician) to management may be necessary.


If possible, patients should avoid stimuli that precipitate pain:

  • Stress
  • Heat or sun exposure
  • Temperature changes
  • Physical exertion

Drinking large amounts of fluid, especially during hot weather and before and during exercise may also help prevent Fabry crises.

For patients with frequent and severe painful attacks, prophylactic therapy with anticonvulsant drugs (diphenylhydantoin, carbamazepine, gabapentin, topiramate) or anti-dpressants [amitriptyline] may be helpful. Phenoxybenzamine has also been shown to provide pain relief.

Angiokeratomas can be removed for cosmetic reasons by argon laser treatment, usually with little scarring.

Cardiac complications

The pathology that underlies cardiac complications in Fabry disease differs from that of most heart diseases in the general population. However, standard treatment modalities such as valve replacement, pacemaker insertion, angioplasty, and coronary artery bypass grafting are employed as warranted by presenting signs and symptoms.

Cerebrovascular complications

Cerebrovascular complications associated with Fabry disease, like cardiovascular complications, are managed with standard treatment modalities. Oral anticoagulant or antiplatelet agents may be administered to prevent stroke. Delineation of possible co-morbid pro-thromobotic risk factors may allow important therapy initiation.

Renal complications

Renal complications are one of the more common and concerning aspects of Fabry disease. The degree of renal involvement generally correlates with the progressions of GL-3 accumulation and may lead to renal insufficiency and failure may ensue.

Mild reductions in renal function may be managed in part by a low-protein diet. When renal function becomes severely compromised, dialysis and/or renal transplantation may be warranted. Renal transplantation has been shown to improve uremia, prolongs life, and may even improve clinical symptoms in Fabry disease. However, renal transplantation is not a cure as it does not address the underlying pathology of the disease - progressive GL-3 accumulation. Cardiac disease progression has been noted in renal transplant patients, and renal allografts have demonstrated GL-3 deposition after transplantation.

Gastrointestinal symptoms

A low fat diet and/or pancrelipase or metoclopramide taken before meals can temporarily ameliorate gastrointestinal symptoms associated with Fabry disease. Other symptomatic therapies that may be helpful include:


While symptom management may improve a patient's quality of life, treatment to prevent or reverse accumulation of GL-3 may offer the potential to stem disease progression and prevent organ damage.

Enzyme Replacement Therapy (ERT)

Enzyme replacement therapy [ERT] has been approved for use in many countries throughout the world including the United States and those in the European Union.

There are other treatments for Fabry disease that are currently under investigation. They include:

Gene therapy for Fabry disease is in the early stages of investigation. Research has identified two different approaches:

  • Direct delivery of the alpha-GAL gene using modified adenoviral and adeno-associated viral vectors in order to genetically modify the liver, lung, or muscle of the patient and use these organs as internal sources of alpha- GAL
  • Genetic alteration of hematopoietic stem cells from Fabry patients to produce alpha-GAL and restoration of the altered cells to the patient through bone marrow transplantation

Both methods have shown potential promise in pre-clinical studies in Fabry mice.

Small molecule therapies

Research has also identified two approaches involving "small molecules." Both of these require some residual alpha-GAL activity to be effective and could potentially be used in conjunction with either gene therapy or enzyme replacement therapy.

The first approach involves substrate inhibition therapy to reduce cellular synthesis of glycosphingolipids. Two potentially promising small molecules are N-butyldeoxynojirimycin and D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4).

A second approach involves use of a competitive inhibitor of alpha-GAL to increase the activity of residual enzyme. In animal studies, oral administration of small doses of 1-deoxy-galactonojirinmycin increased the transport and maturation of mutant alpha-GAL, and increased activity in some organs.

The Fabry Registry - A Collective Resource to Optimize Outcomes
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The Fabry Registry is a global outcomes assessment and disease management program that compiles patient data from routine clinical practice to provide the medical community with information to help optimize patient care by:

  • Facilitating significant research publications.
  • Encouraging collaboration and shared expertise with your colleagues.
  • Enabling the clinical practice of evidence-based medicine.
  • Developing individualized care plans based on benchmark comparisons of similar patients.

Through the Fabry Registry, the Fabry community has access to an important resource on a disease that affects a small patient population. Management guidelines and publications from the Fabry Registry may contribute to:

  • Earlier diagnosis.
  • Earlier intervention.
  • Enhanced clinical evaluation and monitoring.
  • Defining the therapeutic goals of treatment.
  • Improved quality of care.
  • Optimal patient outcomes.

This open database allows for the exploration of issues, evaluation of trends, and the generation of peer-reviewed. Physicians may publish their own data or on the Registry population as a whole (aggregate data analyses). They may do this by:

  • Requesting individualized patient reports and informative clinical summaries to monitor disease status.
  • Build a decision support system by exchanging aggregate clinical data among physicians to facilitate clinical decision-making.
  • Access new information on current treatment guidelines and practice patterns.
  • Tap into an international "virtual practice" of patients with Fabry disease.

The Fabry Registry complies with applicable national privacy regulations and other state and local laws relating to medical information. All patient and physician information submitted to the Fabry Registry is maintained as confidential.

  • Confidentiality is maintained as patients are referenced by Registry ID number only.
  • Patients must authorize release of their clinical data.
  • No site-to-site data comparisons are made.

Contact the Fabry Registry

In the United States
617- 591-7024 or
800-745-4447, ext. 17024

In Europe
+31 (0) 35 699 1232

Or visit:

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