Fabry's Disease

Electron microscopy showed laminated bodies in pericytes about a capillary. The patient was a 15-year-old male with Fabry disease. A biopsy was taken of the conjunctiva. Source: National Eye Institute.

Fabry disease is a genetic disease caused by the absence of or improper fuctioning of an enzyme needed to metabolize lipids (fat-like substances that include oils, waxes, and fatty acids). The affected enzyme is known as ceramide trihexosidase, also called alpha-galactosidase-A. Fabry disease is one of several lipid storage disorders. Other diseases in this family include Gaucher disease, Niemann-Pick disease, Farber disease, the gangliosidoses (including Tay-Sachs disease), Krabbé disease, and Wolman’s disease .

Other Names

• Alpha-galactosidase A deficiency
• Anderson-Fabry Disease
• Angiokeratoma Corporis Diffusum
• Angiokeratoma diffuse
• Ceramide trihexosidase deficiency
• Fabry's Disease
• GLA deficiency
• Hereditary dystopic lipidosis

Types

Classic

GLA mutations that result in an absence of alpha-galactosidase A activity lead to the classic, severe form of Fabry disease.

Late-onset

Mutations that decrease but do not eliminate the enzyme's activity usually cause the milder, late-onset forms of Fabry disease that affect only the heart or kidneys.

Signs and Symptoms

Symptoms of Fabry disease usually begin during childhood or adolescence and include:

• Episodes of pain, particularly in the hands and feet (acroparesthesias)
• Clusters of small, dark red spots on the skin called angiokeratomas
• A decreased ability to sweat (hypohidrosis)
• Cloudiness of the front part of the eye (corneal opacity)
• Hearing loss

Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Milder forms of the disorder may appear later in life and affect only the heart or kidneys.

Causes

Mutations in the GLA gene cause Fabry disease.

The GLA gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease.

Diagnosis

When a diagnosis of Fabry disease is suspected, most often from the characteristic skin lesions and corneal changes, diagnosis is confirmed by decreased {alpha}-galactosidase activity in blood and tissue samples. Classically affected males usually have no detectable {alpha}-galactosidase activity, and concentrations in atypical hemizygous Fabry patients range from 5% to 35% of normal. ^{[1] [2]}

The National Society of Genetic Counselors has released recommendations for genetic counseling for Fabry disease. ^[3]

Treatment

Enzyme replacement may be effective in slowing the progression of the disease. A recombinant human α-GAL enzyme replacement is marketed in the U.S. as Fabrazyme by Genzyme Therapeutics and is marketed in countries outside the U.S. as Replagal by Transkaryotic Therapies, Inc.

The pain in the hands and feet usually responds to anticonvulsants such as phenytoin and carbamazepine. 

Gastrointestinal hyperactivity may be treated with metoclopramide. 

Some individuals may require dialysis or kidney transplantation.

Chances of Developing Fabry's Disease

Genetics

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all.

Unlike other X-linked disorders, Fabry disease causes significant medical problems in many females who have one altered copy of the GLA gene. These women may experience many of the classic features of the disorder, including nervous system abnormalities, kidney problems, chronic pain, and fatigue. They also have an increased risk of developing high blood pressure, heart disease, stroke, and kidney failure. The signs and symptoms of Fabry disease usually begin later in life and are milder in females than in their affected male relatives.

Since the gene that is altered is carried on a mother’s X chromosome, her sons have a 50 percent chance of inheriting the disorder and her daughters have a 50 percent chance of being a carrier.

Clinical Trials

A list of U.S. government-sponsored trials is available at ClinicalTrials.gov: Fabry disease trials.

Research

Recent discoveries

• Tissue doppler imaging is determined to be an effective method of predicting Fabry cardiomyopathy before patients develop left ventricular hypertrophy, a characteristic finding in the disease. ^[4]
• The changes in exercise capacity, electrocardiogram and echocardiograph findings after enzyme replacement therapy (ERT) was evaluated in a group of Australian patients. Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year. ^[5]
• A registry of children with Fabry disease, involving a number of facilities in several different countries, was evaluated for disease signs and symptoms. The study found that many pediatric Fabry patients report early symptoms, particularly pain, gastrointestinal symptoms, and impaired quality of life and that some children experience major complications during the pediatric years. ^[6]
• Screening for Fabry disease among kidney transplant recipients appears to be a cost-effective, feasible and clinically valuable practice. ^[7]

Current research

• The optimal dosage of replagal, used to replace deficient alpha-galactosidase A in patients with Fabry disease, is being studied by the National Institutes of Health. ^[8]
• The safety and efficacy of replagal in treating children with Fabry disease is being studied. ^[9]

Expected Outcome

Survival rates

Patients with Fabry disease often survive into adulthood but are at increase risk of strokes, heart attack and heart disease, and renal failure.

History

Signs and symptoms of the disease that would later be named Fabry disease were described by British dermatologist Dr William Anderson and German dermatologist Dr Johannes Fabry in 1898. The two doctors published separate papers describing patients with angiokeratomas. The disease was later determined to be caused by a buildup of fatty deposits in blood vessels. The enzymatic deficiency was determined and identified in the 1960s and 1970s and Fabrazyme received FDA approval in 2003. ^[10]

Epidemiology

Incidence

Fabry disease affects an estimated 1 in 40,000 to 60,000 males. ^[11] This disorder also occurs in females, although less frequently. Milder, late-onset forms of the disorder are probably more common than the classic, severe fo

References

1. ↑ Mayes JS, Scheerer JB, Sifers RN, Donaldson ML. Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease. Clin Chim Acta. 1981 May 5;112(2):247-51. Abstract
2. ↑ Fuller M, Lovejoy M, Brooks DA, Harkin ML, Hopwood JJ, Meikle PJ. Immunoquantification of alpha-galactosidase: evaluation for the diagnosis of Fabry disease. Clin Chem. 2004 Nov;50(11):1979-85. Epub 2004 Sep 13. Abstract
3. ↑ Bennett RL, Hart KA, O'Rourke E, et al. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2002 Apr;11(2):121-46. Abstract
4. ↑ Toro R, Perez-Isla L, Doxastaquis G, et al. Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy. Int J Cardiol. 2008 Aug 6. [Epub ahead of print] Abstract
5. ↑ Lobo T, Morgan J, Bjorksten A, et al. Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropic incompetence and improved anaerobic threshold after enzyme replacement. Intern Med J. 2008 Jun;38(6):407-14. Abstract
6. ↑ Hopkin RJ, Bissler J, Banikazemi M, et al. Characterization of Fabry Disease in 352 Pediatric Patients in the Fabry Registry. Pediatr Res. 2008 Jun 25. [Epub ahead of print] Abstract
7. ↑ De Schoenmakere G, Poppe B, Wuyts B, et al. Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant. 2008 Jul 2. Abstract
8. ↑ ClinicalTrials.gov. Dosing Study of Replagal in Patients With Fabry Disease
9. ↑ ClinicalTrials.gov. Replagal Enzyme Replacement Therapy for Children With Fabry Disease
10. ↑ U.S. Food and Drug Administration. FDA News. FDA Approves First Treatment for Fabry Disease. April 24, 2003.
11. ↑ Genetics Home Reference. Fabry disease

External Links

Fabry Support and Information Group

National Organization for Rare Disorders (NORD)

National Tay-Sachs and Allied Diseases Association