Fabry disease is a genetic condition that typically affects males. It is caused by deficiency of an enzyme, a chemical that speeds up another chemical reaction. Fabry disease can affect many parts of the body including the kidneys, eyes, brain, and heart. Pain in the hands and feet and a characteristic rash are classic features of this disease.
The symptoms of Fabry disease were first described by Dr. Johann Fabry and Dr. William Anderson in 1898. The enzyme deficiency that leads to the disease was identified in the 1960s. Fabry disease is caused by a change (mutation) in the GLA gene. This gene is responsible for the production of the enzyme alpha-galactosidase A. Alpha-galactosidase A normally breaks down globotriaosylceramide. Globotriaosylceramide is a natural substance in the body, made of sugar and fat. A mutation in the GLA gene leads to a decrease in alpha-galactosidase A activity which, in turn, leads to an excess of globotriaosylceramide. The excess globotriaosylceramide builds up in blood vessels (veins, arteries, and capillaries) and obstructs normal blood flow. It also builds up in parts of the skin, kidneys, heart, and brain. It is this build-up that inhibits normal function and leads to the symptoms associated with the disease.
The symptoms of Fabry disease are variable. Some individuals with Fabry disease have severe complications, while others have very mild symptoms. The first sign of the disease may be a painful burning sensation in the hands and feet (acroparesthesias). A red rash, most commonly between the belly button and the knees (angiokeratoma) is also common. The outer portion of the eye (cornea) may also become clouded in individuals with Fabry disease. The progressive buildup of globotriaosylceramide can also lead to kidney problems and heart disease in adulthood.
The gene that produces alpha-galactosidase A is located on the X chromosome. It is called the GLA gene. Since the GLA gene is located on the X chromosome, Fabry disease is considered to be X-linked. This means that it generally affects males.
A person's sex is determined by his or her chromosomes. Males have one X chromosome and one Y chromosome. Females, on the other hand, have two X chromosomes. Males who possess a mutation or change in their GLA gene will develop Fabry disease. Females who possess a mutation in one of their GLA genes typically do not develop many of the symptoms associated with Fabry disease. This is because a female's other X chromosome does not have the mutation, and the normal chromosome can take over the function of the abnormal chromosome and keep her from getting the disease. These women are considered to be carriers. If a woman is a carrier, she has a 50% risk with any pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk of having an affected son, and with every female pregnancy she has a 50% risk of having a daughter who is a carrier.
Fabry disease affects approximately one in 40,000 live births. It occurs evenly among all ethnic groups. Almost always, only male children are affected. Although female carriers of the disease occasionally develop symptoms of the disease, it is rare for a female carrier to be severely affected.
Signs and symptoms
The signs and symptoms of Fabry disease vary. Some individuals with Fabry disease have many severe
A painful burning sensation in the hands and feet (acroparesthesias) is one of the first symptoms of Fabry disease. This pain can be severe and may grow worse with exercise, stress, illness, extreme heat, or extreme cold. Another symptom of Fabry disease typically present during childhood is a red rash (angiokeratoma). This rash typically develops between the navel and the knees. Children with Fabry disease may also have a clouding of the outer most portion of the eye (cornea). This symptom is usually diagnosed by an eye doctor (ophthalmologist). The cloudiness may increase with time. A decreased ability to sweat is another common symptom of Fabry disease.
Due to the progressive nature of Fabry disease, most affected individuals develop additional symptoms by 40 years of age. The buildup of globotriaosylceramide in the heart can lead to heart problems. These heart problems can include changes in the size of the heart (left ventricular enlargement), differences in the heart beat, and leaky heart valves. Mitral valve prolapse is a particular type of leaky heart valve that is common in Fabry disease, even in childhood. The excess globotriaosylceramide can also disrupt normal blood flow in the brain. In some cases this can cause dizziness, seizures, and stroke. The kidneys are other organs affected by Fabry disease. Kidney problems can lead to an abnormal amount of protein in the urine (proteinuria). Severe kidney problems can lead to kidney failure.
Although the symptoms of Fabry disease usually occur in males, female carriers may occasionally exhibit symptoms of the disease. Some carriers experience pain in their hands and feet. Carrier females may also have proteinuria and clouding of their cornea. It is rare for a female to experience all of the symptoms associated with Fabry disease.
Initially, the diagnosis of Fabry disease is based on the presence of the symptoms. It should also be suspected if there is a family history of the disorder. The diagnosis of Fabry disease is definitively made by measuring the activity of the alpha-galactosidase enzyme. When the activity is very low, it is diagnostic of Fabry disease. This enzyme analysis can be performed through a blood test. Measuring the activity of the enzyme can also detect a female carrier. Women who are carriers of Fabry disease have enzyme activity that is lower than normal.
Prenatal diagnosis is possible by measuring the alpha-galactosidase A activity in fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). Fetuses should be tested if the mother is a carrier. A woman is at risk of being a carrier if she has a son with Fabry disease or someone in her family has Fabry disease.
Treatment and management
There is currently no cure for Fabry disease. However, there are clinical trials underway in which individuals with Fabry disease are being given the alpha-galactosidase A enzyme as a form of enzyme replacement therapy. If successful, this enzyme replacement therapy may reduce or eliminate the symptoms associated with Fabry disease.
Until the enzyme replacement therapy is proven to be safe and effective, individuals with Fabry disease must rely on traditional treatments. Individuals with Fabry disease are recommended to have routine evaluations of the their heart and kidneys. Some individuals with kidney disease require a special diet that is low in sodium and protein. Dialysis and kidney transplantation may be necessary for patients with severe kidney disease. Certain medications may reduce the risk of stroke. Finally, individuals with Fabry disease are recommended to avoid the situations that cause the pain in their hands and feet to grow worse. In some situations medication may be required to reduce the pain.
The prognosis for individuals with Fabry disease is good, especially with the arrival of enzyme replacement therapy. Currently, affected individuals survive into adulthood, with the symptoms increasing over time.
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Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.
Deptartment of Human Genetics, International Center for Fabry Disease. Box 1497, Fifth Ave. at 100th St., New York, NY 10029. (866) 322-7963. <http://www.mssm.edu/genetics/fabry>.
Fabry Support and Information Group. PO Box 510, 108 NE 2nd St., Suite C, Concordia, MO 64020. (660) 463-1355. <http://www.cpgnet.com/fsig.nsf>.
National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424. <http://www.ninds.nih.gov>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
Fabry Disease Home Page. <http://www.sci.ccny.cuny.edu/~fabry/>.
Online Mendelian Inheritance in Man (OMIM). <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?301500>.
Holly Ann Ishmael, MS, CGC.