Related Diseases
Fabry
Symptoms
Management
Treatment
Inheritance
Carrier Testing
Additional Information Links
Fabry disease was first described in 1898 by Anderson and Fabry. Today this lysosomal storage disease affects an estimated 1 in 40,000 males. Fabry disease results from a deficiency of an enzyme called a-galactosidase. This enzyme is necessary to break down globotriaosylceramide (GL-3), one of the fatty substances known as glycosphingolipids. Without enough a-galactosidase these fatty substances build up throughout the body but primarily in the kidneys, eyes and heart.
Symptoms
Males
Typically, the disease begins in childhood with episodes of pain and burning sensations in the hands and feet. In addition, young patients often develop a spotted, angiokeratomas - dark red skin rash, seen most densely from the umbilicus to the knees, a decreased ability to perspire, and a characteristic change on the cornea of the eye which does not affect vision. The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions.
The disease is slowly progressive and symptoms of kidney, heart and/or neurologic involvement usually occur between the ages of 30 to 45. Many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Therefore, it is important to annually monitor kidney function by blood and urine tests because kidney disease is a major complication that can occur in affected males.
A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
Other symptoms may include varying degrees of abdominal discomfort, frequent bowel movements shortly after eating, joint pain, back pain primarily in the kidney region or tinnitus - ringing of the ears.
Females
Females may show a wide range of clinical manifestations. Some individuals remain completely asymptomatic and have normal levels of a gal a while some are as severely affected as homozygous males. This variability is most likely to be caused by random inactivation of one copy of the X-chromosome in each cell. The most common symptom of Fabry disease seen in heterozygous females is corneal dystrophy, which occurs in around 70% of females. Other symptoms that have been reported in females with Fabry disease include: angiokeratomas, acroparesthesias, anhidrosis, gastrointestinal disturbances, vascular lesions in the conjunctiva and retina, kidney disease, autonomic and other neurological complications such as tinnitus and vertigo, cardiovascular abnormalities, cerebrovascular abnormalities, fatigue. Women may often be misdiagnosed as having lupus or other conditions.
Children
Although the signs and symptoms of Fabry disease generally appear during childhood, the diagnosis may often be missed. The earliest symptoms of Fabry disease in children are usually pain and angiokeratomas. The pain may, however, be dismissed as 'growing pains', while angiokeratomas may be overlooked during a routine clinical examination, particularly if they are confined to locations such as the backs of the ears. Cardiac and renal involvement can also begin in childhood, thus early diagnosis and careful monitoring are necessary. Other symptoms include hypohidrosis -inability to sweat, gastrointestinal disturbances that mimic chronic inflammatory bowel disease, recurrent nausea and vomiting, vertigo, tinnitus, headaches, and fevers.
| Fact: Fabry Disease follows an x-linked pattern of inheritance and therefore affects males more often and more severely than females. |
The manifestations of Fabry disease are diverse and affected individuals benefit from regular monitoring and treatment by a multidisciplinary team of medical sub-specialists.
Management of pain and fatigue often involves avoiding stress and temperature changes and getting plenty of fluids and rest. Patients with frequent and severe pain may be treated with medications.
Kidney problems vary greatly from mild to severe. Mild kidney problems may be controlled with a low-protein diet. In severe cases hemodialysis –removing, purifying and replacing blood and kidney transplantation can be lifesaving measures for patients with severe kidney involvement, but they do not improve the other manifestations of the disease.
Heart or Cardiac complications are often controlled with medications. Heart problems include enlarged heart and heart valve abnormalities. In some cases coronary angioplasty or coronary bypass surgery may be necessary. Additionally, a pacemaker may be inserted to control heart beats if medications are not sufficient.
Brain vascular involvement can occur when significant amounts of GL-3 accumulate causing small arteries in the brain to thicken. To help prevent stroke, physicians may prescribe medications that prevent the blood from clotting.
Skin rashes or angiokeratomas commonly associated with Fabry disease can be removed with laser treatments, which generally cause little scarring.
Gastrointestinal symptoms, including stomach pain, nausea, and diarrhea, may improve with a low-fat diet. Alternatively, your doctor may prescribe one of two treatments: 1) an enzyme that helps with digestion, or 2) a motility agent that improves the rate at which food moves through the digestive tract
More recently, enzyme replacement therapy has become commercially available and has been successful in reducing the amount of GL-3. The treatment involves infusions of Fabrazyme®, a chemically modified enzyme that acts like the naturally occurring alpha-GAL enzyme and targets GL-3 inside the cell. Once inside the cell, it breaks up the GL-3 into smaller components that can then be removed from the cell by natural processes. The relationship between GL-3 reduction and the improvement of specific signs and symptoms, however, has not been established. The disadvantages of this therapy are its high cost and the need for repeated infusions of the enzyme. To learn more visit www.fabrazyme.com.
Fabry disease may affect individuals of any ethnic background. It differs from Tay-Sachs and most of the other allied diseases in that it follows an X-linked pattern of inheritance and therefore affects males more often and more severely than females. The term “X-linked” refers to the location of the a-galactosidase gene on the X chromosome. The degree to which a person experiences symptoms depends on the amount of a-galactosidase they have. Males, with only one X chromosome bearing the faulty gene, have little or no enzyme activity. Females with one normal gene and one faulty gene, are said to be carriers. The absence or presence of symptoms in female carriers is related to the level of residual enzyme activity in their cells. There is a high degree of symptom variability in females.
The first male in a family to be diagnosed with Fabry disease is often the son of an unsuspecting female carrier with no symptoms of the disease. A woman who is a carrier of Fabry disease has a 25% chance with each pregnancy of having an affected child; in other words, on average, half of her sons will be affected. She may have a daughter who is a carrier, a daughter who is not a carrier, a son without the disease, or a son with the disease. A male with Fabry disease who has children will have daughters who are carriers but sons will not be affected with Fabry disease.
Carrier testing for Fabry disease can be done by measuring the level of a-galactosidase in women who are potential carriers. It is not possible to identify 100% of carriers by this method because the levels of enzyme in carriers and non-carriers overlap slightly. The identification and cloning of the gene for a-galactosidase has opened new options for carrier identification through direct mutation testing and linkage analysis (a type of DNA-based testing which compares the DNA of affected and unaffected relatives to that of the fetus). Genetic counselors can help explain options for carrier testing to women with a family history of Fabry disease.
There are several approaches to prenatal diagnosis: (1) a-galactosidase levels can be measured from amniocentesis or CVS samples; (2) DNA mutations in the a-galactosidase gene can be looked for; or (3) linkage analysis can be performed. In prenatal diagnosis of an X-linked disorder, determining the sex of the fetus is the first step in determining risk since females will usually be healthy. Again, carrier and prenatal testing for people with a family history of Fabry disease should be offered in conjunction with genetic counseling so that people can be aware of their options and make informed decisions.
Additional Informational Links
The following online resources may be helpful in learning more about Fabry Disease or locating support: