Fabry Disease

Fabry disease is a rare genetic disease and symptoms that affect the kidneys, heart, or brain most often occur when patients are age 30 to 45 years.

Fabry disease is a rare genetic disease a deficiency of the enzyme alpha-galactosidase A (a-Gal A) that causes a buildup of a type of fat called globotriaosylceramide (Gb3, or GL-3) in the body. Fabry disease is classified as a type of lysosomal storage disorder. Lysosomes are isolated areas of cells that contain enzymes. In a lysosomal storage disorder these enzymes do not properly metabolize certain fatty molecules. As a result, the undigested fat molecules accumulate and impair a cell's ability to function. In Fabry disease, the alpha-galactosidase A enzymes are deficient and globotriaosylceramide accumulates, which can affect the function of the skin, eyes, gastrointestinal system, kidney, heart, brain, and nervous system.

Fabry disease is the result of a mutation of the gene responsible for making alpha-galactosidase enzyme, which is located on the X chromosome. Fabry affects mostly males though rarely females may inherit the disease.

Fabry disease is a progressive disorder and symptoms that affect the kidneys, heart, or brain most often occur when patients are age 30 to 45 years.

What is the prevalence of Fabry disease?

It is estimated that Fabry disease affects 1 in 40,000 males. The prevalence of Fabry disease in females is unknown. It can affect all ethnicities, but it predominantly affects Caucasians. Late-onset forms of Fabry disease, which tend to be milder, are more common than the classic severe form diagnosed earlier in life.

• Fabry disease is a genetic disorder. A genetic disorder is caused by a mutation, or change, in a part of a person's DNA.
• In Fabry disease, the defective gene is on the X-chromosome, which is one of two sex chromosomes.
• Sex chromosomes determine a person's gender at birth. Everyone inherits one sex chromosome from each parent. Mothers pass on only X chromosomes while fathers can pass on either an X or a Y chromosome.
• The chromosome passed on by the father then determines the sex of the offspring: females have two X chromosomes (XX), and males have one X chromosome and one Y chromosome (XY).
• Fabry disease affects mostly males, who receive one X chromosome with the abnormal gene.
• Females with Fabry disease also receive one X chromosome with the defective gene, however; since females have two X chromosomes, the normal X chromosome can offer some protection against developing the disorder.
• Fabry disease is caused by a genetic mutation resulting in a deficiency of an enzyme called alpha-galactosidase A (a-Gal A). The genetic defect causes the body to not make enough of this enzyme leading to a buildup of a type of fat called globotriaosylceramide (Gb3, or GL-3) in the body cause the symptoms of Fabry disease.
• Fabry disease is the result of what is called an X-linked inheritance, that is, the disease is caused by a defect on the X chromosome. X-linked genetic mutations tend to occur mostly in males and rarely in females.
• If a mother is carrying the defective gene for Fabry disease, both male and female children have a 50% chance of inheriting it from their mother. If the father is carrying the Fabry gene, the female children will inherit the defective gene because the father passes along an X chromosome to them, but the male children, who get a Y chromosome, will not.
• Females who inherit a defective X chromosome are called carriers and they may pass the genetic mutation on to their male children.

Signs and symptoms include:

• Episodes of pain and burning sensations in the hands and feet (acroparesthesias) that can be triggered by exercise, stress, fatigue, fever, or changes in weather
• Small, dark red spots on the skin (angiokeratomas), mostly in clusters from the belly button to the knees
• Decreased ability to sweat
• Cloudiness of the front part of the eye
• Problems with the gastrointestinal system
• Ringing in the ears (tinnitus)
• Hearing loss
• Mitral valve prolapse
• Abdominal discomfort
• Frequent bowel movements after eating
• Joint pain
• Back pain in the kidney area

Complications of Fabry disease include kidney damage, heart disease and heart attack, and strokes.

Fabry disease can be difficult to diagnose because it is so rare. The standard test to diagnose Fabry disease is a measurement of leukocyte alpha-Gal A enzyme activity. This test can detect the presence of the mutation for Fabry disease in males, however, it will only identify about 50% of the female carriers.

Fabry disease may be treated using enzyme replacement therapy with agalsidase-alpha or agalsidase beta to help normalize kidney function, heart function, and blood supply to the brain.

Other treatments for Fabry disease are aimed at relieving individual symptoms.

• phenytoin, carbamazepine, or gabapentin may help prevent episodes of pain and burning sensations (acroparesthesias). Opioids may be prescribed for severe pain.
• Antiplatelet drugs such as aspirin, ticlopidine, clopidogrel, and aspirin-dipyridamole are prescribed to prevent recurrent ischemic strokes.
• Warfarin may be prescribed to prevent cardioembolic strokes.
• In severe Fabry disease that has progressed to kidney failure, hemodialysis and kidney transplantation may be necessary.
• Pancrelipase, metoclopramide, H2 blockers, such as cimetidine, famotidine, and others, and loperamide can help and soothe relieve gastrointestinal symptoms.
• ACE inhibitors and/or blockers are prescribed for high levels of protein in the urine (proteinuria) due to kidney damage.
• Hearing loss may be treated with hearing aids.
• Patients with high blood pressure (hypertension) may be prescribed antihypertensive medications and they should keep blood pressure under control.
• High cholesterol should also be treated.
• In addition to medications, patients should eat a balanced diet, exercise, and avoid smoking.

Because Fabry disease can affect many different organs many specialists may be consulted:

• Nephrologist for kidney problems
• Cardiologist for heart problems
• Neurologist or neurosurgeon for brain and nervous system symptoms
• Ophthalmologist for eye problems
• Gastroenterologist for digestive problems
• Otolaryngologist (ear, nose, and throat specialist, or ENT) for hearing problems
• Additionally, patients may benefit from working with physical therapists, nutritionists, and psychologists to help manage symptoms.

Patients may also wish to consult with genetic counselors.

The life expectancy of males with Fabry disease is about 58 years, and the life expectancy of females with Fabry disease is just over 75 years. The most common cause of death in both genders is cardiovascular disease.