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About Fabry Disease

6 October 2011

Fabry disease is an inherited condition that affects only a few thousand people worldwide. Fabry disease causes a wide range of signs and symptoms that can range from mild to severe and life-threatening.

How Fabry Disease Affects the Body

Our bodies contain thousands of active substances called enzymes. In people without Fabry disease, the enzyme alpha-galactosidase A (pronounced al-fa-ga-lak-toe-si-daze a), or alpha-GAL, helps the body to break down a fatty substance called globotriaosylceramide (pronounced glow-bow-tri-oh-syl-ser-a-mide), or GL-3.

People with Fabry disease are missing or have insufficient amounts of the alpha-GAL enzyme, which is important in the healthy functioning of organs. The alpha-GAL enzyme is responsible for removing a fatty substance, GL-3, from cells throughout the body. Without enough of this enzyme, the GL-3 substance builds up in cells. GL-3 build-up in kidney cells may cause severe kidney problems, including kidney failure.
People with Fabry disease may experience a wide range of signs and symptoms, including severe conditions such as kidney failure, heart problems, and stroke.

The illustrations below show how unaffected cells can clear GL-3 (left), whereas GL-3 builds up in cells affected by Fabry disease (right).

Genetics and Fabry Disease

Fabry disease is a genetic disease passed down from parents to children. To better understand how Fabry disease is inherited, and who may be affected in the family, a basic understanding of genetics and inheritance is helpful.
Genetics

All of our hereditary information is contained on genes. We have genes that determine our physical characteristics like our hair color, eye color, height, etc. We also have genes that are responsible for specific functions such as our metabolism and growth.

All of our thousands of genes are contained on chromosomes. Each human cell contains 46 chromosomes (23 pairs). We inherit 23 chromosomes from our mother and 23 from our father for a total of 46 chromosomes. Two of the 46 chromosomes (or one pair) are called the sex chromosomes and are referred to as either an X or a Y chromosome. Women have two X chromosomes (XX) and men have one X chromosome and one Y chromosome (XY). Since women only have X chromosomes (XX), they will always pass an X chromosome to their children. On the other hand, men can pass an X or a Y chromosome to their child. If a man passes the X chromosome to his child, the child will be female. If a Y chromosome is passed on, the child will be male. It is completely random whether a man will pass an X or Y chromosome to his child.

The X and Y chromosomes are called sex chromosomes because most of the genes located on them are involved with determining a person's sex and sexual function. What may be confusing is that, while some genes on the X chromosome are responsible for sexual function and fertility, there are also other genes located on this chromosome that have nothing to do with sex. For example, the gene that helps our blood to clot and the gene that allows us to see color are located on the X chromosome. Likewise, the gene that makes alpha-GAL is located on the X chromosome. In patients with Fabry disease, this gene does not function properly and the body does not make sufficient quantities of alpha-GAL.

Inheritance

The Fabry gene is passed on in one of two ways:

1) A father with Fabry disease (Affected Father) will pass the gene onto all of his daughters and none of his sons (see the figure below). As discussed above, the Fabry gene is located on the X chromosome and a man will only pass his X chromosome (which carries the Fabry gene) on to his daughters. His daughters will likely not have Fabry disease but will be Fabry carriers. This is because the daughters' other X chromosome will likely carry a healthy gene that is capable of making alpha-GAL. However, some female Fabry carriers experience symptoms of  Fabray disease.

Xr= chromosome w/ Fabry gene

2) If a mother carries the Fabry gene (Carrier Mother), there is a 50% chance that she will pass the gene onto her sons or daughters (see the figure below). Her sons who inherit the gene will have Fabry disease. Her daughters who inherit the gene will be carriers.


Xr= chromosome w/ Fabry gene

Fabry Disease in Men and Women

Fabry disease can affect anyone who inherits the faulty gene - both males and females. Virtually all males with the Fabry gene develop the disease and are likely to express some or many of the classic Fabry symptoms. In women with the Fabry gene, however, symptoms can range from none (in asymptomatic carriers) to very serious manifestations similar to those seen in males. That's because the level of symptom severity often depends on the amount of alpha-GAL enzyme produced in the body. Females with the faulty gene can have anywhere from near-normal levels of alpha-GAL to no active enzyme. Males, on the other hand, usually have little or no active alpha-GAL and are more likely to experience more severe symptoms than females.

Tracing Fabry Disease in Your Family

Fabry disease is inherited, so if one person in a family has the disease, others may have the disease as well. The earlier Fabry disease is diagnosed, the sooner doctors can begin monitoring and treating the associated symptoms.

A medical family tree can help you understand how Fabry disease has affected relatives, both living and deceased, as well as how the gene may affect generations to come. The link below provides an example of a medical tree that you can download to your computer. In this family tree, you can fill out health information about yourself, your immediate and extended family, and family members from past generations. It is recommended that you seek the assistance of a health care provider or a medical genetic counselor to complete this historical account.

Signs and Symptoms

Because Fabry disease is rare and not always well recognized, its symptoms are sometimes overlooked or attributed to other more common conditions. There are, however, a number of signs and symptoms that people with Fabry disease typically experience:

• Burning, tingling pain in the hands and feet
• Pain radiating throughout the body
• Impaired sweating
• Heat/cold intolerance
• Skin rashes (angiokeratomas)
• Corneal whorling (pattern on the cornea of the eye – generally does not affect vision and can only be seen using special eye exam equipment called a slit lamp)
• Hearing problems
• Gastrointestinal problems, such as diarrhea or vomiting
• Heart problems (including enlarged heart and heart valve problems)
• Kidney problems
• Nervous system problems, such as stroke
• Psychological issues, such as depression
 
The graphic below demonstrates how the signs and symptoms may become progressively more serious and numerous as people with Fabry disease get older.

Since Fabry disease is X-linked, it predominantly affects males, although females may have disease manifestations to a greater extent than previously thought. The rates of progression of organ impairment may be slower in females than in males with Fabry disease, and severity of signs and symptoms is variable.

Diagnosis

Signs and symptoms of Fabry disease may be first noted in childhood or adolescence. However, because physicians often do not attribute those signs and symptoms to Fabry disease, patients may not be diagnosed until adulthood.

Studies have shown the average age of diagnosis of Fabry disease was approximately 29 years. Delayed diagnosis may be due to under-recognition of the disease.

Delayed diagnosis may also be due to the fact that Fabry disease symptoms are similar to those of other more common disorders, such as rheumatoid or juvenile arthritis, rheumatic fever, erythromelalgia, neurosis, Raynaud’s syndrome, multiple sclerosis, lupus, acute appendicitis, “growing pains” or malingering, petechiae, or collagen vascular disease.
Fabry disease is a progressive disorder, therefore it important that patients be identified as early as possible. Earlier identification and diagnosis is important. Please note: The safety and effectiveness in pediatric patients have not been established.

Fabry Disease Testing

Fabry disease is inherited, which means it is passed down in families. A genetic counselor can help you to better understand your risk of having Fabry disease and passing it on. For more information on how Fabry disease is inherited in families, see Genetics and Fabry Disease.

If you or a family member experience signs and symptoms common to Fabry disease, consult with your doctor. After an examination, he or she can determine whether to run a test for Fabry disease. This test, called an enzyme assay, measures the amount of alpha-GAL enzyme activity in the blood.

Treatment

Until the availability of enzyme replacement therapy, there was not a specific treatment for Fabry disease. Doctors managed their patients' signs and symptoms with measures such as medications for pain or dialysis for kidney failure. Today, those measures still play a role in treatment, but it is also possible to replace the deficient enzyme using Fabrazyme® (agalsidase beta).

Treatment with Fabrazyme is not a cure for Fabry disease; that is, it does not correct the genetic defect. Fabrazyme reduces GL-3 in certain cells. Treatment with Fabrazyme may improve signs and symptoms of Fabry disease; however, the relationship between GL-3 reduction and specific signs and symptoms has not been established. In order to benefit from the treatment, patients need to receive regular infusions.



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