Fabry disease is a rare hereditary disorder, affecting approximately one in 40,000 people, where abnormal amounts of a fatty substance called ceramide trihexoside (CTH) build up throughout the body. This is due to an inherited deficiency of a vital enzyme called alpha galactosidase A (Alpha Gal-A), which normally breaks down the CTH into harmless by-products. CTH is produced constantly within all cells as part of normal metabolism. Because the CTH is not being broken down and removed from the cells, it tends to accumulate to toxic levels. Because of this accumulation, Fabry disease is often referred to as a storage disorder.
How the Disease Is Inherited
Fabry disease is an inherited disorder - it is passed down from generation to generation. Every cell in the body has 23 pairs of chromosomes, with one chromosome in each pair derived from each parent. One pair of chromosomes is responsible for determining your sex; females have two X-chromosomes, one inherited from each parent, while males have one X-chromosome inherited from their mother and one Y-chromosome inherited from their father.
The Alpha Gal-A gene is found on the X-chromosome. This means that females have two copies of the Alpha Gal-A gene, whereas males only have one copy of the gene. This means there are five possible combinations of the Alpha Gal-A gene:
A male can have one X-chromosome with the normal Alpha Gal-A gene, and one Y-chromosome. This male will not have Fabry disease.
A male can have one X-chromosome with a defective Alpha Gal-A gene, and one Y-chromosome. This male will have Fabry disease.
A female can have two X-chromosomes, both with the normal Alpha Gal-A gene. This female will not have Fabry disease.
A female can have one X-chromosome with the normal Alpha Gal-A gene, and one X-chromosome with the defective Alpha Gal-A gene. This female will be a carrier who is usually somewhere between being asymptomatic and having Fabry disease (carriers are usually at the asymptomatic end of the spectrum).
A female can have two X-chromosomes, both with the defective Alpha Gal-A gene. This female will have Fabry disease. This is extremely rare.
What this Means for your Family
If you are a male with Fabry disease your children will be:
Boys who do not have Fabry disease - they do not have the defective gene.
Girls who are carriers of Fabry disease - they have one copy of the defective gene and one copy of the normal gene.
If you are a female carrier things are a little more complicated:
If you have a son, he has a 50% chance of having Fabry disease.
If you have a daughter, she has a 50% chance of being a carrier of Fabry disease.
It is all down to chance, so it is possible that all or none of your children are unaffected by Fabry disease in any way.
Occasionally, a child with or carrying Fabry disease is born to parents who do not have the defective gene. This is due to a new mutation of the Alpha Gal-A gene, and is not something that can be predicted.
Symptoms Of Fabry Disease
People with Fabry disease may experience a wide range of symptoms, because CTH accumulates in cells throughout the body. Most of the symptoms seem to be related to deposition of CTH in the cells that make up small blood vessels, particularly those that supply blood to the brain, heart, kidneys and nerves.
For a lot of patients, the most prominent symptom of Fabry disease is pain. Many patients experience severe pains in their hands and feet, especially in hot weather or after exercise or illness. They often describe the pain as 'burning' or 'severe ache'. The pains are due to damage to the nerves due to CTH build-up and is called neuropathic pain. Because these pains often start in childhood and are associated with exercise, many children with Fabry disease have the added indignity of being seen as being difficult or neurotic as physical education can be such an ordeal. Some patients with Fabry disease have an inability to perspire, and so can overheat with exercise or in hot weather. This will exacerbate the pain.
Most people with Fabry disease develop a spotted, dark-red rash called Angiokeratoma Corporis Diffusum Universale1. This rash can be found anywhere on the body, but is most commonly found in the belly button, the groin, buttocks, flanks and genitals. The spots occasionally bleed when rubbed, and this can be distressing during sexual intercourse.
People with Fabry disease usually have a characteristic 'whorl' haziness of their cornea, located at the front of the eye. This does not affect vision, and is a good way of making an initial diagnosis of Fabry disease. Many carriers have this haziness as well.
As people with Fabry disease get older, the accumulation of CTH throughout the body can cause more and more problems. This can include heart and kidney disease; a lot of Fabry patients experience a slow and steady decline in their kidney function, with increased quantities of blood and protein in their urine. Sometimes this decline in kidney function can reach the stage where dialysis or a kidney transplant is needed. Transplants in people with Fabry disease are usually very successful, and can provide significant benefit2.
Some people with Fabry disease experience heart and circulatory problems, such as heart attacks, an enlarged heart, high blood pressure and defective heart valves, as well as an increased risk of stroke.
Other symptoms of Fabry disease include swollen ankles, occasional diarrhoea, abdominal discomfort or bloating, ringing in the ears and anaemia.
Carriers of Fabry disease can experience any of the symptoms described above. It is uncommon to find a carrier who has symptoms as severe as a male with Fabry disease. Not everybody with Fabry disease will have the whole range of symptoms - everybody is unique and has their own combination of problems.
This is difficult to determine, because everybody with Fabry disease is affected in a different way. The average life-span of somebody with Fabry disease is 42 years of age, but with careful medical supervision, many people can live to a ripe old age. If you have Fabry disease, don't think that you will drop down dead soon after your 40th birthday - the average lifespan is low because of the very short lifespan of a few very severely affected individuals. Fabry patients are more likely to die of a stroke or heart attack than the average population.
Currently there is no licensed cure for Fabry disease, although a number of companies are researching the use of Alpha Gal-A replacement therapy. Results are not yet publicly available. Until then, treatment is symptomatic. Fabry pain is often difficult to treat, but often responds to medication used to treat epilepsy such as carbamazepine or gabapentin, along with conventional painkillers such as paracetamol (called acetaminophen in parts of North America). Heart and kidney problems can be dealt with as they arise, but often kidney damage cannot be reversed and a transplant or dialysis is required.
If you would like more information about Fabry disease, the Fabry Support & Information Group have a discussion group and other resources.