A wide variety of signs and symptoms are associated with Fabry disease. A person with Fabry disease may not experience them all and the severity of symptoms can vary from person to person. This is why Fabry disease can be such a difficult condition to identify and diagnose, although a detailed family history can help. However, as GL-3 builds up, health problems and symptoms tend to get progressively worse.

Although symptoms of Fabry disease will almost certainly be apparent in affected males, females may also have symptoms. Symptoms in females may be no less severe, but they tend to appear at an older age than in males.1,2

Pain

Pain is one of the more common symptoms of Fabry disease and is often one of the first symptoms people experience. For many, pain is brought on and worsens with exposure to hot temperatures, changes in weather, stress, fatigue, exercise and illness

There are two major types of pain associated with Fabry disease:

1. Ongoing burning, tingling pain and discomfort. This type of pain is called acroparesthesia and mainly affects the hands and feet.
2. "Fabry crises" are usually experienced as episodes of intense, excruciating, burning pain, felt initially in the hands and feet and radiating to other parts of the body. These crises can be debilitating and can last from minutes to several days.

Impaired Sweating

Many people with Fabry disease sweat less than people without the disease. They may either perspire very little (hypohidrosis) or not at all (anhidrosis). This can cause overheating, frequent fevers, and sensitivity to weather extremes. Impaired sweating is generally caused by damage to the nerves and sweat glands.

Exercise Intolerance

Some people with Fabry disease are unable to tolerate physical exertion, and may tire or become overheated even after mild activity. Physical exertion may also trigger episodes of pain. For these reasons, people with Fabry disease may need to modify their physical activities and/or avoid certain activities all together.

Gastrointestinal Symptoms

Early symptoms of Fabry disease can include abdominal cramps, frequent bowel movements shortly after eating, diarrhea and nausea.

Skin – Angiokeratomas

Angiokeratomas are the most visible, recognisable clinical feature of Fabry disease.

These dark red or purple skin lesions (ranging in size from pinpoint to several millimetres in diameter) do not blanch with pressure and are usually distributed on the buttocks, groin, umbilicus, and upper thighs (bathing trunk distribution). This rash-like skin condition is not painful. It can also appear on other parts of the body such as the lips, tongue, hands and toes. It can be confined to a small area of the body or may affect a larger area. Lesions generally appear in adolescence or young adulthood. Angiokeratomas are almost universal in males and they occur in approximately 30% of females

References

1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001;3733-3774.
2. Menkes DL. Images in neurology. The coetaneous stigmata of Fabry disease: an X-linked phakomatosis associated with central and peripheral nervous system dysfunction. Arch Neurol. 1999;56:487.

Angiokeratomas in the umbilical region

Example of angiokeratomas reproduced with permission from www.dermnet.com

Eyes

The surface layer of the eye (cornea) may appear abnormal when examined using special equipment that an optician or an eye specialist (ophthalmologist) may have. This starburst, or whorling appearance, which is called cornea verticillata, does not affect vision but may increase with time. It occurs in approximately three-quarters of patients and can be a reliable indicator of Fabry disease.3 

Ocular manifestations of Fabry disease: data from the Fabry Outcome Survey British Journal of Ophthalmology  

Ears

Fabry disease can affect hearing and patients can experience a ringing in the ears that is called tinnitus. Most patients will have some degree of hearing loss at some time and this can either progress over time or be quite sudden.

Kidneys

The progressive build-up of GL-3 can lead to kidney problems, with over 80% of people with Fabry disease experiencing some reduction of kidney function.5 This can lead to an abnormal amount of protein in the urine (proteinuria). Kidney problems are common in males with Fabry disease; however, serious kidney problems are uncommon in females. Severe kidney problems can lead to kidney failure requiring dialysis or transplant.

Heart

Heart problems are also common to Fabry disease and may become progressively worse with age. These problems include:

• Enlarged heart
• Malfunctioning heart valves
• Irregular heartbeat
• Heart attack
• Heart failure

Brain and Nervous System

Excess GL-3 can disrupt normal blood flow in the brain. As a result, people may experience a number of symptoms including:

• Weakness
• Head pain
• Numbness
• Dizziness
• Stroke

Emotional Issues

Living with difficult physical symptoms is only one of the challenges people with Fabry disease may face. They may experience feelings of fear, depression, isolation or guilt about passing the disease along. Family members may be affected as well.

You may find it helpful to talk with someone else from the Fabry Support Group Australia – someone in a similar situation with similar concerns and fears. See Blogs

A medical genetic counsellor can help you deal with these issues as well. See Genetic Counselling.

References

1. Deegan P, et al. Journal of Medical Genetics 2006; 43: 347-352.
2. Mehta A, et al. European Journal of Clinical Investigation 2004; 34: 236-242.
3. Sodi A, et al. British Journal of Ophthalmology 2007; 91: 210-214.
4. Sodi A, et al. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS, 2006.
5. Beck M, et al. European Journal of Clinical Investigation 2004; 34: 834-844.
6. Mehta A, et al. Acta Paediatric 2005; 94 (Suppl. 447): 24-27.

Onset of Signs and Symptoms

In Fabry disease, GL-3 accumulates over time and so some signs and symptoms may not appear until a person gets older, although symptoms have been reported in children as young as two years old.1

Pain, skin rashes, heat intolerance, stomach upsets, fatigue, lack of energy and the inability to exercise are generally the first signs and symptoms to appear, but because these can be associated with other conditions, it may take many years for a diagnosis of Fabry disease to be made. In fact, up to 25% of patients are misdiagnosed.2

Kidney, heart and brain problems tend to become noticeable between the ages of 30 to 45 and it is at this point that many individuals with Fabry disease are first diagnosed.3

What is particularly concerning about Fabry disease is that there is an average delay between the onset of symptoms and diagnosis of 12 years.3 This is the same for both sexes, although the onset of symptoms tends to occur about six years later in females than males.3

Testing and diagnosis are very important as an early diagnosis is essential for good symptom management.3 Early diagnosis can also be important in helping to identify other affected family members. It has been shown that the lifespan of a man with Fabry disease is reduced by approximately 20 years and by approximately 15 years for a woman.4,5

References

1. Ramaswami U, et al. Acta Paediatrica 2006; 95: 86-92.
2. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS, 2006.
3. MacDermot KD, et al. Journal of Medical Genetics 2001; 38: 750-760.
4. MacDermot KD, et al. Journal of Medical Genetics 2001; 38: 769-775.