Fabry Disease (Fabry Syndrome): Causes, Symptoms & Treatment

Fabry disease (Fabry syndrome) is a rare hereditary metabolic disorder with a progressive course, which is due to a disturbance in the breakdown of fat in the body’s cells as a result of an enzyme deficiency. The course of the disease is more pronounced in males than in females. Enzyme replacement therapy can slow the progression of Fabry disease and limit secondary diseases.

What is Fabry disease?

Fabry disease or Fabry syndrome is the name given to a rare genetic metabolic disorder associated with a disorder of enzyme activity. In Fabry disease, there is an organism-wide deficiency of the enzyme alpha-galactosidase as a result of decreased or absent synthesis of the enzyme. Alpha-galactosidase regulates the degradation of certain lipid metabolic substances in the lysosomes (cell organelles responsible for the degradation of foreign substances). The present disruption of this lipid degradation causes glycosphingolipids, primarily ceramide trihexoside, to be deposited in the cells, leading to the cellular damage characteristic of Fabry disease, up to and including death.

Causes

Fabry disease is a genetically determined deficiency of the enzyme alpha-galactosidase, which leads to a disturbance in the breakdown of fat in the lysosomes of the cells (lysosomal storage disease). In Fabry disease, there is a genetic defect on the X chromosome (X-linked disease) that results in impaired synthesis of the enzyme. In Fabry disease, this manifests itself either in a complete absence or reduced concentration of alpha-galactosidase in the organism or in the synthesis of an inactive or only weakly active form of the enzyme. The resulting accumulation of glycosphingolipids, particularly the nondegradable ceramide trihexoside, in the endothelial (inner-walled cells of the lymphatic and blood vessels) and smooth muscle cells of the blood vessels and in the neurons of the central and peripheral nervous systems causes the symptoms significant for Fabry disease.

Symptoms, complaints, and signs

Characteristically, Fabry disease affects men significantly more severely and more often than women. In women, the disease usually begins later with an overall milder course. The first symptoms appear in the first decade of life. There are sudden attacks of pain in the feet and hands. The pain subsides again within a few days. Furthermore, patients suffer from tingling and burning sensations in the hands and feet, which can be aggravated by temperature changes. In addition, nausea, vomiting and diarrhea are also frequently observed in the children. This can lead to malnutrition due to chronic loss of appetite. Sweating is often decreased. This can cause heat exhaustion during physical exertion. Some patients also sweat more. So-called angiokeratomas develop on the buttocks, groin, thighs or belly button. These are benign red-purple skin elevations caused by local dilation of blood vessels. Very early on, corneal opacities may also appear. In later stages, the kidneys, heart and brain are increasingly affected. Without treatment, these organ involvement inevitably lead to death as the disease progresses. Renal failure usually begins in the second or third decade of life and used to be considered the most common cause of death in Fabry disease. Furthermore, heart diseases such as angina pectoris, cardiac arrhythmias or valvular heart disease often occur. Strokes caused by vascular changes in the brain also often occur before the age of 50.

Diagnosis and progression

In Fabry disease, initial suspicion is based on characteristic symptoms such as eye changes (corneal changes, lens opacities), blue-red to blackish changes in the skin and mucous membranes (so-called angiokeratomas), paresthesias (tingling and/or numb, burning sensation in the hands or feet), disturbances in the body’s thermoregulation (decreased or increased sweating), and hearing loss and proteinuria (protein in the urine). The diagnosis of Fabry disease is confirmed by determining the alpha-galactosidase activity and ceramide trihexoside concentration in the blood. An absent or reduced activity of the enzyme as well as an increased concentration of ceramide trihexoside indicate Fabry disease.In addition, the diagnosis can be confirmed by a kidney biopsy and a genetic test. Fabry disease usually has a progressive, lethal course and, if left untreated, leads to damage to the kidneys (renal insufficiency), heart (valvular insufficiency) and brain (ischemic insults). However, the symptoms and sequelae of Fabry disease can be limited by early initiation of therapy.

Complications

As a result of Fabry disease, affected individuals suffer from severe pain. These can thereby also occur in the form of pain at rest and lead to sleep disturbances or other complaints, especially at night. Sensitivity disorders or paralysis of various parts of the body can also occur, making the patient’s daily life more difficult. Sufferers also suffer from increased perspiration and various changes in the skin. These can also have a negative impact on the patient’s aesthetics. If Fabry disease is not treated, it can also lead to problems with the cardiovascular system, which in the worst case can lead to the death of the affected person. The patient’s quality of life is significantly reduced by Fabry disease. Likewise, hearing loss or, in the worst case, complete deafness may develop. Affected individuals may also experience renal insufficiency and die from it. Fabry disease is treated with the help of infusions. As a rule, affected individuals are dependent on lifelong therapy, since causal treatment of the disease is not possible. In some cases, transplantation of a kidney is also necessary. Patients must also maintain a healthy lifestyle and usually avoid nicotine.

When should you see a doctor?

Pain as well as pain attacks should be presented to a doctor. If they occur, action is needed as soon as possible. Pain medications should not be taken until the attending physician has been consulted, as there is a high risk of possible complications. If vomiting, diarrhea, nausea or a general feeling of malaise occurs, a doctor is needed. If there is a loss of appetite or unwanted weight loss, a visit to the doctor should be made to determine the cause. Decreased sweat production is a sign of a health condition that should be investigated. If a feeling of internal dryness occurs during physical exertion, dehydration is imminent in severe cases. Thus, the sufferer suffers a potentially life-threatening condition that must be treated as soon as possible. If there are fluctuations in body temperature or sensory disturbances, a doctor is also needed. A tingling sensation in the limbs or a burning sensation should be presented to a physician. Impaired vision or clouding of the cornea are signs of a disease that needs to be examined and treated. In case of general dysfunction, irregularities of the heart rhythm as well as circulatory disorders, a visit to the doctor is advisable. Reduced performance or persistent psychological problems should be discussed with a physician so that the cause can be clarified. Since Fabry disease can lead to the death of the affected person if left untreated, a visit to the doctor should already take place at the first discrepancies.

Treatment and therapy

Fabry disease is usually treated causally with enzyme replacement therapy using genetically synthesized alpha-galactosidase. Infusion of synthetic alpha-galactosidase compensates for enzyme deficiency and alleviates symptoms by successively degrading metabolites stored in cells while preventing further accumulation. Accordingly, enzyme replacement therapy can significantly slow disease progression. Since the synthetic enzyme is also degraded within these endogenous degradation processes, regular (usually every two weeks) and lifelong infusions are required. While the first infusions should take place under medical supervision, these can also be given as part of home therapy in the further course of therapy and if the drug is well tolerated. In addition, the symptoms and complaints present are treated in parallel (symptomatic therapy). Thus, in an advanced stage of Fabry disease, which in many cases is accompanied by renal insufficiency, dialysis or a kidney transplant may become necessary.Concomitant recommendations for Fabry disease include a low-fat diet, adequate fluid intake, abstaining from nicotine use, and avoiding factors that trigger stress and pain.

Outlook and prognosis

For the prognosis of all Fabry disease sufferers, it is critical that the disease be detected and treated early. If left untreated, increasing accumulation of globotriaosylsphingosine (LysoGb3) causes more and more damage to vital organs to develop until they can no longer perform their function. In non-treated affected individuals, the average life expectancy is 50 years in men and 70 years in women. Compared with the general population, this is equivalent to a reduction in life expectancy of 20 and 15 years respectively. Those affected eventually die of terminal renal failure or cardio- or cerebrovascular complications such as cerebral hemorrhage, cerebral infarction or myocardial infarction. With adequate and early treatment, the prognosis is good. In general, the later the diagnosis and the start of treatment, the greater the reduction in life expectancy. If nephropathy (kidney disease) or advanced cardiomyopathy (heart muscle disease) has already developed, this has a negative impact on the prognosis. Repeated strokes and transient ischemic attacks (circulatory disorders of the brain) also worsen the prognosis. In addition, renal, cerebrovascular as well as cardiovascular complications can reduce life expectancy. In individual cases, strokes and transient ischemic attacks can even occur as the first manifestation of Fabry disease. For example, according to one study, 50 percent of males and 38 percent of females with Fabry disease suffered their first stroke before the initial diagnosis was made.

Prevention

Because Fabry disease is a genetic metabolic disorder, no preventive measures exist. However, early diagnosis and early initiation of therapy can positively influence the course of the disease and limit secondary diseases. For example, Fabry disease in children of an affected parent can be diagnosed as early as the 15th week of pregnancy as part of prenatal diagnostics, which ensures an early start of therapy.

Follow-up

In Fabry syndrome, the measures of a follow-up are very limited in most cases. Because it is a hereditary disease, it usually cannot be completely cured. Affected individuals are therefore dependent on early diagnosis to prevent further complications or worsening of symptoms. In case of a renewed desire to have children, genetic testing and counseling can be performed to prevent a recurrence of the syndrome. Affected individuals themselves are usually dependent on taking various medications for Fabry syndrome. The doctor’s instructions should be followed, and the doctor should always be contacted first if there are any questions or if there is any uncertainty. Since the disease cannot be completely treated, some of those affected are dependent on dialysis or, in the further course, on the transplantation of a kidney. In this case, the support and care of one’s own family also has a very positive effect on the further course of the disease and can also prevent depression or other psychological upsets. Fabry syndrome in many cases reduces the life expectancy of the affected person.

Here’s what you can do yourself

The many symptoms related to digestion and the gastrointestinal tract can be counteracted with a suitable and balanced diet. It helps many patients to keep a food diary and thus to be able to classify the tolerance of different foods for themselves. In this diary, patients note which foods they have eaten and when. At the same time, subsequent gastrointestinal complaints are also written down so that possible intolerances can be analyzed. There is no general dietary recommendation, as each patient suffers from different digestive problems and the food selection should therefore be adapted to individual needs. In principle, experts advise Fabry disease patients to follow a diet that is as low in fat as possible.In the advanced stage of the disease, special diets may be necessary, as kidney function can be impaired by a high-sodium diet (too much salt), for example. For many sufferers, contact with a self-help group is also helpful. Especially for the psychological suffering that can accompany the disease, the exchange with other patients is an important support. In addition, tips can be shared on how to deal with Fabry disease on a day-to-day basis. Contact points and discussion groups can be found online.