Fabry Disease

Fabry disease is an inherited disorder caused by a defective gene. A person who inherits this gene is unable to produce an enzyme called alpha-galactosidase A (pronounced al-fa-ga-lak-toe-si-daze a, and commonly referred to as alpha-GAL) in amounts needed to do the job it is supposed to do.

 

The Role of GL-3

Alpha-GAL breaks down a substance, called globotriaosylceramide, (glow-bow-tri-a-oh-syl-ser-a-mide) or GL-3. Since a person with Fabry disease does not produce enough alpha-GAL, the GL-3 is not broken down, but instead builds up in the cells throughout the body. As GL-3 builds up in the walls of blood vessels and many body tissues over time, it can cause more and more damage. Because of this, major organ systems involving the heart, kidney, and brain may not function properly, causing potentially life-threatening problems.

The most serious health issues in Fabry disease usually occur in the fourth or fifth decade of life. However, signs and symptoms may appear much earlier. The earlier Fabry disease is recognized, the earlier intervention can begin.

 

Fabry disease symptoms

Most of the symptoms of Fabry disease can be attributed to GL-3 accumulation and the resulting damage to body tissues. It is important to remember that the symptoms of Fabry disease are variable, and not everyone will experience the same symptoms. 

Pain

Pain is the most common symptom of Fabry disease and is often the first symptom that brings children and adolescents to their pediatricians. For many, pain is brought on by changes in weather, exposure to hot or cold temperatures, stress, or fatigue. Most people with the disease experience two types of pain:

  • Neuropathic pain - a burning, tingling pain that mainly affects the palms of the hands and soles of the feet. Some people experience this type of pain every day, while others experience it less often.
  • "Fabry crises" - episodes of intense, burning pain that start in the hands and feet and spread to other parts of the body. These crises can last from minutes to several days.

Impaired Sweating

Most people with Fabry disease either perspire very little (hypohidrosis) or not at all (anhidrosis). This can cause frequent fevers, overheating with exercise, and sensitivity to hot weather.

Skin Rash

Small, reddish-purplish skin spots called angiokeratomas are the most visible sign of Fabry disease. Angiokeratomas ("angio" refers to blood vessels, and "keratoma" refers to callous or hardened) are often found in the area from the bellybutton to the knees, but they can occur anywhere on the body. They usually appear during adolescence. Angiokeratomas range in size from pinpoint to several millimeters.

Corneal Pattern

A distinct pattern on the cornea of the eye is often seen in people with Fabry disease. This pattern can only be seen with a common eye test called a slit-lamp exam. It is sometimes the first sign that causes doctors to suspect Fabry disease. Most males and females with Fabry disease share this common sign. The corneal pattern is sometimes called corneal whorling and it typically does not affect vision.

Gastrointestinal Problems

Many people with Fabry disease experience abdominal pain. This may include pain after eating a meal, intense diarrhea, and nausea, all of which can be severe enough to disrupt daily life.

Hearing Problems

Tinnitus, or ringing in the ears, and hearing loss are common in Fabry disease.

Kidney Problems

Reduced kidney function can begin in adolescence or young adulthood and eventually progress to renal failure, a common symptom of advanced Fabry disease. Mild reduction in kidney function can be managed in part by a low-sodium, low-protein diet. Severe kidney problems can be treated with chronic dialysis, or with transplantation in people with kidney failure.

Heart Problems

An enlarged heart, heart valve problems such as mitral valve prolapse, irregular heartbeat or arrhythmia, heart attack, and heart failure can occur as Fabry disease progresses. Some heart problems can be treated with a pacemaker or bypass surgery.

Cerebrovascular/Central Nervous System Problems

Dizziness or vertigo, headache, and early stroke are all cerebrovascular symptoms of Fabry disease. Anticoagulants (blood thinners) may be prescribed for those at risk of stroke.

Emotional Issues

People with Fabry disease may experience feelings of depression, hopelessness, alienation, and denial. It may be helpful to talk with someone else from the Fabry community – someone in a similar situation with similar concerns and fears. A medical genetic counselor may help deal with these issues.

How Fabry Disease is Inherited

To understand how Fabry disease is inherited, it helps to know something about genetics.

All males have an X chromosome and a Y chromosome in every cell in their body; women have two X chromosomes in every cell. We each inherit an X chromosome from our mother and an X or Y chromosome from our father. This determines whether we are male (XY) or female (XX).

The X chromosome contains the gene for alpha-GAL, the enzyme that is deficient in people with Fabry disease. If a man's X chromosome contains a defective alpha-GAL gene, he will pass it on to all of his daughters and none of his sons. If one of a woman's X chromosomes contains the defective gene, she will have a 50% change with each pregnancy of passing the gene on to both her sons and daughters.

Because females have two X chromosomes, and therefore two copies of the alpha-GAL gene, Fabry disease may affect them differently than it affects males. See Fabry disease in males and females for more information.

The genetic pathway of Fabry disease gives you an indication of who else in your family is affected or at risk for Fabry disease, and helps you understand who should consider testing. If you have questions about family planning, talk to your doctor or contact Genzyme Medical Information for help in locating a genetic counselor who can help you understand the inheritance pattern in your family.

If a woman with Fabry disease has children, she has a 50-50 chance (with each birth) of passing the faulty gene to both sons and daughters. Any sons and daughters who inherit the gene will have Fabry disease.

If a man with Fabry disease has children, any and all of his daughters will inherit the gene and will have Fabry disease. None of his sons will have the disease.

Indication and Usage

Fabrazyme® (agalsidase beta) is used to treat patients with Fabry disease. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. The lowering of GL-3 suggests that Fabrazyme may improve how Fabry disease affects your body; however a relationship of lower GL-3 to specific signs and symptoms of Fabry disease has not been proven.

Important Safety Information

Life-threatening severe allergic (anaphylactic) reactions have been seen in patients during Fabrazyme infusions. Approximately 1% of patients who have received Fabrazyme either during a clinical study or after Fabrazyme was approved have experienced anaphylactic or severe allergic reactions during their infusion. These reactions have included: localized swelling of the face, mouth and throat, narrowing of breathing airways, low blood pressure, hives, difficulty swallowing, rash, trouble breathing, flushing, chest discomfort, itching and nasal congestion. People who have experienced these reactions have required treatment including heart/lung resuscitation, oxygen, fluids given through the vein, hospitalization, and have needed treatment with inhaled drugs called beta-adrenergic agonists to help open the breathing airways, antihistamines, epinephrine (also known as adrenalin), and a medication given through the vein called a corticosteroid (or steroid) which helps to decrease the body’s allergic reaction by decreasing inflammation. If you experience a severe allergic or anaphylactic reaction, your healthcare professional will immediately stop the infusion of Fabrazyme and provide you the necessary emergency medical treatment. Because of the possibility that severe allergic reactions may occur, appropriate medical support should be available during your Fabrazyme infusion.

  • For patients who have had reactions to their infusions, it is recommended that they be given anti-fever and antihistamine medications right before their next infusions.
  • Infusion reactions have happened in some patients even after taking these medications and steroids by mouth before their infusions.
  • If an infusion reaction occurs, slowing the infusion rate, stopping the infusion for a short time and/or giving more anti-fever and antihistamine medications and or steroids may improve the symptoms.
  • If severe infusion reactions happen, your healthcare professional should consider stopping the Fabrazyme infusion right away and should provide medical care for your condition.
  • Severe reactions are generally managed by giving antihistamine medications, corticosteroids, fluids through the vein, and/or oxygen when needed.
  • Because severe infusions reactions may happen, medical treatment should be readily available during your Fabrazyme infusion.

Providing Fabrazyme to patients who have experienced severe or serious allergic reactions to Fabrazyme should only be done after carefully considering the risks and benefits of continuing the treatment, and only under the direct supervision of a qualified healthcare professional and with appropriate medical support readily available.

The most common side effects reported with Fabrazyme are infusion reactions, some of which were severe. When Fabrazyme was tested in clinical studies, infusion reactions occurred in approximately 50-55% of patients. Serious and/or frequently occurring side effects (occurring in 5% or more of the patients) thought to be related to Fabrazyme have included one or more of the following: chills, fever, feeling hot or cold, trouble breathing, nausea, flushing of the skin, headache, vomiting, burning and/or tingling sensation, fatigue, itching, pain in the hands and feet, high blood pressure, chest pain, throat tightness, abdominal pain, dizziness, rapid heart rate, nasal congestion, diarrhea, swelling in the legs, muscle pain, back pain, paleness of the skin, slow heart rate, hives, low blood pressure, face swelling, rash and sleepiness.

People with advanced Fabry disease may have heart problems, which may put them at a higher risk for severe complications from infusion reactions, and these patients should be watched closely during their infusion if the decision is made to give them Fabrazyme.

Other serious side effects that were seen in the clinical studies included stroke, pain, lack of muscle coordination, slow or irregular heartbeat, stopping of the heartbeat, decreased blood pumped by the heart, dizziness, hearing loss, and kidney problems resulting in too much protein leaving the body in the urine (nephrotic syndrome). These side effects also occur as part of Fabry disease.

Severe and serious infusion reactions have been reported since Fabrazyme has been approved, some of which were life threatening including anaphylactic shock (a severe allergic reaction). In addition to the above side effects, the following have been reported since Fabrazyme has been approved: joint pain, lack of strength or energy, redness of the skin, increased sweating, reactions at the place where the catheter to give the infusion is placed, increased tearing from the eyes, allergic inflammation of blood vessels, enlarged lymph nodes, decreased sensitivity to touch or pressure, decreased sensitivity of the mouth, sensations of an abnormal heartbeat, runny nose, low oxygen (in general), and low oxygen levels reaching different parts of the body.

Since Fabrazyme has been approved, there have been side effects that resulted in death that may or may not be related to the use of Fabrazyme. These included: the heart and/or lungs stop working (known as cardiorespiratory arrest, respiratory failure, and/or cardiac failure), life-threatening infection in the blood stream (known as sepsis), stroke, heart attack, kidney failure, and pneumonia. Some of these side effects were reported in Fabry disease patients with significant underlying disease.

The safety and effectiveness of Fabrazyme in patients younger than 8 years of age have not been studied.

Most patients taking Fabrazyme who develop IgG antibodies, which are commonly produced by your immune system in response to things it does not recognize as naturally being part of your body, do so within the first three months of taking the medication. In children, the development of these IgG antibodies was associated with Fabrazyme staying in the body for a longer time (prolonged half-life), which was rarely seen in adult patients.

In the clinical studies, a few patients developed IgE antibodies or a reaction to an allergy skin test specific to Fabrazyme. IgE antibodies are usually produced by the body’s immune system during an allergic reaction. Your doctor should consider testing for IgE antibodies if you experience suspected allergic reactions and consider the risks and benefits of continued treatment with Fabrazyme if you have IgE antibodies against Fabrazyme.

Fabrazyme is available by prescription only. Side effects should be reported promptly to Genzyme Medical Information at 800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Genzyme at 1-800-745-4447.

Fabry Fact

For many people, it was their eye doctor who first suspected they might have Fabry disease. That’s because nearly every person who has Fabry disease has a distinct pattern on their cornea that can only be seen during an eye exam.