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Research and DevelopmentFabry DiseaseIntroduction and Biochemistry The human body depends on a vast array of biochemical reactions to support critical functions, including the production of energy, growth and development, communication within the body, and protection from infection. Another critical function is the breakdown of large biomolecules, which is the underlying problem in Fabry disease. Fabry disease is one of several dozen lysosomal storage disorders that interferes with the body's ability to break down a specific fatty substance, termed globotriaosylceramide or Gb3 (sometimes referred to as ceramidetrihexoside). Gb3 is present in many cell types of the body, particularly in the membranes of red blood cells. Since approximately 1% of the red blood cells in circulation are replaced each day, the body has a significant amount of Gb3 to break down at all times. One of the major lysosomal enzymes involved in the breakdown of Gb3 is alpha-galactosidase A (pronounced alfa-gahlak- toe-sigh-dase A, which we will refer to as a-gal A). In patients with Fabry disease, the a-gal A enzyme is either partially or completely inactive. As a result, Gb3 accumulates in lysosomes throughout the body and impairs the function of several major organs including the kidney and heart. This can become a major problem in parts of the body that depend on small blood vessels, since these vessels can become clogged by the built-up Gb3. The areas that are most affected by the closing of small blood vessels are the kidneys, heart, nervous system, and skin. The Symptoms of Fabry disease For many patients, the earliest and most troublesome symptom of Fabry disease is pain. The pain may be characterized by periods of intense burning in the hands and feet, or by sharp, "lancinating" pain that shoots through the body. Pain may be brought on by exercise, fever, fatigue, stress, or exposure to temperature changes and can be debilitating. These painful periods are most common in childhood, and may become less common once the patient reaches the age of about 20 to 30. However, the pain may actually become worse in some patients as they grow older. In addition, many patients with Fabry disease are unable to perspire, causing further discomfort with exercise or exposure to high temperatures. Patients with Fabry disease may also develop a particular kind of rash, which is so distinctive that it is often the first clue that the patient is affected by the disease. This spotted, dark-red skin rash can occur anywhere over the body, but is most commonly found between from the belly button and the knees. Occasionally, this rash is called a "bathing trunk" rash because it affects the parts of the body that would be covered by bathing trunks. Another common symptom of Fabry disease is the development of a hazy or opaque cornea, located at the front of the eye. This finding is observed by means of a "slit-lamp" eye examination, and is often one of the earliest signs of the disease. Fortunately, this haziness does not affect vision. By the time most patients with Fabry disease reach their twenties, the buildup of Gb3 throughout the body will begin to produce symptoms. In fact, many people with Fabry disease are not diagnosed until this time, especially if their earlier symptoms were mild. In some patients, the effects on kidney or heart function will be the first to be noticed. The loss of kidney function can show up on routine blood or urine tests; for this reason, these tests are also useful for monitoring patients' disease progression as they grow older. As kidney function deteriorates, the kidneys can fail; many patients require dialysis as a result. Heart and circulatory problems may include high blood pressure, heart attacks, heart failure, mitral valve prolapse, arrhythmias, and stroke. Other symptoms associated with Fabry disease can include chronic bronchitis and shortness of breath, swelling of the legs, occasional diarrhea, osteoporosis, growth retardation, and delayed puberty. It is important to note that the symptoms of the disease are variable; no two patients will be affected in precisely the same way. Most of the symptoms of Fabry disease have been described in the medical literature as occurring in males. It is important to note, however, that a significant percentage of females suffer from the same symptoms as male patients. The Diagnosis of Fabry disease The disease is typically identified and diagnosed based on the symptoms described above. Hallmark signs such as the intense burning pain in the hands and feet, especially in those who have difficulty in perspiring, together with the "bathing-trunk" rash and changes in the eye all support the diagnosis of Fabry disease. Tests showing lower than normal activity or no activity of the a-gal A enzyme in the blood or skin can confirm this diagnosis. The signs and symptoms of Fabry disease are not widely recognized because the disease is so rare that most clinicians have never seen an affected patient. For example, the pain of Fabry disease is sometimes misdiagnosed as "growing pains" in adolescents. Unfortunately, this lack of knowledge can lead to many years or even decades of undiagnosed or misdiagnosed Fabry disease. The diagnosis of Fabry disease in one family member may lead to the evaluation and diagnosis of the disease in other relatives (discussed below). A simple test for the level of a-gal A in the blood can confirm the diagnosis of Fabry disease in individuals who have not yet shown symptoms. The following section explains why Fabry disease tends to run in families. The Genetics of Fabry disease Fabry disease is quite rare, affecting approximately one in 40,000 people in the U.S. Since Fabry disease is an inherited disorder, it is passed down from one generation to the next in a specific way. Every cell in the human body has 46 chromosomes, with 23 derived from each parent. The a-gal Agene is located on the X-chromosome, which is the only chromosome that is different in males and females. Females have two X-chromosomes, one inherited from each parent, whereas males have one X-chromosome that they inherit from their mothers and one Y-chromosome that they inherit from their fathers. This means that females have two copies of the a-gal A gene, but males only have one copy of the gene. Of note, the male Y-chromosome is never affected in Fabry disease. There are four main possibilities for the status of the a-gal A gene in an individual:
For the sake of completeness, there is a fifth possibility:
Will Fabry disease Affect My Children? This question is only relevant if you are a male with Fabry disease or a female carrier (categories 2 and 4 of the previous section). If you fall into categories 1 or 3, none of your children will have the disease or be carriers. A male with Fabry disease (category 2 above) will have:
A female carrier (category 4) will have:
I Suffer from Fabry disease and Have a Relative or Family Member with Some Similar Symptoms. Could He/She Have the disease? Yes. Fabry disease runs in families. It is important for anyone, male or female, who may have symptoms associated with Fabry disease to see their doctor or a genetic counselor. This is particularly important in light of the treatments for Fabry disease that are currently being tested. Psychological Issues Associated with Fabry disease and its Treatment Due to the varying clinical ways that Fabry disease manifests itself, patients with the disease should be aware of the potential for misunderstanding by those who are not familiar with the disease or the extent of their symptoms. Parents of patients with Fabry disease will need to devote special attention to the needs of their children in school and social settings. Parents should be up front with teachers about their child's disease and physical limitations, so that the child's special needs can be addressed. Adults with Fabry disease may be misunderstood in the work setting because they look normal to their colleagues, however, at times their disease may affect their ability to do their job. This should be kept in mind by patients while seeking employment, however, the Americans with Disabilities Act is in place to protect against discrimination in the workplace. |
U A male can have one X-chromosome with the normal a-gal A gene; this will be an unaffected male. 
U A female can have two X-chromosomes, both with normal a-gal A genes; this will be an unaffected female. 