International Center for Fabry Disease
What Is the Nature of the Metabolic Defect in Fabry Disease?
The body performs thousands of metabolic processes which are necessary for the production of vital compounds and the recycling or removal of others. One such compound called globotriaosylceramide is formed of three sugars and a fatty substance called ceramide, and is found in most cells of the body. Normally globotriaosylceramide is broken down (metabolized) to lactosylceramide by the enzyme a-galactosidase A. In patients with Fabry disease, this enzyme does not function properly or is absent, and globotriaosylceramide cannot be broken down in cells, leading to its progressive accumulation. Thus, Fabry disease is often referred to as a "storage disorder" because of the abnormal accumulation of globotriaosylceramide. In patients with Fabry disease, globotriaosylceramide accumulates preferentially in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally fed by these vessels. This process occurs in all blood vessels throughout the body, but particularly affects small vessels in the skin, kidneys, heart, and nervous system.
How Is Fabry Disease Inherited?
Fabry disease is an inherited disorder. The defective gene is on the X chromosome, which is one of the two chromosomes that determine an individual's sex. Males have one X chromosome inherited from their mothers and one Y chromosome inherited from their fathers. Since males have only one X-chromosome, if it contains a mutant Fabry disease gene, affected males exhibit the clinical symptoms of Fabry disease. A female Fabry carrier has one X chromosome with a defective Fabry gene and one X chromosome with the normal gene. In all females, one of the two X chromosomes in somatic cells is randomly inactivated to compensate for the differences between males (XY) and female (XX). This inactivation occurs early in development and the X chromosome that is inactivated in a given embryonic cell will remain inactive in all descendents of that cell. X chromosome inactivation has major consequences for females who have a mutant Fabry gene. Depending on the which and how many cells of a particular tissue have the X chromosome active containing the mutant gene, the female carrier may have clinical symptoms of Fabry disease which range from mild to as severe as affected males.
The inheritance pattern of Fabry disease is termed "X-linked recessive inheritance." As illustratrated in Figure 1 below, a female carrier of Fabry disease has a 50% chance of transmitting the defective Fabry gene to her sons who will develop Fabry disease. In addition, she has a 50% chance of transmitting the Fabry gene to her daughters who will be carriers like their mother. It must be emphasized that these risk figures apply to each pregnancy individually, that is, for each male child there is a 50% chance to have the disease, and for each female child there is a 50% risk to be a carrier.
As illustrated in Figure 2 below, if a male with Fabry disease and an unaffected (non-carrier) female have children, all of their daughters will be Fabry carriers and none of their sons will be affected with Fabry disease.
Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has the disease.
What are the clinical symptoms of Fabry disease?
How does Fabry disease affect males?
Typically, the disease begins in childhood with episodes of pain and discomfort in the hands and feet (known as acroparesthesias). The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions. In addition, young patients develop a spotted, dark red skin rash (known as angiokeratoma) seen most densely from the umbilicus to the knees, a decreased ability to perspire, and a characteristic change on the cornea of the eye that does not affect vision.
The disease progresses very slowly and symptoms of kidney, heart and/or neurologic involvement occur between the ages of 30 to 45. In fact, many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Therefore, it is important to annually monitor kidney function by blood and urine tests because kidney disease is a major complication that can occur in affected males.
A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
Clinical manifestations in carrier females
The clinical manifestations in carrier females for Fabry disease range from asymptomatic throughout a normal lifespan to as severe as affected males. Carriers are generally less severely affected than males. Symptoms in carriers can be classified in two categories, mild manifestations and more severe, life-threatening or incapacitating manifestations. The mild manifestations are more common and generally begin in childhood or adolescence while the more severe manifestations are less frequent and typically occur in adulthood or late maturity (50s to 80s).
The mild manifestations include the characteristic corneal and lenticular opacities which do not impair vision, skin lesions (angiokeratomas) which are usually isolated or sparse, pain in the extremities (acroparesthesia), and decreased ability to sweat (hypohidrosis). In addition, carriers may have chronic abdominal pain and diarrhea. With advancing age, carriers may develop mild to moderate enlargement of their left heart (left ventricular hypertrophy) and mitral valve prolapse.
More serious manifestations in carrier females include significant left ventricular hypertrophy, cardiomegaly, myocardial ischemia and infarction, arrhythmia, transient ischemia attacks, strokes, and renal failure. About 10 percent of carriers develop renal failure requiring dialysis or transplantation according the US and European dialysis and transplant registries. A few carriers have been reported in which the expression of symptoms was comparable to that seen in fully affected males. The frequencies of manifestations in carriers, based on several recent studies, is shown in the Table below.
|Table 1. Frequency of Manifestations in Carrier Females|
MacDermot, et al.1
Galanos, et al.2
Whybra, et al.3
|Mean Age (Range) Yrs||46 (17-60)||42 (16-78)||38 (12-65)|
|Percent of Carriers with Symptoms|
How is the diagnosis of Fabry disease made?
When Fabry disease is suspected either on the basis of clinical signs and symptoms or by the discovery of a relative with Fabry disease, the diagnosis of affected males can be confirmed by a simple blood test that measures the activity of the enzyme a-galactosidase.
In contrast, the enzymatic identification of carrier females is less reliable due to random X-chromosomal inactivation in carriers (see above “How is Fabry Disease Inherited”). For example, some obligate carriers (daughters of classically affected males) have a aGal A enzyme activities ranging from normal to very low activities. Since carriers can have normal a-Gal A enzyme activity, only the identification of an a-Gal A mutation provides precise carrier identification. Thus, it is important to determine the mutation status in all at-risk females in families with Fabry disease, particularly those who are asymptomatic.
What treatment is available for individuals with Fabry disease?
The first level of treatment for Fabry patients is preventive. The episodes of pain generally have precipitating causes such as stress, exposure to the sun or heat, changes in temperature, physical exertion, or fever and illness. One must recognize the cause-and-effect relationship between these factors and the pain. Patients must make every effort to avoid these precipitating factors, if possible. Patients with frequent severe pain may benefit from medications such as diphenylhydantoin (Dilantin) or carbamazapine (Tegretol). These medications must be taken every day to prevent the onset of pain and to reduce the frequency and severity of painful attacks. Other preventive measures include avoidance of smoking and in those patients with mitral valve prolapse, taking prophylactic antibiotics when undergoing dental procedures or surgery. Regular visits to a physician who will monitor general health is a vital part of preventive therapy.
The next level of treatment is specific therapy for the possible complications of Fabry disease. For those patients with mild reductions in kidney function, a low sodium and low protein diet may be recommended. For those patients with severe compromise of kidney function, dialysis and kidney transplantation are available. The success of kidney transplantation offers the ability to restore kidney function in Fabry patients and has improved the overall prognosis for this disease.
What role does Enzyme replacement therapy play in Fabry disease?
At The Mount Sinai Medical Center, our researchers and clinicians developed enzyme replacement therapy for Fabry disease. Through ongoing efforts in our laboratory, we have been involved in the development of enzyme replacement therapy for Fabry disease for over 30 years. The gene for a-galactosidase A was isolated in our laboratories and was subsequently introduced into a system that manufactures large quantities of the enzyme. This technology is being further refined for the large-scale production of enzyme for human enzyme replacement therapy by the Genzyme Corporation.
Extensive preclinical evaluations were carried out in a -Gal A deficient mice and demonstrated that enzyme delivery to the heart and kidney and GL-3 clearance from those organs was dose-dependent. These animal studies provided the rationale for human clinical trials. In 1998, an FDA reviewed Phase 1/ 2 clinical trial was performed at Mount Sinai with 15 Fabry Patients. This study evaluated various enzyme doses and their dose-response clearance of the accumulated glycolipid in key tissues including the blood, skin, kidneys, heart, and liver. Based on the results of the Phase 1/2 trial, an FDA-reviewed Phase 3 clinical trial was conducted. This was a double-blind placebo-controlled, randomized multicenter study involving 58 patients with Fabry disease in four countries (US, France , England , and the Netherlands ). This study achieved its primary goal of demonstrating that the enzyme effectively cleared the accumulated glycolipid from key cells in the kidney, as well as from cells in the skin and heart. Additional studies showed that enzyme replacement therapy stabilized renal function, improved cardiac function, and quality of life. All patients who participated in clinical trials continued in open-label extension studies. In January, 2003, the clinical trials were reviewed by an FDA Advisory Committee who supported approval of Fabrazyme and in April, 2003 the FDA approved Fabrazyme for treatment of Fabry disease.
Recently, a panel of physicians expert in Fabry disease recommended that enzyme replacement therapy be initiated in all patients with Fabry disease as soon as possible – ideally, as soon as clinical signs and symptoms such as pain or isosthenuria are observed. Although enzyme replacement therapy has not yet been evaluated in children with Fabry disease, experience in type 1 Gaucher disease has indicated that enzyme replacement infusions are well tolerated by young children. Carrier females with significant disease manifestations should also be treated with enzyme replacement therapy. This is an active area of research. Also, there currently are no published studies of enzyme replacement therapy in Fabry patients who are undergoing dialysis or have received a kidney transplant; however, because such patients are at high risk for cardiac, cerebrovascular, and neurological complications such as transient ischemic attacks and stroke, enzyme replacement therapy in this population is also recommended.
What is available at The Mount Sinai Medical Center for families with Fabry disease?
The Mount Sinai Medical Center is the International Center for the diagnosis and treatment of Fabry disease. We follow over 500 Fabry families, offering a full range of clinical services including medical evaluations and prenatal diagnosis. In addition, our research laboratories continue to investigate the basic biochemical and molecular defects underlying Fabry disease. In the past 15 years, our laboratories have published numerous articles in scientific journals describing the results of our research efforts (see References). Currently, much attention is focused on developing improved diagnostic methods and on testing the effectiveness of enzyme replacement therapy.
On the General Clinical Research Center (GCRC) at The Mount Sinai Medical Center, we provide comprehensive medical care to Fabry patients and their families. The GCRC is a special in-patient and out-patient unit that is staffed by nurses specifically trained to care for Fabry patients. Patients on the unit are attended to by physician staff under the direct supervision of Dr. Desnick and his expert physician specialists. A complete evaluation of a patient typically requires a stay of four to five weekdays during which consultations with other physicians who are expert in cardiology, neurology, ophthalmology, pulmonary and other medical disciplines are obtained. Blood and urine specimens are obtained for laboratory tests. Special studies such as magnetic resonance imaging (MRI), ultrasonography, echocardiography and pulmonary function testing also may be performed. At the conclusion of these studies, we discuss all results and make recommendations for current and future management with the patient and/or their parents.
Is prenatal diagnosis for Fabry disease available?
Couples at-risk for having offspring with Fabry disease who request prenatal diagnosis have several options which can be described in full during a counseling session with a genetic counselor and medical geneticist. Prenatal diagnosis for Fabry disease can be performed at 10 to 12 weeks from the last menstrual period by chorionic villus sampling or at 15 to 18 weeks by amniocentesis. Sex determination and measurement of a-galactosidase A activity are performed on the fetal sample to determine whether or not a male fetus is affected with Fabry disease.
How can I obtain additional information?
You may contact Dana Doheny, M.S., G.C.G., genetic counselor, at The International Center for Fabry Disease:
Toll Free Number (USA): (866) Fabry-MD (866-322-7963)
Address: International Center for Fabry Disease
Department of Genetics and Genomic Sciences
Icahn School of Medicine
Fifth Avenue at 100th Street
New York , NY 10029