Information on the following diseases can be found in the Related Disorders section of this report:

• Schindler disease
• Gaucher disease
• Fucosidosis
• Erythromelalgia
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The symptoms of Fabry disease usually begin during childhood or adolescence, but may not become apparent until the second or third decade. Early symptoms include the appearance of a reddish to dark-blue skin rash, especially in the area between the hips and the knees. These skin lesions, which vary in color from pink to blue-black, may be flat or raised. In some cases, people with Fabry disease may not have these characteristic skin lesions. Affected individuals may notice a decrease in the amount of sweat production (hypohidrosis) and a growing discomfort in warm temperatures (heat intolerance).

Pain may also be an early symptom associated with Fabry disease. Affected individuals may experience episodes (paroxyms) of severe burning pain in the hands and the feet (acroparesthesia) and sometimes in the arms and legs. These episodes (Fabry's crises) may last for minutes or days and are frequently associated with exercise, fatigue, and/or fever. Episodes of abdominal pain that is similar to the pain experienced by people with appendicitis may also occur. Pain may be extreme. Affected individuals may also experience nagging, chronic discomfort in between episodes of Fabry’s crises.

Additional symptoms associated with Fabry disease may include dizziness, headache, generalized weakness, nausea, and/or vomiting. Fevers may be brought on by exercise.

Fabry disease may also affect the eyes, but usually has no effect on vision. There may be abnormal deposits of fatty substances (glycolipids) on the cornea resulting in clouding (opacity) of the corneas. Blood vessels in the eyes may become twisted (contorted) and/or enlarged (dilated) because of excessive glycolipid accumulation.

Episodes of symptoms may increase with age due to the progressive involvement of the vascular system (i.e., inflammation or the formation of blood clots). Kidney dysfunction progressing to failure; heart problems such as chest pain (angina), high blood pressure (hypertension), stroke, and/or congestive heart failure; and/or neurological complications such as seizures may develop as affected individuals age. Additional late symptoms may include cough with excessive mucous production (chronic bronchitis), difficulty breathing, swelling of the arms and legs, diarrhea, behavioral changes, and/or depression. Some older individuals with Fabry disease have developed obstructive lung disease.

Additional symptoms sometimes associated with Fabry disease include delayed puberty, lack of or sparse hair growth, retarded growth, malformation of the joints of the fingers, and/or gastrointestinal abnormalities such as diarrhea. In some cases, affected individuals have abnormal accumulation of lymph within certain tissues and associated swelling (lymphedema). (Lymph, a bodily fluid containing certain white blood cells, fats, and proteins, accumulates outside blood vessels in spaces between cells and drains or flows back into the bloodstream via lymph vessels. Lymphedema may result from disruption of lymph's normal drainage.)

Atypical variants of Fabry disease exist in which affected individuals may not have skin (cutaneous) symptoms or variants in which individuals have only isolated eye or kidney abnormalities. Some individuals may experience symptoms affecting only the heart (cardiac variant).
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Fabry disease is inherited as an X-linked recessive trait. The gene that causes this disease is located on the long arm of the X chromosome (Xq21.33-Xq22). There are many variations in the exact genetic defect that is responsible for Fabry Disease (allelic variety). Thus, the severity and range of symptoms of Fabry disease may vary among individuals; not all males with Fabry disease have all of the symptoms of the disease.

Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons.

Investigators have determined that Fabry disease may be caused by disruption or changes (mutations) of the alpha-galactosidase A (GLA) gene located on the long arm (q) of the X chromosome (Xq21.33-q222). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome Xq21.33-q22" refers to bands 21.33-22 on the long arm of the X chromosome.

The symptoms of Fabry disease develop due to a deficiency of the enzyme alpha-galactosidase A. Very low levels or inactivity of this enzyme lead to the accumulation of fatty substances (glycolipids) in various tissues of the body, especially blood vessels and the eyes.
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Fabry disease is a rare disorder that affects males more frequently than females. Females with this disorder typically have a mild form of the disease when compared to males. Symptoms usually begin during childhood or adolescence and progress slowly through adulthood.

It is estimated that Fabry disease affects approximately one in 40,000 men. More than 400 cases have been reported in the medical literature. People of any race may be affected by Fabry disease. However, most affected individuals have been of Western European descent.
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Symptoms of the following disorders can be similar to those of Fabry disease. Comparisons may be useful for a differential diagnosis:

Schindler disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA), which leads to an abnormal accumulation of certain complex compounds (glycosphingolipids) in many tissues of the body. There are two forms of Schindler disease. The classical form of the disorder, known as Schindler disease, type I, has an infantile onset. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe mental retardation, hearing and visual impairment, and a lack of response to stimuli in the environment. Schindler disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Schindler" as your search term in the Rare Disease Database.)

Gaucher disease is the most common of the lipid storage diseases and is characterized by the abnormal accumulation of certain fatty substances in various parts of the body. Symptoms develop due to a deficiency in the enzyme glucocerebrosidase and may include enlargement of the liver (hepatomegaly) and spleen (splenomegaly), a general feeling of ill health (malaise), visual difficulties, abdominal swelling, severe pain and/or bone problems. Gaucher disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Gaucher" as your search term in the Rare Disease Database.)

Fucosidosis is an extremely rare inherited lysosomal storage disease characterized by a deficiency of the enzyme alpha-L-fucosidase. Many researchers believe there are two types of Fucosidosis (i.e., Type 1 and Type 2), determined mainly by the severity of the symptoms. Other scientists theorize there are three types, with the age of onset and the disease severity being the determining factors. The symptoms of Fucosidosis Type 1, the most severe form of the disease, may become apparent as early as six months of age. Symptoms may include progressive deterioration of the brain and spinal cord (central nervous system), mental retardation, loss of previously acquired intellectual skills, and growth retardation leading to short stature. Other physical findings and features become apparent over time, including multiple deformities of the bones (dysostosis multiplex), coarse facial features, enlargement of the heart (cardiomegaly), enlargement of the liver and spleen (hepatosplenomegaly), and/or episodes of uncontrolled electrical activity in the brain (seizures). Additional symptoms may include increased or decreased perspiration and/or malfunction of the gallbladder and/or salivary glands. Fucosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)

Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands. It is characterized by intense burning pain of affected extremities, severe redness, and increased skin temperature that may be episodic or almost continuous in nature.
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Diagnosis
The diagnosis of Fabry disease is frequently made by a physician who specializes in the care of the eyes (ophthalmologist). An examination of the eyes with special instrumentation (slit-lamp) may reveal the accumulation of fatty deposits on the corneas. The microscopic examination of tissue samples from people with Fabry disease reveals characteristic "Maltese cross" shaped deposits of crystalline glycosphingolipids. These findings, combined with other clinical findings (pain and/or skin lesions), confirm the diagnosis of Fabry disease.

Prenatal diagnosis of Fabry disease is made by measuring alpha-galactosidase A activity in cells that are removed from the amniotic fluid surrounding the developing fetus. This test may also be performed on newborn infants, using cells from blood or tears.

TREATMENT
The U.S. Food and Drug Administration (FDA) has approved (April 2003) an enzyme replacement therapy called agalsidase beta (Fabrazyme) as a treatment for patients with Fabry disease. Fabrazyme, which is administered intravenously, is a version of the human form of the natural enzyme produced by recombinant DNA technology. This replacement of the missing enzyme reduces the accumulation of lipids in many types of cells, including blood vessels in the kidney and other organs. It is believed that this reduction of fat deposition will prevent the development of life-threatening organ damage.

Fabrazyme had been designated an orphan drug and was approved by the FDA under an accelerated or early approval mechanism. One of the requirements of the accelerated approval is that the sponsor complete a post-market study verifying that patients will benefit from the product.

For additional information on Fabrazyme, contact the manufacturer:

Genzyme Corporation
One Kendall Square
Cambridge, MA, 02139
Tel: (617) 252-7500
Fax: (617) 252-7600

Low doses of diphenylhydantoin or carbamazepine may help to prevent the chronic discomfort in the hands and feet. Laser therapy has been used to treat scarring associated with angiokeratomas.

Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of people with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment is supportive.
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Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Enzyme replacement therapy is being studied for the treatment of individuals with Fabry disease. Initial studies have shown it to be an effective form of treatment. More research is necessary to determine the long-term safety and effectiveness of enzyme replacement therapy for the treatment of Fabry disease.

Studies involving adults and children ages 7-17 of either gender are currently recruiting volunteers at the National Institutes of Health (NIH) to improve the understanding of Fabry disease. Knowledge gained as a result of these studies may contribute to the development of effective therapies for Fabry disease in the future. For information, contact the following:

National Institute of Neurological Disorders and Stroke (NINDS)
9000 Rockville Pike
Bethesda, Maryland 20892
Phone: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
NIH Clinical Center Website: www.cc.nih.gov

The U.S. Food and Drug Administration (FDA) has granted orphan drug status to AT1001, manufactured by Amicus Therapeutics, Inc., for the treatment of Fabry disease. This oral therapy was designed to enhance an individual’s alpha-galactosidase A activity. Additional study is needed to determine its safety and effectiveness. For information, contact:

Amicus Therapeutics, Inc.
675 U.S. Route 1
North Brunswick
N.J. 08902
Phone: (732) 745-9977
Fax: (732) 745-9769
Website: www.Amicustherapeutics.com
Email: info@amicustherapeutics.com

The International Center for Fabry Disease at the Mount Sinai School of Medicine in New York provides patient care and research on Fabry disease. For more information, contact:

International Center for Fabry Disease
Mount Sinai School of Medicine
Fifth Avenue at 100th Street
New York, NY 10029
(212) 659-6700
Toll-free: 1-866-FABRY-MD

Researchers are studying the use of the drug, miglustat, which has been approved for the treatment of Gaucher disease and for the treatment of additional lysosomal storage diseases including Fabry disease. More research is necessary to determine the effectiveness and safety of miglustat as a potential treatment for individuals with Fabry disease.

McKusick VA, Ed. Online Mendelian Inheritance In Man (OMIM). Johns Hopkins University, Last Edit Date 9/10/01, Entry Number 301500.

TEXTBOOKS
Scriver CR, et al eds. The Metabolic Basis of Inherited Disease, 7th ed. New York, NY: McGraw Hill Companies; 1995:2741-84.

Bennett and Plum, eds. Cecil Textbook Of Medicine, 20th Ed. Philadelphia, PA: W.B. Saunders Co; 1996:1095-97.

Berkow R. and Beers M, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:214.

Adams RD, Victor M, and Ropper AA, eds. Principles Of Neurology, 6th ed. McGraw-Hill Companies; 1997:979-80.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:374, 1841.

Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:224-26.

Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:100-01.

REVIEW ARTICLES
Saborio P, et al. Genetic Renal Disease. Curr Opin Pediatr. 1998;10:174-83.

Peters FP, et al. Fabry’s disease: a multidisciplinary disorder. Postgrad Med J. 1997;73:710-12

Eng CM, et al. Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. Hum Mutat. 1994;3:103-11.

JOURNAL ARTICLES
Eng CM, et al. A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet. 2001;68:711-22.

Eng CM, et al. Safety and efficacy of recombinant human alpha-galactosidase A – replacement therapy in Fabry’s disease. N Engl J Med. 2001;345:9-16.

Moore DF, et al. Regional cerebral hyperperfusion and mitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation. 2001;104:1506-12.

Altarescu GM, et al. Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease. Clin Genet. 2001;60:46-51.

Brady RO et al. Clinical features of and recent advances in therapy for Fabry disease. JAMA. 2000;284:2771-75.

Syed NA, et al. Cutaneous silent periods in patients with Fabry disease. Muscle Nerve. 2000;23:1179-86.

Ojo A, et al. Excellent outcome of renal transplantation in patients with Fabry’s disease. Transplantation. 2000;69:2337-39

Schiffmann R, et al. Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A. 2000;97:365-70

INTERNET:

Fabry’s Diseases-Genetic Home Reference
http://ghr.nlm.nih.gov/condition=fabrydisease/show/htm