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

• Schindler disease
• Gaucher disease
• Fucosidosis
• Erythromelalgia
• .

The symptoms of classic Fabry disease usually begin in childhood or adolescence. 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 red 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 discomfort in warm temperatures (heat intolerance).

Pain is an early symptom associated with the classic subtype of Fabry disease. Affected individuals may experience episodes of severe burning pain in the hands and the feet (acroparesthesia) and sometimes in the arms and legs. Severe episodes of pain (Fabry's crises) may last for minutes or days and are frequently associated with exercise, fatigue, and/or fever. Abdominal cramping and diarrhea may also occur, particularly after a heavy meal. Affected individuals may also experience nagging, chronic discomfort in between episodes of Fabry pain crises.

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

Patients with classical Fabry disease have abnormal deposits of fatty substances (glycolipids) on their corneas resulting in an opacity seen by an ophthalmologist examination of the corneas, which does not affect vision. Blood vessels in the eyes may become twisted (contorted) and/or enlarged (dilated) because of excessive glycolipid accumulation.

Symptoms may increase with age due to the progressive involvement of the vascular system leading to kidney failure, heart disease, and/or strokes. Kidney function decreases progressing to failure and the need for dialysis or transplantation by about 35 to 45 years of age in affected males. Kidney involvement in female heterozygotes is more variable. Heart disease includes heart enlargement (typically left ventricular hypertrophy), rhythm abnormalities, and heart failure. Involvement of blood vessels in the brain leads to strokes.

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.)

Patients with the "later-onset" subtype typically do not have skin (cutaneous) symptoms, they sweat normally, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in life.

Fabry disease is inherited as an X-linked 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 ( different mutations). Thus, the severity and range of symptoms of Fabry disease may vary among individuals. Absent enzyme activity results in the classic subtype, while patients with the later-onset subtype have residual enzyme activity. Not all males with Fabry disease have all of the symptoms of the disease.

Human traits, including genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. X-linked 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 "heterozygotes", but never to their sons. Women who are heterozygotes of an X-linked disorder have a 50 percent risk of transmitting the heterozygous 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. Absent or very low levels (less than 1% of normal) of this enzyme lead to the accumulation of fatty substances (glycolipids) in various tissues of the body, especially blood vessels and the eyes. Patients with residual enzyme activity (1-10% of normal) have a less sever form of the disease.

Fabry disease is a rare disorder that affects males more frequently than females. Females with this disorder may have no symptoms or may be symptomatic. Their symptoms usually begin during childhood or adolescence and progress slowly through adulthood.

It is estimated that the classical subtype of Fabry disease affects approximately one in 40,000 men. The later-onset subtype is more frequent with about 1 in 3,000 males. People of any race may be affected by Fabry disease.

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 one of 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. There are at least two types of Fucosidosis (i.e., Type 1 and Type 2), determined mainly by the severity of the enzyme deficiency and resulting symptoms. 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 ìfucosidosisî 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.

Diagnosis

The diagnosis of Fabry disease is frequently made by physicians who recognize the pain, absent or decreased sweating, gastrointestinal abnormalities, corneal involvement and heart symptoms present in childhood, adolescence or adulthood. The diagnosis is confirmed by demonstrating the enzyme deficiency in males and by identifying the specific alpha-galactosidase A gene mutation in males and females.
Prenatal diagnosis of Fabry disease is made by measuring alpha-galactosidase A activity and demonstrating the family-specific alpha-galactosidase A mutation in cells that are removed from the amniotic fluid surrounding the developing fetus at about 15 weeks of pregnancy. Early prenatal diagnosis at about 10 weeks of pregnancy can be made by alpha-galactosidase A enzyme and gene analyses of villi obtained by chronic villus sampling.

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 form of the human 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. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of enzyme replacement therapy for Fabry disease.

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, which was accomplished and reported in 2007.

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.
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.

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

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

Desnick R, Ioannou Y, and Eng C. alpha-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease (8th ed.). McGraw-Hill, New York, USA: 2001; 3733-3774


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

REVIEW ARTICLES

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

Thurberg BL, et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 2002; 62:1933-1946

Tondel C, et al. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008; 51: 767-776

Thadhani R, et al. Patients with Fabry disease on dialysis in the United States. Kidney Int. 2002; 61: 249-255

Ortiz A, et al. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant 2008; 23: 1600-1607

Wilcox WR, et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol Genet Metab. 2008; 93: 112-128

Desnick RJ et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003; 138: 338-346

Shabbeer J, et al. Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2006; 2: 297-309

Branton M, Schiffmann R, Kopp JB. Natural history and treatment of renal involvement in fabry disease. J Am Soc Nephrol. 2002; 13: 139-143

Banikazemi M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007; 146: 77-86

Germain DP, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007; 18: 1547-1557

Schiffmann R, et al. Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. J Am Soc Nephrol. 2007; 18: 1576-1583

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

Eng CM, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006; 8: 539-548

Fellgiebel A, et al. CNS manifestations of Fabry's disease. Lancet Neurol. 2006; 5: 791-795

MacDermot KD, et al. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 oligate carrier females. J Med Genet. 2001; 38: 769-775

Hopkin RJ, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry registry. Pediatr Res. 2008; 64: 550-555

Ramaswami U, et al. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr. 2006; 95: 86-92

Spada M, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006; 79: 31-40.

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 ñ replacement therapy in Fabryís 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.


INTERNET:

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