Fabry Disease

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report Fabry Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • alpha-galactosidase A deficiency
  • Anderson-Fabry disease
  • angiokeratoma corporis diffusum
  • angiokeratoma diffuse
  • ceramide trihexosidase deficiency
  • GLA deficiency
  • hereditary dystopic lipidosis

Disorder Subdivisions

  • None

General Discussion

Fabry disease is a rare genetic disorder of fat (lipid) metabolism characterized by a deficiency of the enzyme alpha-galactosidase A (previously known as ceramide trihexosidase). The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. Alpha-galactosidase functions to remove the terminal galactose moieties from complex sugary-fat molecules termed glycosphingolipids. Absence or less than 1% of the alpha-galactosidase A enzyme results in the classic subtype of Fabry disease due to the abnormal accumulation of a specific sugary-fat material (termed globotriaosylceramide, GL-3 or Gb3) in various organs of the body, particularly in the blood vessels. Symptoms of classic Fabry disease typically include onset in childhood or adolescence, the appearance of clusters of rash-like discolorations on the skin (angiokeratomas), excruciating pain in the hands and feet, and abdominal pain, absent or markedly decreased sweating (anhidrosis or hypohidrosis), and specific changes in the cornea of the eye (corneal dystrophy) that do not affect vision. Later in the course of the disease, kidney failure, heart disease, and/or strokes cause life-threatening complications.

Individuals with alpha-galactosidase A levels greater than 1% of normal have a somewhat milder or attenuated, later-onset subtype of the disease, and typically do not have the early-onset symptoms including the skin lesions, eye changes, decreased sweating, and pain in the extremities. They develop kidney, heart, or cerebrovascular (i.e., stroke) disease in adult life.

Fabry disease, which is inherited as an X-linked trait, affects males and females. Males are more uniformly affected whereas females have variable affects and may be asymptomatic or as severely affected as males.


The symptoms of the classic subtype of 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 (later-onset subtype). Classically affected individuals have decreased or absent sweat production (hypohidrosis or anhidrosis) and discomfort in warm temperatures (heat intolerance).

Pain is an early symptom associated with the classic subtype. 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 hours to 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 significant fatigue.

Additional symptoms associated with Fabry disease may include dizziness, headache, generalized weakness, nausea, and/or vomiting.

Patients with classical Fabry disease have abnormal deposits of fatty substances (glycolipids) in 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 appear twisted (cork screw-like; contorted) and/or enlarged (dilated) due to the glycosphingolipid accumulation in the vessel walls.

Symptoms may increase with age due to the progressive involvement of the micro-vascular system leading to kidney failure, heart disease, and/or strokes. Kidney function decreases, progressing to kidney failure and the need for dialysis or transplantation typically by 35 to 45 years of age in affected males. Kidney involvement in female heterozygotes is more variable. Only about 10-15% of affected females develop kidney failure. Heart disease includes heart enlargement (typically left ventricular hypertrophy, leading to hypertrophic cardiomyopathy), rhythm abnormalities, and heart failure. Involvement of very well blood vessels in the brain leads to strokes.

Additional symptoms sometimes associated with Fabry disease include delayed puberty, lack of or sparse hair 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 in the feet and legs 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 due to the glycosphingolipid accumulation in the lymphatic vessels and lymph nodes.)

Patients with the later-onset subtype typically do not have the skin lesions (angiokeratoma), they usually sweat normally, do not experience the Fabry pain or crises, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in adult life.


Fabry disease is caused by alterations (mutations) of the alpha-galactosidase A (GLA) gene located on the long arm (q) of the X chromosome (Xq21.33-q222 ) and inherited as an X-linked condition.

There are over 600 mutations in the GLA gene that is responsible for Fabry disease, thus, the severity and range of symptoms 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.

The symptoms of Fabry disease develop due to a deficiency of the enzyme alpha-galactosidase A. Patients with the classic subtype, who have no or very low levels (less than 1% of normal) of this enzyme, accumulate the sugary-fat substance (GL-3 or Gb-3) in various tissues of the body, especially small blood vessels, as well as other cells in the heart and kidneys. Patients with the later-onset subtype have residual enzyme activity (1-10% of normal), and also accumulate GL-3, but to a lesser degree and at a slower rate; they tend to have a less severe form of the disease.

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.

X-linked disorders are conditions caused by abnormal genes on the X chromosome. Females have two X chromosomes, while 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. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially "turned off", usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable features of the disorder. Since males only have one X chromosome, if they inherit a disease gene present on the X, it will be expressed. Males with Fabry disease are more uniformly affected, whereas females may be asymptomatic or as severely affected as males due to random X-inactivation.

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 condition to their daughters, and a 50 percent risk of transmitting the disease to their sons.

Affected Populations

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 1,500 to 4,000 males, depending on the demographic, racial, or ethnic population. People of any race or ethnicity may be affected by Fabry disease.

Standard Therapies


The diagnosis of Fabry disease is frequently made by physicians who recognize the pain in the extremeties, absent or decreased sweating (anhidrosis or hypohidrosis), typical skin lesions (angiokeratoma), 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.


The U.S. Food and Drug Administration (FDA) approved an enzyme replacement therapy called agalsidase beta (Fabrazyme) as a treatment for patients with Fabry disease in 2003. 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 Fabrazyme? 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, carbamazepine, or neurontin, 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.

Investigational Therapies

The 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 being conducted to determine its safety and effectiveness. For information, contact:

Amicus Therapeutics, Inc.

6 Cedar Brook Drive

Cranbury, NJ 08512

Phone: (609) 662-2000

Fax: (609) 662-2001

Website: www.Amicustherapeutics.com

Email: info@amicustherapeutics.com

Amicus is conducting the first Phase 3 global clinical study, the FACETS Study (Study AT1001-011) to assess the efficacy and safety of AT1001 (migalastat hydrochloride or migalastat HCl) in individuals with Fabry disease who have never had enzyme replacement therapy (ERT). Patient recruitment for this study was closed on October 19, 2011.

Amicus is also conducting a second Phase 3 study entitled the ATTRACT Study (AT1001-012). This is a global clinical study to measure the efficacy and safety of migalastat HCl when compared to ERT in individuals with Fabry disease who currently are receiving ERT. Patient recruitment for this study was closed on October 22, 2012.

The AT1001-013 Co-Administration Study is a Phase 2A clinical trial designed to evaluate the safety and effects of migalastat HCl on agalsidase (ERT), in subjects with Fabry disease, when migalastat HCl is orally administered prior to the agalsidase (ERT) infusion. The duration of study participation for each study subject is approximately 2 to 4.5 months.

For more information about these studies, please see www.fabrystudy.com or http://clinicaltrials.gov/.

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:


Contact for additional information about Fabry disease:

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



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Togawa T, Tsukimura T, Kodama T, et al. Fabry disease: biochemical, pathological and structural studies of the a-galactosidase A with E66Q amino acid substitution. Mol Genet Metab. 2012;105(4):615-20.

Benjamin ER, Khanna R, Schilling A, et al. Co-administration with the pharmacological chaperone AT1001 increases recombinant human a-galactosidase A tissue uptake and improves substrate reduction in Fabry mice. Mol Ther. 2012;20(4):717-26.

Reisin RC, et al. Brain MRI findings in patients with Fabry disease. J Neurol Sci. 2011;305:41-4.

Saito S, et al. Fabry-database.org: database of the clinical phenotypes, genotypes and mutant a-galactosidase A structures in Fabry disease. J Hum Genet. 2011;56:467-8.

Burlina AP, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011;11:61.

Dobrovolny R, et al. Detection of large gene rearrangements in X-linked genes by dosage analysis: Identification of novel a-galactosidase A deletions causing Fabry disease. Hum Mut. 2011;32:688-695.

Elliott P, et al. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry Disease survey. Heart. 2011;97:1957-60.

Feldt-Rasmussen U, et al. Diagnostic Dilemma: A Young Woman with Fabry Disease Symptoms, No Family History, and a "Sequencing Cryptic" a-Galactosidase A Large Deletion. Mol. Genet Metab. 2011;104:314-318.

Hwu WL, et al.Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009;30:1397-1405.

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.

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.

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.

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

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.

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.

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Fabry Disease. Genetics Home Reference. http://ghr.nlm.nih.gov/condition=fabrydisease/show/htm. Reviewed February 2012. Accessed July 31, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Fabry Disease. Entry No: 301500. Last Edited March 14, 2011.Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 31, 2012.


CLIMB (Children Living with Inherited Metabolic Diseases)

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Email: info@ntsad.org

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March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Internet: http://www.marchofdimes.com

International Center for Fabry Disease

Mount Sinai School of Medicine

Fifth Avenue at 100th Street

New York, NY 10029


Tel: (212)659-6700

Tel: (866)322-7963

Email: fabry.disease@mssm.edu

Internet: http://www.mssm.edu/research/programs/international-center-for-fabry-disease

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/

Canadian Society for Mucopolysaccharide and Related Diseases, Inc.

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Tel: 6049245130

Fax: 6049245131

Tel: 8006671846

Email: info@mpssociety.ca

Internet: http://www.mpssociety.ca

Fabry Support & Information Group

108 NE 2nd Street

Suite C

P.O. Box 510

Concordia, MO 64020-0510


Tel: (660)463-1355

Fax: (660)463-1356

Email: info@fabry.org

Internet: http://www.fabry.org

Genetic and Rare Diseases (GARD) Information Center

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Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/

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Hide & Seek Foundation for Lysosomal Disease Research

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Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org

National Fabry Disease Foundation

4301 Connecticut Ave. N.W., Suite 404

Washington, DC 20008-2369

Fax: (800)651-9135

Tel: (800)651-9131

Email: info@fabrydisease.org

Internet: http://www.fabrydisease.org/

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For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.