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Fabry Disease

NORD is very grateful to R.J. Desnick, PhD, MD, Dean for Genetic and Genomic Medicine, Professor and Chairman Emeritus, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, for assistance in the preparation of this report.

Synonyms of Fabry Disease

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

Disorder Subdivisions

  • classical
  • later-onset

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.

Symptoms

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.

Causes

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.

Related Disorders

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 and oligosaccharides) 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 intellectual disability, 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 bone pain and bone disease. 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 a skin lesion similar to Fabry disease (angiokeratoma), progressive deterioration of the brain and spinal cord (central nervous system), intellectual disability, 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.

Standard Therapies

Diagnosis
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.

Treatment
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:
www.centerwatch.com

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

Fabry Disease Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Desnick R, Ioannou Y, 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. New York, NY: McGraw-Hill; 2001:3733-3774.

JOURNAL ARTICLES
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.

Desnick RJ. Prenatal diagnosis of Fabry disease. Prenat Diag. 2007;27:693-694.

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.

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. 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.

Wilcox WR, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am. J. Hum. Genet. 2004;75:65-74.

Desnick RJ, Brady RO. Fabry disease in childhood. J. Pediatr. 2004;144:520-526.

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.

Froissart R, Guffon N, Vanier MT, Desnick RJ, Maire I. Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. Mol Genet Metab. 2003;80:307-314.

Nakao S, et al. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int. 2003;64:801-807
.
Desnick RJ, Schuchman EH. Enzyme replacement and enhancement therapies: Lessons from lysosomal disorders. Nature Rev Genet. 2002;3:954-966.

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

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.

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 Fabry's disease. N Engl J Med. 2001;345:9-16.

INTERNET
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.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/10/24 00:00:00 GMT+0

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