Fabry disease

Definition

Fabry disease is a genetic condition that typically affects males. It is caused by deficiency of an enzyme, a chemical that speeds up another chemical reaction. Fabry disease can affect many parts of the body including the kidneys, eyes, brain, and heart. Pain in the hands and feet and a characteristic rash are classic features of this disease.

Description

The symptoms of Fabry disease were first described by Dr. Johann Fabry and Dr. William Anderson in 1898. The enzyme deficiency that leads to the disease was identified in the 1960s.

The symptoms of Fabry disease are variable. Some individuals with Fabry disease have severe complications, while others have very mild symptoms. The first sign of the disease may be a painful burning sensation in the hands and feet (acroparesthesias). A red rash, most commonly between the belly button and the knees (angiokeratoma) is also common. The outer portion of the eye (cornea) may also become clouded in individuals with Fabry disease. The progressive buildup of globotriaosylceramide can also lead to kidney problems and heart disease in adulthood.

Demographics

Fabry disease affects approximately one in 40,000 live births. It occurs evenly among all ethnic groups. Almost always, only male children are affected. Although female carriers of the disease occasionally develop symptoms of the disease, it is rare for a female carrier to be severely affected.

Causes and symptoms

Fabry disease is caused by a change (mutation) in the GLA gene. This gene is responsible for the production of the enzyme alpha-galactosidase A. Alpha-galactosidase A normally breaks down globotriaosylceramide. Globotriaosylceramide is a natural substance in the body, made of sugar and fat. A mutation in the GLA gene leads to a decrease in alpha-galactosidase A activity which, in turn, leads to an excess of globotriaosylceramide. The excess globotriaosylceramide builds up in blood vessels (veins, arteries, and capillaries) and obstructs normal blood flow. It also builds up in parts of the skin, kidneys, heart, and brain. It is this buildup that inhibits normal function and leads to the symptoms associated with the disease.

The gene that produces alpha-galactosidase A is located on the X chromosome. It is called the GLA gene. Since the GLA gene is located on the X chromosome, Fabry disease is considered to be X-linked. This means that it generally affects males.

The signs and symptoms of Fabry disease vary. Some individuals with Fabry disease have many severe symptoms, while other individuals' symptoms may be few and mild. The symptoms typically increase or intensify over time. This progression is caused by the slow buildup of globotriaosylceramide as the person ages.

A painful burning sensation in the hands and feet (acroparesthesias) is one of the first symptoms of Fabry disease. This pain can be severe and may grow worse with exercise, stress, illness, extreme heat, or extreme cold. Another symptom of Fabry disease typically present during childhood is a red rash (angiokeratoma). This rash typically develops between the navel and the knees. Children with Fabry disease may also have a clouding of the outer most portion of the eye (cornea). This symptom is usually diagnosed by an eye doctor (ophthalmologist). The cloudiness may increase with time. A decreased ability to sweat is another common symptom of Fabry disease.

Due to the progressive nature of Fabry disease, most affected individuals develop additional symptoms by age 40. The buildup of globotriaosylceramide in the heart can lead to heart problems. These heart problems can include changes in the size of the heart (left ventricular enlargement), differences in the heart beat, and leaky heart valves.

Mitral valve prolapse is a particular type of leaky heart valve that is common in Fabry disease, even in childhood. The excess globotriaosylceramide can also disrupt normal blood flow in the brain. In some cases this can cause dizziness, seizures, and stroke. The kidneys are other organs affected by Fabry disease. Kidney problems can lead to an abnormal amount of protein in the urine (proteinuria). Severe kidney problems can lead to kidney failure.

Although the symptoms of Fabry disease usually occur in males, female carriers may occasionally exhibit symptoms of the disease. Some carriers experience pain in their hands and feet. Carrier females may also have proteinuria and clouding of their cornea. It is rare for a female to experience all of the symptoms associated with Fabry disease.

Diagnosis

Initially, the diagnosis of Fabry disease is based on the presence of the symptoms. It should also be suspected if there is a family history of the disorder. The diagnosis of Fabry disease is definitively made by measuring the activity of the alpha-galactosidase A enzyme. When the activity is very low, it is diagnostic of Fabry disease. This enzyme analysis can be performed through a blood test. Measuring the activity of the enzyme can also detect female carriers. Women who are carriers of Fabry disease have enzyme activity that is lower than normal.

Prenatal diagnosis is possible by measuring the alpha-galactosidase A activity in fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). Fetuses should be tested if the mother is a carrier. A woman is at risk of being a carrier if she has a son with Fabry disease or someone in her family has Fabry disease.

Treatment team

A number of specialized practitioners are necessary to care for patients with Fabry disease. Depending on the specific manifestations, these specialists may include a dermatologist to treat skin problems; a neurologist to treat such complications as dizziness, seizure, stroke; an ophthalmologist to treat eye problems; a nephrologist to treat kidney problems; a cardiologist to treat heart problems. A pain specialist may be helpful, as well.

Treatment

There is currently no cure for Fabry disease. Until such time as enzyme replacement therapy is proven to be safe and effective, individuals with Fabry disease must rely on traditional treatments. Pain can be treated with medications such as carbamazepine and dilantin. Individuals with Fabry disease are recommended to have routine evaluations of their heart and kidneys. Some individuals with kidney disease require a special diet that is low in sodium and protein. Dialysis and kidney transplantation may be necessary for patients with severe kidney disease. Certain medications may reduce the risk of stroke. Finally, individuals with Fabry disease are recommended to avoid the situations that cause the pain in their hands and feet to grow worse. In some situations medication may be required to reduce the pain.

Clinical trials

A number of clinical trials are underway. Some are studying the specific nervous system effects of the disase. Others are giving individuals with Fabry disease the alpha-galactosidase A enzyme (Replagal) as a form of enzyme replacement therapy. If successful, this enzyme replacement therapy may reduce or eliminate the symptoms associated with Fabry disease. Clopidogrel, a blood thinner, is also being studied to see if its administration may decrease the rate/severity of such complications as stroke and heart attack.

Prognosis

The prognosis for individuals with Fabry disease is good, especially with the arrival of enzyme replacement therapy. Currently, affected individuals survive into adulthood with the symptoms increasing over time.

Resources

BOOKS

Desnick, Robert J., Yiannis Ioannou, and Christine Eng. "Galactosidase A Deficiency: Fabry Disease." In The Molecular Bases of Inherited Disease. 8th ed. New York: McGraw Hill, 2001.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org.

Department of Human Genetics, International Center for Fabry Disease. Box 1497, Fifth Ave. at 100th St., New York, NY 10029. (866) 322-7963. http://www.mssm.edu/genetics/fabry.

Fabry Support and Information Group. PO Box 510, 108 NE 2nd St., Suite C, Concordia, MO 64020. (660) 463-1355. http://www.cpgnet.com/fsig.nsf.

National Fabry Disease Foundation. 4301 Connecticut Ave. N.W., Suite 404, Washington, DC 20008. (800) 651-9131. www.TheNFDF.org

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424. http://www.ninds.nih.gov.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www.rarediseases.org.

WEBSITES

Fabry Disease Home Page. http://www.sci.ccny.cuny.edu/~fabry/.

Online Mendelian Inheritance in Man (OMIM). http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?301500.

Holly Ann Ishmael, MS, CGC

Rosalyn Carson-Dewitt, MD

A sex-linked disorder of glycolipid metabolism characterized by a variety of progressive symptoms including fevers, hypertension, and purple skin lesions, with death resulting from renal, cardiac, or cerebrovascular complications. Also called angiokeratoma corporis diffusum.

Fabry disease ICD10 = E75.2 (ILDS E75.25)
Classification and external resources
Alpha galactosidase - the protein that is deficient in Fabry disease.
ICD-9	272.7
OMIM	301500
DiseasesDB	4638
eMedicine	neuro/579 derm/707 ped/2888
MeSH	[1]

Fabry disease (also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency) is a rare X-linked recessive (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms.^[1] The disease is named after one of its discoverers, Johannes Fabry.^[2]

Contents 1 Pathophysiology 2 Symptoms 3 Diagnosis 4 Treatment 5 Related articles 6 References 7 External links

Pathophysiology

A deficiency of the enzyme alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs.^[3] This accumulation leads to an impairment of their proper function.

The DNA mutations which cause the disease are X-linked recessive. The condition affects hemizygous males (i.e. all males), as well as homozygous, and potentially heterozygous (carrier), females. Whilst males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.^[4]

Symptoms

Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.

Renal involvement

Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure may worsen throughout life. Proteinuria (which causes foamy urine) is often the first sign of kidney involvement. End stage renal failure in males can typically occur in the third decade of life, and is a common cause of death due to the disease.

Cardiac manifestations

Cardiac complications occur when glycolipids build up in different heart cells; heart related effects worsen with age and may lead to increased risk of heart disease. Hypertension (high blood pressure) and cardiomyopathy are commonly observed.

Dermatological manifestations

Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the belly-button, buttocks, lower abdomen, and groin) are a common symptom.

Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).

Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain).

Ocular manifestations

Cosmetic ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic carriers, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision.

Other ocular findings that can be seen include conjunctival aneurysms, posterior spoke-like cataracts, papilloedema, macular edema, optic atrophy and retinal vascular dilation.

Other manifestations;

Fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, and diarrhea are other common symptoms.

Diagnosis

Fabry disease is indicated when associated symptoms are present, and can be diagnosed by a blood test to measure the level of alpha-galactosidase activity, however this may be misleading in female carriers due to the random nature of X-inactivation. Chromosomal analysis of the GLA gene is the most accurate method of diagnosis, and many mutations which cause the disease have been noted. Kidney biopsy may also be suggestive of Fabry Disease if excessive lipid buildup is noted.

Naturally, alpha-galactosidase A (a-GAL A) is likely to be present only at very low levels in the blood, particularly in males. In females, owing to X-inactivation patterns, levels are commonly normal even if the patient is not asymptomatic. The Sifap (stroke in young Fabry patients) project will investigate the relation between stroke and Fabry's disease.

Treatment

Until recently, treatment of Fabry disease targeted the symptomatic effects.

In 2001, two Enzyme Replacement Therapies (ERTs) were released: Agalsidase alpha (Replagal, Shire) and Agalsidase beta (Fabrazyme, Genzyme). These attempt to replace the deficient enzyme by means of fortnightly infusion. The cost of these drugs is problematic (approximately $250,000 US a year/patient) and remains a barrier to many patients in some countries. The infusion may be performed by the patient themselves, in the patient's home by a registered nurse, or at a medical facility. Enzyme replacement therapy is not a cure, but can allow normal metabolism and both prevent disease progression as well as potentially reverse symptoms.

Related articles

• Lysosomal storage disorder
• Sphingolipidoses
• Enzyme replacement therapy

References

1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. p. 538. ISBN 0-7216-2921-0. 
2. ^ synd/1761 at Who Named It?
3. ^ Karen JK, Hale EK, Ma L (2005). "Angiokeratoma corporis diffusum (Fabry disease)". Dermatol. Online J. 11 (4): 8. PMID 16403380. http://dermatology.cdlib.org/114/NYU/NYUtexts/0419054.html. 
4. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. pp. ^{[page needed]}. ISBN 0-7216-2921-0. 

External links

• GeneReview entry on Fabry disease by NIH
• Fabry Disease Information Page at NINDS
• Fabry disease at NLM Genetics Home Reference
• Fabry Registry
• Stroke in young Fabry patients

Support groups

• Fabry International Network
• Focus on Fabry by Shire
• Fabry Community by Genzyme
• Fabry Support & Information Group (FSIG)
• Fabry support at MPS Society
• Canadian Fabry Association
• National Fabry Disease Foundation

v • d • e (LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7-272.8) Sphingolipidoses (to ceramide) From ganglioside (gangliosidoses) Ganglioside: GM1 gangliosidoses · GM2 gangliosidoses (Sandhoff disease, Tay-Sachs disease, AB variant) From globoside Globotriaosylceramide: Fabry's disease From sphingomyelin Sphingomyelin: phospholipid: Niemann-Pick disease (SMPD1-associated, type C) Glucocerebroside: Gaucher's disease From sulfatide (sulfatidoses, leukodystrophy) Sulfatide: Metachromatic leukodystrophy · Multiple sulfatase deficiency Galactocerebroside: Krabbe disease To sphingosine Ceramide: Farber disease NCL Infantile · Jansky-Bielschowsky disease · Batten disease Other Cerebrotendineous xanthomatosis · Cholesteryl ester storage disease (Wolman disease) · Sea-blue histiocyte syndrome see also enzymes, sphingolipids

v • d • e Sex linkage: X-linked disorders X-linked recessive Immune Chronic granulomatous disease (CYBB) · Wiskott-Aldrich syndrome · X-linked severe combined immunodeficiency · X-linked agammaglobulinemia · Hyper-IgM syndrome type 1 · IPEX · X-linked lymphoproliferative disease Hematologic Haemophilia A · Haemophilia B · X-linked sideroblastic anemia Endocrine Androgen insensitivity syndrome/Kennedy disease · KAL1 Kallmann syndrome · X-linked adrenal hypoplasia congenita Metabolic amino acid: Ornithine transcarbamylase deficiency · Oculocerebrorenal syndrome dyslipidemia: Adrenoleukodystrophy carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency · Pyruvate dehydrogenase deficiency · Danon disease/glycogen storage disease Type IIb lipid storage disorder: Fabry's disease mucopolysaccharidosis: Hunter syndrome purine-pyrimidine metabolism: Lesch-Nyhan syndrome mineral: Menkes disease Nervous system X-Linked mental retardation: Coffin-Lowry syndrome · Fragile X syndrome · MASA syndrome · X-linked alpha thalassemia mental retardation syndrome eye disorders: Color blindness (red and green, but not blue) · Ocular albinism (1) · Norrie disease · Choroideremia other: Charcot-Marie-Tooth disease (CMTX2-3) · Pelizaeus-Merzbacher disease · SMAX2 Skin and related tissue Dyskeratosis congenita · Hypohidrotic ectodermal dysplasia (EDA) · X-linked ichthyosis · X-linked endothelial corneal dystrophy Neuromuscular Becker's muscular dystrophy/Duchenne · Centronuclear myopathy (MTM1) · Conradi-Hünermann syndrome Urologic Alport syndrome · Dent's disease · X-linked nephrogenic diabetes insipidus No primary system Barth syndrome · McLeod syndrome · Simpson-Golabi-Behmel syndrome X-linked dominant X-linked hypophosphatemia · Focal dermal hypoplasia · Aicardi syndrome · Incontinentia pigmenti · Rett syndrome · CHILD syndrome · Lujan-Fryns syndrome

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)