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Alternative Name: Fabry’s disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency
Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect which allows this to occur is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide
The body continuously performs metabolic processes which produce, recycle and remove vital compounds. In patients with Fabry disease one such common compound formed of three sugars and a fatty substance (globotriaosylceramide) does not get broken down due to the missing or non-functioning enzyme alpha galactosidase A. Since this fatty compound (lipid) is not being broken down and removed, it begins to accumulate. Thus, Fabry disease is often referred to as a “storage disorder” due to this abnormal accumulation. In patients with Fabry disease, this accumulation occurs primarily in the blood and in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels. This abnormal process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.
All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.
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.
Full body or localized pain to the extremities (known as acroparesthesia) or GI tract is common in patients with Fabry disease. Acroparesthesia in Fabry disease is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract which obstructs blood flow and causes pain.
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 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.
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).
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.
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, chemical inbalances, and diarrhea are other common symptoms.
Fabry disease is a type of lipid storage disease caused by a defect in the gene that controls an enzyme called alpha-galactosidase A (also known as ceramide trihexosidase). This enzyme is involved in the breakdown of certain lipids (fats).
The deficiency in this enzyme causes certain lipid molecules, called glycosphingolipids, to accumulate in the body’s tissues, particularly the heart, kidneys, eyes and nerve tissue.
The gene that’s altered is on the X chromosome, making its transmission X-linked. So boys have a 50 per cent chance of inheriting the disorder, while girls have a 50 per cent chance of becoming a carrier. The gene responsible can be detected.
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.
You may click to see :Final Diagnosis — Fabry’s Disease
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.
Misdiagnosis of Fabry Disease: Pediatricians as well as internists commonly misdiagnose Fabry disease
There’s no cure for Fabry disease, although it may be treated by enzyme replacement.
Until the 2000s, treatment of Fabry disease targeted the symptomatic effects.
In 2001, three Enzyme Replacement Therapies (ERTs) were released: Agalsidase alpha (Replagal, manufactured by Shire) and Agalsidase beta (Fabrazyme, manufactured by Genzyme). These attempt to replace the deficient enzyme by means of infusion, most commonly, every two weeks. 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.
Pain in Fabry disease responds to ERT, but pain management regimens may also include analgesics, anticonvulsants, and non-steroidal anti-inflammatory drugs.
Patients with Fabry disease often survive into adulthood but are at increase risk of strokes, heart attack and heart disease, and kidney failure.
The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health, conducts and supports research to find ways to treat and prevent lipid storage diseases such as Fabry disease. This research includes clinical studies by the NINDS Developmental and Metabolic Neurology Branch:http://www.ninds.nih.gov/find_people/labs/61.htm.
For more information:
Fabry Support & Information Group
108 NE 2nd Street, Ste. C
P.O. Box 510 Concordia, MO 64020-0510
National Tay-Sachs and Allied Diseases Association
2001 Beacon Street Suite 204
Brighton, MA 02135
Tel: 617-277-4463 800-90-NTSAD (906-8723)
National Organization for Rare Disorders (NORD)
P.O. Box 1968 (55 Kenosia Avenue)
Danbury, CT 06813-1968
Voice Mail 800-999-NORD (6673)
Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.
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