Fabry's disease
Encyclopedia
Fabry disease is a rare X-linked recessive
(inherited) lysosomal storage disease
, which can cause a wide range of systemic symptoms. The disease is named after one of its discoverers, Johannes Fabry (June 1,1860 - June 29,1930).
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 vessel
s, other tissues, and organs. 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 in many cases heterozygous
females. While 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.
Pain
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.
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:
Angiokeratoma
s (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, chemical inbalances, and diarrhea are other common symptoms.
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.
In 2001, two 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.
Support groups:
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
(inherited) lysosomal storage disease
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
, which can cause a wide range of systemic symptoms. The disease is named after one of its discoverers, Johannes Fabry (June 1,1860 - June 29,1930).
Pathophysiology
A deficiency of the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid
Glycolipid
Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
known as globotriaosylceramide
Globotriaosylceramide
Globotriaosylceramide is a ganglioside.It is also known as "CD77". It is one of the few clusters of differentiation that is not a protein.It is also known as "ceramide trihexoside".It is formed by A4GALT.It is metabolized by Alpha-galactosidase....
(abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s, other tissues, and organs. This accumulation leads to an impairment of their proper function.
The DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
mutations which cause the disease are X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
. The condition affects hemizygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
males (i.e. all males), as well as homozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
, and in many cases heterozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
females. While 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
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
patterns during embryonic development of the female.
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.Pain
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.
Renal involvement:
Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
may worsen throughout life. Proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
(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
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(high blood pressure) and cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
are commonly observed.
Dermatological manifestations:
Angiokeratoma
Angiokeratoma
Angiokeratoma a is benign cutaneous lesion of capillaries, resulting in small marks of red to blue color and characterized by hyperkeratosis....
s (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
Anhidrosis
Anhidrosis means lack of sweating. It is also known by a number of other names including Adiaphoresis, Ischidrosis, Hypohidrosis, Oligidria, Oligohidrosis and Sweating deficiency.-Causes:...
(lack of sweating) is a common symptom, and less commonly hyperhidrosis
Hyperhidrosis
Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...
(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
Keratopathy
Keratopathy can refer to:* Florida keratopathy* Thygeson's superficial punctate 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
Macular edema
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell. The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball...
, 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
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
(ringing in the ears), vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, nausea, inability to gain weight, chemical inbalances, 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-galactosidaseAlpha-galactosidase
Alpha-galactosidase is a glycoside hydrolase enzyme that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. It is encoded by the gene.- Function :...
activity, however this may be misleading in female carriers due to the random nature of X-inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
. 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
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
patterns, levels are commonly normal even if the patient is not asymptomatic. The Sifap
Sifap
Sifap is a Pan-European study dedicated to investigating the correlation of juvenile stroke and a genetic disorder known as Fabry's disease. It was initiated by University of Rostock, Germany. In recruiting 5,000 patients aged 18 to 55 it will be the largest study on stroke in the young...
(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.Treatment
Until the 2000s, treatment of Fabry disease targeted the symptomatic effects.In 2001, two Enzyme Replacement Therapies (ERTs)
Enzyme replacement therapy
Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous infusion containing the enzyme...
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
Registered nurse
A registered nurse is a nurse who has graduated from a nursing program at a university or college and has passed a national licensing exam. A registered nurse helps individuals, families, and groups to achieve health and prevent disease...
, 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.
Pop Cultural references
- HouseHouse (TV series)House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
(Epic FailEpic Fail (House)"Epic Fail" is the third episode of the sixth season of House. It first aired on September 28, 2009.-Plot:Players in a video game known as SavageScape battle ferocious creatures. After the game ends, the testers find their boss, Vince Pearson, claiming that his hands are "on fire." House walks into...
, season 6 episode 3) centers on a patient with Fabry Disease. - ScrubsScrubs (TV series)Scrubs is an American medical comedy-drama television series created in 2001 by Bill Lawrence and produced by ABC Studios. The show follows the lives of several employees of the fictional Sacred Heart, a teaching hospital. It features fast-paced screenplay, slapstick, and surreal vignettes...
(My Catalyst, season 3 episode 12) features a Fabry Disease diagnosis.
See also
- Lysosomal storage disorder
- SphingolipidosesSphingolipidoses-Accumulated products:* Gangliosides: Gangliosidosis** GM1 gangliosidoses** GM2 gangliosidoses*** Tay-Sachs disease*** Sandhoff disease* Glycolipids** Fabry's disease** Krabbe disease** Metachromatic leukodystrophy*Glucocerebrosides**Gaucher's disease...
- Enzyme replacement therapyEnzyme replacement therapyEnzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous infusion containing the enzyme...
External links
- GeneReview entry on Fabry disease by NIH
- Fabry Disease Information Page at NINDS
- Fabry disease at NLMUnited States National Library of MedicineThe United States National Library of Medicine , operated by the United States federal government, is the world's largest medical library. Located in Bethesda, Maryland, the NLM is a division of the National Institutes of Health...
Genetics Home Reference - Fabry Registry
- Stroke in young Fabry patients
Support groups: