| Fabry disease |
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Alpha galactosidase - the deficient protein Fabry disease
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| Classification and external resources |
| Specialty |
endocrinology |
| ICD-10 |
E75.2 (ILDS E75.25) |
| ICD-9-CM |
272.7 |
| OMIM |
301500 |
| DiseasesDB |
4638 |
| eMedicine |
neuro/579 derm/707 ped/2888 |
| MeSH |
D000795 |
| GeneReviews |
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[edit on Wikidata]
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Fabry disease () (also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum, and alpha-galactosidase A deficiency) is a rare genetic lysosomal storage disease, inherited in an X-linked manner. Fabry disease can cause a wide range of systemic symptoms.[1] It is a form of sphingolipidosis, as it involves dysfunctional metabolism of sphingolipids. The disease is named after one of its discoverers, Johannes Fabry (June 1, 1860 – June 29, 1930).[2]
Contents
- 1 Signs and symptoms
- 1.1 Pain
- 1.2 Kidney involvement
- 1.3 Cardiac manifestations
- 1.4 Dermatological manifestations
- 1.5 Other manifestations
- 2 Pathophysiology
- 3 Diagnosis
- 4 Treatment
- 5 Prognosis
- 6 Epidemiology
- 7 Pop culture references
- 8 See also
- 9 References
- 9.1 Sources and further reading
- 10 External links
Signs and symptoms
A bilateral, whorl-like corneal pattern of cream -colored lines in a patient with Fabry disease
Angiokeratoma, a common dermatological manifestation in Fabry sufferers
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.[citation needed]
Pain
Full body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This acroparesthesia 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.[3]
Kidney involvement
Kidney complications are a common and serious effect of the disease; kidney insufficiency and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life, and is a common cause of death due to the disease.[citation needed]
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. High blood pressure and cardiomyopathy are commonly observed.[citation needed]
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 common.[citation needed]
Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).[citation needed]
Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain).[citation needed]
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 patients, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea).[4] This clouding does not affect vision.[4]
Other ocular findings can include conjunctival and retinal vascular abnormalities, and anterior/posterior spoke-like cataract. Visual reduction from these manifestastions are uncommon.
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 imbalances, and diarrhea are other common symptoms.[citation needed]
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.[5] This accumulation leads to an impairment of their proper functions.
The DNA mutations which cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. 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. New research suggests many women suffer with severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and renal failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.[6]
Diagnosis
Fabry disease is suspected based on the individual's clinical presentation, and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease.[7]
Treatment
The first treatment for Fabry's disease was approved by the US FDA on April 24, 2003. Fabrazyme (agalsidase beta, or Alpha-galactosidase) was licensed to the Genzyme Corporation.[8] It is an enzyme replacement therapy (ERT) designed to provide the enzyme the patient is missing as a result of a genetic malfunction. The drug is expensive — in 2012, Fabrazyme's annual cost was about US$200,000 per patient,[9] which is unaffordable to many patients around the world without enough insurance. ERT is not a cure, but can allow improved metabolism and partially prevent disease progression, as well as potentially reverse some symptoms.
The pharmaceutical company Shire manufactures agalsidase alpha (which differs in the structure of its oligosaccharide side chains[10]) under the brand name Replagal as a treatment for Fabry's disease,[11] and was granted marketing approval in the EU in 2001.[12] FDA approval was applied for the United States.[13] However, Shire withdrew their application for approval in the United States in 2012, citing that the agency will require additional clinical trials before approval.[14]
Clinically the two products are generally perceived to be similar in effectiveness. Both are available in Europe and in many other parts of the world, but treatment costs remain very high.[15]
Pain associated with Fabry disease may be partially alleviated by ERT in some patients, but pain management regimens may also include analgesics, anticonvulsants, and nonsteroidal anti-inflammatory drugs, though the latter are usually best avoided in renal disease.
Prognosis
Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements.[16]
Epidemiology
The incidence of Fabry disease is estimated to be between one in 40,000 and one in 120,000 live births.[17]
Pop culture references
- House ("Epic Fail", season 6 episode 3) centers on a patient with Fabry disease.
- Scrubs ("My Catalyst", season 3 episode 12) features a Fabry disease diagnosis.
- Crossing Jordan ("There's No Place Like Home", season 2 episode 1) features a patient who died suffering Fabry disease.
- The Village: Achiara's Secret[18] (Korean Drama) features daughters of a serial rapist who find each other because they share Fabry disease.
See also
- Lysosomal storage disorder
- Sphingolipidoses
- Migalastat
References
- ^ James, Berger & Elston 2006, p. 538
- ^ synd/1761 at Who Named It?
- ^ Hoffmann, Bjoern; Beck, Michael; Sunder-Plassmann, Gere; Borsini, Walter; Ricci, Roberta; Mehta, Atul (2007). "Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy—a retrospective analysis from the Fabry Outcome Survey". The Clinical Journal of Pain. 23 (6): 535–542. doi:10.1097/AJP.0b013e318074c986. PMID 17575495.
- ^ a b Chew, E.; Ghosh, M.; McCulloch, C. (June 1982). "Amiodarone-induced cornea verticillata". Canadian Journal of Ophthalmology. 17 (3): 96–99. PMID 7116220.
- ^ Karen, Julie K.; Hale, Elizabeth K.; Ma, Linglei (2005). "Angiokeratoma corporis diffusum (Fabry disease)". Dermatology Online Journal. 11 (4): 8. PMID 16403380.
- ^ James, Berger & Elston 2006, pp. [page needed]
- ^ Marchesoni, Cintia L.; Roa, Norma; Pardal, Ana María; Neumann, Pablo; Cáceres, Guillermo; Martínez, Pablo; Kisinovsky, Isaac; Bianchi, Silvia; Tarabuso, Ana Lía; Reisin, Ricardo C. (May 2010). "Misdiagnosis in Fabry disease". The Journal of Pediatrics. 156 (5): 828–31. doi:10.1016/j.jpeds.2010.02.012. PMID 20385321.
- ^ "Fabrazyme Prescribing Information (USA)" (PDF). www.fda.gov.
- ^ Pollack, Andrew (April 15, 2010). "Genzyme Drug Shortage Leaves Users Feeling Betrayed". New York Times.
- ^ Fervenza, Fernando C.; Torra, Roser; Warnock, David G. (December 2008) [13 November 2008]. "Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease". Biologics. 2 (4): 823–843. doi:10.2147/btt.s3770. PMC 2727881. PMID 19707461.
- ^ Keating, Gillian M. (October 2012). "Agalsidase alfa: a review of its use in the management of Fabry disease". BioDrugs. 26 (5): 335–354. doi:10.2165/11209690-000000000-00000. PMID 22946754.
- ^ "Shire Submits Biologics License Application (BLA) for Replagal with the U.S. Food and Drug Administration (FDA)". FierceBiotech.
- ^ "With A Life-Saving Medicine In Short Supply, Patients Want Patent Broken". 2010-08-04. Archived from the original on 14 September 2010. Retrieved 2010-09-02.
- ^ Grogan, K. (2012-03-15). "Shire withdraws Replagal in USA as FDA wants more trials". PharmaTimes.
- ^ Waldek, S. Fabry Disease: management and outcome. Chapter 338 in Oxford Textbook of Nephrology (4th ed) 2015, eds Turner, Lameire, et al.
- ^ Waldek, Stephen; Patel, Manesh R.; Banikazemi, Maryam; Lemay, Roberta; Lee, Philip (November 2009). "Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry". Genetics in Medicine. 11 (11): 790–796. doi:10.1097/GIM.0b013e3181bb05bb. PMID 19745746.
- ^ Mehta, A.; Ricci, R.; Widmer, U.; Dehout, F.; Garcia de Lorenzo, A.; Kampmann, C.; Linhart, A.; Sunder-Plassmann, G.; Ries, M.; Beck, M. (March 2004). "Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey". European Journal of Clinical Investigation. 34 (3): 236–42. doi:10.1111/j.1365-2362.2004.01309.x. PMID 15025684.
- ^ "The Village: Achiara's Secret".
Sources and further reading
- James, William D.; Berger, Timothy G.; Elston, Dirk (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
- Schiffmann, Raphael; Kopp, Jeffrey B.; Austin, Howard A.; Sabnis, Sharda; Moore, David F.; Weibel, Thais; Balow, James E.; Brady, Roscoe O. (June 2001). "Enzyme replacement therapy in Fabry disease: a randomized controlled trial". JAMA. 285 (21): 2743–2749. doi:10.1001/jama.285.21.2743. PMID 11386930.
- Wilcox, William R.; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E.; Desnick, Robert J.; Germain, Dominique P. (July 2004). "Long-term safety and efficacy of enzyme replacement therapy for Fabry disease". American Journal of Human Genetics. 75 (1): 65–74. doi:10.1086/422366. PMC 1182009. PMID 15154115.
External links
- Fabry Disease Information Page at NINDS
- Fabry disease at NLM Genetics Home Reference
- Fabry Registry
- Stroke in young Fabry patients
- Datagenno - Fabry Disease
- Support groups
- 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, USA
- Fabry Support Group Australia
- Fabry Support Group Poland by Pietka
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(LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7–272.8)
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Sphingolipidoses
(to ceramide) |
From ganglioside
(gangliosidoses) |
- Ganglioside: GM1 gangliosidoses
- GM2 gangliosidoses (Sandhoff disease
- Tay–Sachs disease
- AB variant)
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| From globoside |
- Globotriaosylceramide: Fabry's disease
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| From sphingomyelin |
- Sphingomyelin: phospholipid: Niemann–Pick disease (SMPD1-associated
- type C)
- Glucocerebroside: Gaucher's disease
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From sulfatide
(sulfatidoses
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- Sulfatide: Metachromatic leukodystrophy
- Multiple sulfatase deficiency
- Galactocerebroside: Krabbe disease
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| To sphingosine |
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| NCL |
- Infantile
- Jansky–Bielschowsky disease
- Batten disease
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| Other |
- Cerebrotendineous xanthomatosis
- Cholesteryl ester storage disease (Lysosomal acid lipase deficiency/Wolman disease)
- Sea-blue histiocytosis
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Sex linkage: X-linked disorders
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X-linked recessive
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| 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
- Properdin deficiency
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| Hematologic |
- Haemophilia A
- Haemophilia B
- X-linked sideroblastic anemia
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| Endocrine |
- Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
- KAL1 Kallmann syndrome
- X-linked adrenal hypoplasia congenita
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| 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/Occipital horn syndrome
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| Nervous system |
- X-linked mental retardation: Coffin–Lowry syndrome
- MASA syndrome
- X-linked alpha thalassemia mental retardation syndrome
- Siderius X-linked 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
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| Skin and related tissue |
- Dyskeratosis congenita
- Hypohidrotic ectodermal dysplasia (EDA)
- X-linked ichthyosis
- X-linked endothelial corneal dystrophy
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| Neuromuscular |
- Becker's muscular dystrophy/Duchenne
- Centronuclear myopathy (MTM1)
- Conradi–Hünermann syndrome
- Emery–Dreifuss muscular dystrophy 1
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| Urologic |
- Alport syndrome
- Dent's disease
- X-linked nephrogenic diabetes insipidus
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| Bone/tooth |
- AMELX Amelogenesis imperfecta
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| No primary system |
- Barth syndrome
- McLeod syndrome
- Smith–Fineman–Myers syndrome
- Simpson–Golabi–Behmel syndrome
- Mohr–Tranebjærg syndrome
- Nasodigitoacoustic syndrome
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X-linked dominant
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- X-linked hypophosphatemia
- Focal dermal hypoplasia
- Fragile X syndrome
- Aicardi syndrome
- Incontinentia pigmenti
- Rett syndrome
- CHILD syndrome
- Lujan–Fryns syndrome
- Orofaciodigital syndrome 1
- Craniofrontonasal dysplasia
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