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Fabry's disease

MedGen UID:
8083
Concept ID:
C0002986
Disease or Syndrome
Synonyms: Alpha-galactosidase A deficiency; Anderson-Fabry disease; Angiokeratoma corporis diffusum; Angiokeratoma diffuse; Angiokeratoma, diffuse; Atypical Variants of Fabry Disease; Ceramide trihexosidase deficiency; Ceramide trihexosidosis; Classic Fabry Disease; Fabry Disease; Fabry''s disease; GLA deficiency; Hereditary dystopic lipidosis
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
425042
Concept ID:
CN001297
Genetic Function
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
SNOMED CT: Deficiency of melibiase (124464003); Deficiency of alpha-galactosidase (124464003); Fabry's disease (16652001); Hereditary dystopic lipidosis (16652001); Thesaurismosis lipoidica (16652001); Ceramide trihexosidase deficiency (16652001); Lactosyl ceramidosis (16652001); Ceramide lactoside lipidosis (16652001); alpha-Galactosidase-A deficiency (16652001); Angiokeratoma corporis diffusum universale (16652001); GLA deficiency (16652001); Thesaurismosis hereditaria (16652001); Cardiovasorenal syndrome (16652001); Ruiter-Pompen syndrome (16652001); Anderson-Fabry disease (16652001); Sweeley-Klionsky disease (16652001); Alpha-galactosidase A deficiency (16652001); Angiokeratoma corporis diffusum (16652001); Fabry disease (16652001)
 
Gene: GLA
Cytogenetic location: Xq22.1
OMIM: 301500

Disease characteristics

Excerpted from the GeneReview: Fabry Disease
Fabry disease results from deficient activity of the enzyme α-galactosidase (α-Gal A) and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhydrosis, hypohydosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, males with greater than 1% α-Gal A activity may have either (1) a cardiac variant phenotype that usually presents in the sixth to eighth decade with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria, but without ESRD; or (2) a renal variant phenotype, associated with ESRD but without the skin lesions or pain.  [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Atul Mehta  |  Derralynn A Hughes   view full author information

Additional descriptions

From OMIM
Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (Nance et al., 2006). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (Schiffmann, 2009). An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (Nakao et al., 1995; Nakao et al., 2003). Although previously considered an X-linked recessive disorder, Wang et al. (2007) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. Clarke (2007) and Schiffmann (2009) provided detailed reviews of Fabry disease.  http://www.omim.org/entry/301500
From GHR
Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys.  http://ghr.nlm.nih.gov/condition/fabry-disease

Clinical features

Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Finding
A disorder characterized by laboratory test results that indicate blood in the urine.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
abnormal presence of protein in urine
Renal insufficiency
MedGen UID:
427392
Concept ID:
CN000083
Finding
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Abnormality of the renal tubule
MedGen UID:
424979
Concept ID:
CN000091
Finding
An abnormality of the `renal tubules` (FMA:15627).
Nephrotic syndrome
MedGen UID:
504341
Concept ID:
CN000100
Finding
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Nephropathy
MedGen UID:
504346
Concept ID:
CN000110
Finding
A nonspecific term referring to disease or damage of the kidneys.
Glomerulopathy
MedGen UID:
506545
Concept ID:
CN117710
Finding
Inflammatory or noninflammatory diseases affecting the glomeruli of the nephron.
Thick lower lip vermilion
MedGen UID:
504381
Concept ID:
CN000174
Finding
Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).
Conjunctival telangiectasia
MedGen UID:
504479
Concept ID:
CN000490
Finding
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Optic atrophy
MedGen UID:
504537
Concept ID:
CN000609
Finding
`Atrophy` (MPATH:127) of the `optic nerve` (FMA:50863). Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Corneal dystrophy
MedGen UID:
504738
Concept ID:
CN001063
Finding
An `abnormality of the cornea` (HP:0000481) that is characterized by opacity of one or parts of the cornea.
Sensorineural hearing impairment
MedGen UID:
504436
Concept ID:
CN000380
Finding
A type of `hearing impairment` (HP:0000365) in one or both ears related to an `abnormal` (PATO:0000460) `functionality` (PATO:0001509) of the `cochlear nerve` (FMA:53431).
Vertigo
MedGen UID:
500924
Concept ID:
CN002108
Finding
An abnormal sensation of spinning while the body is actually stationary.
Behavioral abnormality
MedGen UID:
425007
Concept ID:
CN000665
Finding
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Developmental regression
MedGen UID:
505217
Concept ID:
CN002158
Finding
Loss of developmental skills, as manifested by loss of developmental milestones.
Fasciculations
MedGen UID:
505219
Concept ID:
CN002161
Finding
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
Dysautonomia
MedGen UID:
505243
Concept ID:
CN002233
Finding
`Dysfunction` (PATO:0001641) of the `autonomic nervous system` (FMA:9905).
Paresthesia
MedGen UID:
505532
Concept ID:
CN003069
Finding
Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.
Diabetes insipidus
MedGen UID:
504639
Concept ID:
CN000819
Finding
A state of excessive water intake and hypotonic (dilute) polyuria. Diabetes insipidus may be due to failure of vasopressin (AVP) release (central or neurogenic diabetes insipidus) or to a failure of the kidney to respond to AVP (nephrogenic diabetes insipidus).
Abnormality of the hand
MedGen UID:
427857
Concept ID:
CN001087
Finding
An abnormality affecting one or both hands.
Arthritis
MedGen UID:
504815
Concept ID:
CN001254
Finding
Inflammation of a joint.
Abnormality of the femur
MedGen UID:
446457
Concept ID:
CN002549
Finding
Abnormality of the `femur` (FMA:9611).
Abdominal pain
MedGen UID:
505060
Concept ID:
CN001834
Finding
Pain perceived to originate in the abdomen.
Tenesmus
MedGen UID:
776801
Concept ID:
CN185406
Finding
A repeated, painful urge to defecate without excreting stool.
Conjunctival telangiectasia
MedGen UID:
504479
Concept ID:
CN000490
Finding
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Hyperkeratosis
MedGen UID:
504662
Concept ID:
CN000900
Finding
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Angiokeratoma
MedGen UID:
504687
Concept ID:
CN000950
Finding
A vascular lesion defined histologically as one or more dilated blood vessels lying directly subepidermal and showing an epidermal proliferative reaction. Clinically, angiokeratoma presents as a small, raised, dark-red spot.
Teleangiectasia of the skin
MedGen UID:
451896
Concept ID:
CN117478
Finding
Presence of small, permanently dilated blood vessels near the surface of the skin, visible as small focal red lesions.
Hypertension
MedGen UID:
635666
Concept ID:
C0497247
Finding
A finding of increased blood pressure; not necessarily hypertensive disorder
Conjunctival telangiectasia
MedGen UID:
504479
Concept ID:
CN000490
Finding
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Abnormality of the mitral valve
MedGen UID:
428274
Concept ID:
CN001486
Finding
An abnormality of the `mitral valve` (FMA:7235).
Congestive heart failure
MedGen UID:
504881
Concept ID:
CN001488
Finding
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Hypertrophic cardiomyopathy
MedGen UID:
504884
Concept ID:
CN001492
Finding
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Abnormality of the aortic valve
MedGen UID:
425065
Concept ID:
CN001499
Finding
Any abnormality of the `aortic valve` (FMA:7236).
Myocardial infarction
MedGen UID:
504896
Concept ID:
CN001509
Finding
Necrosis of the myocardium caused by an obstruction of the blood supply to the heart and often associated with chest pain, shortness of breath, palpitations, and anxiety as well as characteristic EKG findings and elevation of serum markers including creatine kinase-MB fraction and troponin.
Coronary artery disease
MedGen UID:
504904
Concept ID:
CN001526
Finding
Reduction of the diameter of the coronary arteries as the result of an accumulation of atheromatous plaques within the walls of the coronary arteries, which increases the risk of myocardial ischemia.
Angina pectoris
MedGen UID:
504907
Concept ID:
CN001530
Finding
Paroxysmal chest pain that occurs with exertion or stress and is related to myocardial ischemia.
Abnormality of the endocardium
MedGen UID:
446580
Concept ID:
CN003807
Finding
An abnormality of the `endocardium` (FMA:7280).
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result which indicates decreased levels of hemoglobin in a biological specimen.
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Finding
A disorder characterized by laboratory test results that indicate blood in the urine.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
abnormal presence of protein in urine
Abnormality of lipid metabolism
MedGen UID:
428327
Concept ID:
CN002813
Finding
An abnormality in the of `lipid` (CHEBI:18059) metabolism.
Abnormality of temperature regulation
MedGen UID:
425258
Concept ID:
CN003869
Finding
An abnormality of `temperature homeostasis` (GO:0001659).
Obstructive lung disease
MedGen UID:
505926
Concept ID:
CN005694
Finding
Obstruction of conducting airways of the lung.
Muscle cramps
MedGen UID:
505530
Concept ID:
CN003063
Finding
Sudden and involuntary contractions of one or more muscles.

Professional guidelines

PubMed

Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. [Epub ahead of print] PMID: 23788249Free PMC Article
Gal A, Beck M, Winchester B
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Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN
J Card Fail 2010 Jun;16(6):e1-194. doi: 10.1016/j.cardfail.2010.04.004. PMID: 20610207
Salviati A, Burlina AP, Borsini W
Neurol Sci 2010 Jun;31(3):299-306. Epub 2010 Mar 19 doi: 10.1007/s10072-009-0211-y. [Epub ahead of print] PMID: 20300794Free PMC Article
Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR
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Bennett RL, Hart KA, O'Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R
J Genet Couns 2002 Apr;11(2):121-46. PMID: 12735292

Recent clinical studies

Etiology

Herrera J, Miranda CS
Clin Nephrol 2014 Feb;81(2):112-20. doi: 10.5414/CN108053. PMID: 24365053
Lepedda AJ, Fancellu L, Zinellu E, De Muro P, Nieddu G, Deiana GA, Canu P, Concolino D, Sestito S, Formato M, Sechi G
Biomed Res Int 2013;2013:205948. Epub 2013 Jun 12 doi: 10.1155/2013/205948. PMID: 23841057Free PMC Article
Kaminsky P, Noel E, Jaussaud R, Leguy-Seguin V, Hachulla E, Zenone T, Lavigne C, Marie I, Maillot F, Masseau A, Serratrice C, Lidove O
Int J Clin Pract 2013 Feb;67(2):120-7. doi: 10.1111/ijcp.12016. PMID: 23305474
Kunkala MR, Aubry MC, Ommen SR, Gersh BJ, Schaff HV
Ann Thorac Surg 2013 Jan;95(1):335-7. Epub 2012 Dec 25 doi: 10.1016/j.athoracsur.2012.05.087. [Epub ahead of print] PMID: 23272855
Saposnik G, Lanthier S, Mamdani M, Thorpe KE, Melo M, Pope K, Selchen D, Moore DF; Canadian Stroke Consortium; Stroke Outcome Research Canada (SORCan) Working Group
Int J Stroke 2012 Apr;7(3):265-73. Epub 2012 Jan 20 doi: 10.1111/j.1747-4949.2011.00734.x. [Epub ahead of print] PMID: 22264232

Diagnosis

Mahmud HM
J Pak Med Assoc 2014 Feb;64(2):189-94. PMID: 24640811
Herrera J, Miranda CS
Clin Nephrol 2014 Feb;81(2):112-20. doi: 10.5414/CN108053. PMID: 24365053
Blount JR, Wu JK, Martinez MW
J Card Surg 2013 Nov;28(6):695-8. Epub 2013 Sep 2 doi: 10.1111/jocs.12209. [Epub ahead of print] PMID: 23992477
Nandagudi A, Jury EC, Alonzi D, Butters TD, Hughes S, Isenberg DA
Lupus 2013 Sep;22(10):1070-6. Epub 2013 Jul 17 doi: 10.1177/0961203313497116. [Epub ahead of print] PMID: 23864039Free PMC Article
Saposnik G, Lanthier S, Mamdani M, Thorpe KE, Melo M, Pope K, Selchen D, Moore DF; Canadian Stroke Consortium; Stroke Outcome Research Canada (SORCan) Working Group
Int J Stroke 2012 Apr;7(3):265-73. Epub 2012 Jan 20 doi: 10.1111/j.1747-4949.2011.00734.x. [Epub ahead of print] PMID: 22264232

Therapy

Mahmud HM
J Pak Med Assoc 2014 Feb;64(2):189-94. PMID: 24640811
Herrera J, Miranda CS
Clin Nephrol 2014 Feb;81(2):112-20. doi: 10.5414/CN108053. PMID: 24365053
Blount JR, Wu JK, Martinez MW
J Card Surg 2013 Nov;28(6):695-8. Epub 2013 Sep 2 doi: 10.1111/jocs.12209. [Epub ahead of print] PMID: 23992477
O'Neill F, Rice J
Hip Int 2012 Jan-Feb;22(1):119-21. doi: 10.5301/HIP.2012.9102. PMID: 22383317
Saposnik G, Lanthier S, Mamdani M, Thorpe KE, Melo M, Pope K, Selchen D, Moore DF; Canadian Stroke Consortium; Stroke Outcome Research Canada (SORCan) Working Group
Int J Stroke 2012 Apr;7(3):265-73. Epub 2012 Jan 20 doi: 10.1111/j.1747-4949.2011.00734.x. [Epub ahead of print] PMID: 22264232

Prognosis

Kaminsky P, Noel E, Jaussaud R, Leguy-Seguin V, Hachulla E, Zenone T, Lavigne C, Marie I, Maillot F, Masseau A, Serratrice C, Lidove O
Int J Clin Pract 2013 Feb;67(2):120-7. doi: 10.1111/ijcp.12016. PMID: 23305474
Kunkala MR, Aubry MC, Ommen SR, Gersh BJ, Schaff HV
Ann Thorac Surg 2013 Jan;95(1):335-7. Epub 2012 Dec 25 doi: 10.1016/j.athoracsur.2012.05.087. [Epub ahead of print] PMID: 23272855
Cormican MT, Paschalis T, Viers A, Alleyne CH Jr
BMJ Case Rep 2012 Jul 3;2012 doi: 10.1136/bcr.02.2012.5727. PMID: 22761201Free PMC Article
Bidra AS
J Prosthodont 2011 Oct;20 Suppl 2:S2-8. doi: 10.1111/j.1532-849X.2011.00764.x. PMID: 22003877
Wuest W, Machann W, Breunig F, Weidemann F, Koestler H, Hahn D, Wanner C, Beer M
Rofo 2011 Nov;183(11):1037-42. Epub 2011 Sep 28 doi: 10.1055/s-0031-1281744. [Epub ahead of print] PMID: 21959886

Clinical prediction guides

Kaminsky P, Noel E, Jaussaud R, Leguy-Seguin V, Hachulla E, Zenone T, Lavigne C, Marie I, Maillot F, Masseau A, Serratrice C, Lidove O
Int J Clin Pract 2013 Feb;67(2):120-7. doi: 10.1111/ijcp.12016. PMID: 23305474
Pagnini I, Borsini W, Cecchi F, Sgalambro A, Olivotto I, Frullini A, Cimaz R
Arthritis Care Res (Hoboken) 2011 Mar;63(3):390-5. Epub 2010 Oct 27 doi: 10.1002/acr.20385. [Epub ahead of print] PMID: 20981813
Małek LA, Chojnowska L, Spiewak M, Kłopotowski M, Miśko J, Petryka J, Miłosz B, Ruzyłło W
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Koskenvuo JW, Kantola IM, Nuutila P, Knuuti J, Parkkola R, Mononen I, Hurme S, Kalliokoski R, Viikari JS, Wendelin-Saarenhovi M, Kiviniemi TO, Hartiala JJ
Acta Cardiol 2010 Apr;65(2):185-92. PMID: 20458826
De Cobelli F, Esposito A, Belloni E, Pieroni M, Perseghin G, Chimenti C, Frustaci A, Del Maschio A
AJR Am J Roentgenol 2009 Mar;192(3):W97-102. doi: 10.2214/AJR.08.1201. PMID: 19234246

Recent systematic reviews

Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, Moore D
Health Technol Assess 2006 Jun;10(20):iii-iv, ix-113. PMID: 16729919
Brady RO, Schiffmann R
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Mitsias P, Levine SR
Ann Neurol 1996 Jul;40(1):8-17. doi: 10.1002/ana.410400105. PMID: 8687196

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