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Alkaptonuria(AKU)

MedGen UID:
1413
Concept ID:
C0002066
Disease or Syndrome
Synonyms: AKU; Alcaptonuria; Alkaptonuric ochronosis; Homogentisic acid oxidase deficiency; Homogentisic acidura; Ochronosis, hereditary
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
SNOMED CT: Homogentisicaciduria (360378009); Deficiency of homogentisate 1,2-dioxygenase (360378009); Deficiency of homogentisate oxygenase (360378009); Homogentisic acid oxidase deficiency (360378009); Deficiency of homogentisicase (360378009); Homogentisate 1,2-dioxygenase deficiency (360378009); Alkaptonuria (360381004)
 
Gene (location): HGD (3q13.33)
OMIM®: 203500; 607474
Orphanet: ORPHA56

Disease characteristics

Excerpted from the GeneReview: Alkaptonuria
Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are the presence of HGA in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Oxidation of the HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark upon standing. Ochronosis occurs only after age 30 years; arthritis often begins in the third decade. Other manifestations include pigment deposition, aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation, renal stones, and prostate stones. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Wendy J Introne  |  William A Gahl   view full author information

Additional descriptions

From OMIM
Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves (summary by Vilboux et al., 2009). Alkaptonuria enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed (by Garrod, 1902, on the suggestion of Bateson) and of being 1 of the 4 conditions in the charter group of inborn errors of metabolism. The manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and arthritis, especially characteristic in the spine.  http://www.omim.org/entry/203500
From GHR
Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age 30. People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Other features of this condition can include heart problems, kidney stones, and prostate stones.  http://ghr.nlm.nih.gov/condition/alkaptonuria

Clinical features

Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Prostatitis
MedGen UID:
504306
Concept ID:
CN000025
Finding
The presence of inflammation of the prostate.
Abnormality of the urinary system
MedGen UID:
427792
Concept ID:
CN000079
Finding
An abnormality of the urinary system.
Nephrolithiasis
MedGen UID:
504597
Concept ID:
CN000736
Finding
The presence of calculi (stones) in the kidneys.
Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an amino acid in the urine.
Abnormality of the nose
MedGen UID:
427806
Concept ID:
CN000342
Finding
An abnormality of the nose.
Blue sclerae
MedGen UID:
342813
Concept ID:
C1853175
Finding
Pigmentation of the sclera
MedGen UID:
347969
Concept ID:
C1859882
Finding
Hearing abnormality
MedGen UID:
427820
Concept ID:
CN000340
Finding
An abnormality of the sensory perception of sound.
Abnormality of the ear
MedGen UID:
427827
Concept ID:
CN000560
Finding
An abnormality of the ear.
Calcification of the auricular cartilage
MedGen UID:
425309
Concept ID:
CN004528
Finding
Ossification affecting the external ear cartilage.
Kyphosis
MedGen UID:
335104
Concept ID:
C1845112
Finding
Arthralgia
MedGen UID:
409545
Concept ID:
C1963066
Finding
Back pain
MedGen UID:
409546
Concept ID:
C1963071
Finding
Reduced bone mineral density
MedGen UID:
393152
Concept ID:
C2674432
Finding
Intervertebral disc degeneration
MedGen UID:
404625
Concept ID:
C2717759
Finding
Chondrocalcinosis
MedGen UID:
504652
Concept ID:
CN000875
Finding
Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .
Arthritis
MedGen UID:
504815
Concept ID:
CN001254
Finding
Inflammation of a joint.
Limitation of joint mobility
MedGen UID:
446405
Concept ID:
CN001260
Finding
A reduction in the freedom of movement of one or more joints.
Joint swelling
MedGen UID:
504823
Concept ID:
CN001268
Finding
Coronary artery calcification
MedGen UID:
504928
Concept ID:
CN001562
Finding
Calcification, that is, pathological deposition of calcium salts, affecting the coronary arteries.
Osteoarthritis
MedGen UID:
505348
Concept ID:
CN002503
Finding
Vertebral fusion
MedGen UID:
505419
Concept ID:
CN002669
Finding
A developmental defect leading to the union of two adjacent vertebrae.
Arthropathy
MedGen UID:
505436
Concept ID:
CN002746
Finding
Aortic valve calcification
MedGen UID:
505613
Concept ID:
CN003879
Finding
Deposition of calcium salts in the aortic valve.
Mitral valve calcification
MedGen UID:
505615
Concept ID:
CN003881
Finding
Abnormal calcification of the mitral valve.
Thickened Achilles tendon
MedGen UID:
505665
Concept ID:
CN004153
Finding
An abnormal thickening of the Achilles tendon.
Calcification of the auricular cartilage
MedGen UID:
425309
Concept ID:
CN004528
Finding
Ossification affecting the external ear cartilage.
Intervertebral disk calcification
MedGen UID:
425349
Concept ID:
CN004996
Finding
The presence of abnormal calcium deposition of the intervertebral disk.
Abnormal tendon morphology
MedGen UID:
451636
Concept ID:
CN117157
Finding
An abnormality of the structure or form of the tendons, also often called sinews.
Cartilage destruction
MedGen UID:
452007
Concept ID:
CN117663
Finding
Irregular hyperpigmentation
MedGen UID:
349760
Concept ID:
C1860236
Finding
Abnormality of the nail
MedGen UID:
446417
Concept ID:
CN001454
Finding
Abnormality of the nail.
Hypertension
MedGen UID:
635666
Concept ID:
C0497247
Finding
A finding of increased blood pressure; not necessarily hypertensive disorder
Abnormality of the aortic valve
MedGen UID:
425065
Concept ID:
CN001499
Finding
Any abnormality of the aortic valve.
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.
Coronary artery calcification
MedGen UID:
504928
Concept ID:
CN001562
Finding
Calcification, that is, pathological deposition of calcium salts, affecting the coronary arteries.
Mitral stenosis
MedGen UID:
504929
Concept ID:
CN001563
Finding
Ab abnormal narrowing of the orifice of the mitral valve.
Aortic dilatation
MedGen UID:
504933
Concept ID:
CN001568
Finding
Aortic valve calcification
MedGen UID:
505613
Concept ID:
CN003879
Finding
Deposition of calcium salts in the aortic valve.
Mitral valve calcification
MedGen UID:
505615
Concept ID:
CN003881
Finding
Abnormal calcification of the mitral valve.
Joint swelling
MedGen UID:
504823
Concept ID:
CN001268
Finding
Abnormality of metabolism/homeostasis
MedGen UID:
446429
Concept ID:
CN001754
Finding
Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an amino acid in the urine.
Chondrocalcinosis
MedGen UID:
504652
Concept ID:
CN000875
Finding
Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .
Thickened Achilles tendon
MedGen UID:
505665
Concept ID:
CN004153
Finding
An abnormal thickening of the Achilles tendon.

Recent clinical studies

Etiology

Khan UN, Wenokor C, Altschuler EL
Am J Phys Med Rehabil 2015 May;94(5):e42. doi: 10.1097/PHM.0000000000000253. PMID: 25768073
Sakthivel S, Zatkova A, Nemethova M, Surovy M, Kadasi L, Saravanan MP
Ann Hum Genet 2014 May;78(3):155-64. Epub 2014 Feb 12 doi: 10.1111/ahg.12055. [Epub ahead of print] PMID: 24575791
Aquaron R
Indian J Biochem Biophys 2013 Oct;50(5):339-44. PMID: 24772955
Thakur S, Markman P, Cullen H
Heart Lung Circ 2013 Oct;22(10):870-2. Epub 2013 Jan 26 doi: 10.1016/j.hlc.2012.12.015. [Epub ahead of print] PMID: 23357094
Hannoush H, Introne WJ, Chen MY, Lee SJ, O'Brien K, Suwannarat P, Kayser MA, Gahl WA, Sachdev V
Mol Genet Metab 2012 Feb;105(2):198-202. Epub 2011 Oct 30 doi: 10.1016/j.ymgme.2011.10.017. [Epub ahead of print] PMID: 22100375Free PMC Article

Diagnosis

Isa Y, Nihei S, Irifukuhama Y, Ikeda T, Matsumoto H, Nagata K, Harayama N, Aibara K, Kamochi M
Intern Med 2014;53(16):1797-800. Epub 2014 Aug 15 PMID: 25130113
Tokuhara Y, Shukuya K, Tanaka M, Mouri M, Ohkawa R, Fujishiro M, Takahashi T, Okubo S, Yokota H, Kurano M, Ikeda H, Yamaguchi S, Inagaki S, Ishige-Wada M, Usui H, Yatomi Y, Shimosawa T
PLoS One 2014;9(1):e86606. Epub 2014 Jan 23 doi: 10.1371/journal.pone.0086606. PMID: 24466168Free PMC Article
Hamada T, Yamamoto T, Shida J, Inokuchi A, Arizono T
Skeletal Radiol 2014 Jun;43(6):827-30. Epub 2013 Dec 20 doi: 10.1007/s00256-013-1796-z. [Epub ahead of print] PMID: 24357124
Damian LO, Felea I, Boloşiu C, Botar-Jid C, Fodor D, Rednic S
Med Ultrason 2013 Dec;15(4):321-5. PMID: 24286097
Thakur S, Markman P, Cullen H
Heart Lung Circ 2013 Oct;22(10):870-2. Epub 2013 Jan 26 doi: 10.1016/j.hlc.2012.12.015. [Epub ahead of print] PMID: 23357094

Therapy

Sakthivel S, Zatkova A, Nemethova M, Surovy M, Kadasi L, Saravanan MP
Ann Hum Genet 2014 May;78(3):155-64. Epub 2014 Feb 12 doi: 10.1111/ahg.12055. [Epub ahead of print] PMID: 24575791
Braconi D, Millucci L, Ghezzi L, Santucci A
Expert Rev Proteomics 2013 Dec;10(6):521-35. doi: 10.1586/14789450.2013.858020. PMID: 24206226
Ranganath LR, Cox TF
J Inherit Metab Dis 2011 Dec;34(6):1141-51. Epub 2011 Jul 12 doi: 10.1007/s10545-011-9374-9. [Epub ahead of print] PMID: 21748407
Cox TF, Ranganath L
J Inherit Metab Dis 2011 Dec;34(6):1153-62. Epub 2011 Jul 9 doi: 10.1007/s10545-011-9367-8. [Epub ahead of print] PMID: 21744089
Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA
Mol Genet Metab 2011 Aug;103(4):307-14. Epub 2011 May 6 doi: 10.1016/j.ymgme.2011.04.016. [Epub ahead of print] PMID: 21620748Free PMC Article

Prognosis

Khan UN, Wenokor C, Altschuler EL
Am J Phys Med Rehabil 2015 May;94(5):e42. doi: 10.1097/PHM.0000000000000253. PMID: 25768073
Isa Y, Nihei S, Irifukuhama Y, Ikeda T, Matsumoto H, Nagata K, Harayama N, Aibara K, Kamochi M
Intern Med 2014;53(16):1797-800. Epub 2014 Aug 15 PMID: 25130113
Hiroyoshi J, Saito A, Panthee N, Imai Y, Kawashima D, Motomura N, Ono M
Ann Thorac Surg 2013 Mar;95(3):1076-9. doi: 10.1016/j.athoracsur.2012.07.058. PMID: 23438536
Yang YJ, Guo JH, Chen WJ, Zhao R, Tang JS, Meng XH, Zhao L, Tu M, He XY, Wu LQ, Zhu YM
Gene 2013 Apr 15;518(2):467-9. Epub 2013 Jan 24 doi: 10.1016/j.gene.2013.01.020. [Epub ahead of print] PMID: 23353776
Aquaron RR
J Inherit Metab Dis 2011 Dec;34(6):1115-26. Epub 2011 Sep 17 doi: 10.1007/s10545-011-9392-7. [Epub ahead of print] PMID: 21927854

Clinical prediction guides

Sakthivel S, Zatkova A, Nemethova M, Surovy M, Kadasi L, Saravanan MP
Ann Hum Genet 2014 May;78(3):155-64. Epub 2014 Feb 12 doi: 10.1111/ahg.12055. [Epub ahead of print] PMID: 24575791
Curtis SL, Roberts NB, Ranganath LR
Clin Biochem 2014 May;47(7-8):640-7. Epub 2013 Dec 27 doi: 10.1016/j.clinbiochem.2013.12.016. [Epub ahead of print] PMID: 24373924
Yang YJ, Guo JH, Chen WJ, Zhao R, Tang JS, Meng XH, Zhao L, Tu M, He XY, Wu LQ, Zhu YM
Gene 2013 Apr 15;518(2):467-9. Epub 2013 Jan 24 doi: 10.1016/j.gene.2013.01.020. [Epub ahead of print] PMID: 23353776
Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, Gallagher JA
Arthritis Rheum 2011 Dec;63(12):3887-96. doi: 10.1002/art.30606. PMID: 22127706
Vinjamuri S, Ramesh CN, Jarvis J, Gallagher JA, Ranganath LL
Nucl Med Commun 2011 Oct;32(10):880-6. doi: 10.1097/MNM.0b013e32834955df. PMID: 21876398

Recent systematic reviews

Lindner M, Bertelmann T
BMC Ophthalmol 2014 Jan 30;14:12. doi: 10.1186/1471-2415-14-12. [Epub ahead of print] PMID: 24479547Free PMC Article
Ranganath LR, Jarvis JC, Gallagher JA
J Clin Pathol 2013 May;66(5):367-73. Epub 2013 Mar 13 doi: 10.1136/jclinpath-2012-200877. [Epub ahead of print] PMID: 23486607
Drakoulakis E, Varvitsiotis D, Psarea G, Feroussis J
Am J Orthop (Belle Mead NJ) 2012 Feb;41(2):80-3. PMID: 22482092

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