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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
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
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
Orphanet: ORPHA56

Definition

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 on 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 GTR]

Additional descriptions

From GeneReviews
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 on 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.  https://www.ncbi.nlm.nih.gov/books/NBK1454
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.  https://ghr.nlm.nih.gov/condition/alkaptonuria

Clinical features

Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Back pain
MedGen UID:
2530
Concept ID:
C0004604
Sign or Symptom
Acute or chronic pain located in the posterior regions of the THORAX; LUMBOSACRAL REGION; or the adjacent regions.
Pigmentation of the sclera
MedGen UID:
347969
Concept ID:
C1859882
Finding
Abnormality of the urinary system
MedGen UID:
867444
Concept ID:
C4021821
Disease or Syndrome
An abnormality of the urinary system.
Thickened Achilles tendon
MedGen UID:
214714
Concept ID:
C0919997
Disease or Syndrome
An abnormal thickening of the Achilles tendon.
Aortic dilatation
MedGen UID:
78118
Concept ID:
C0265004
Pathologic Function
Aortic valve calcification
MedGen UID:
140899
Concept ID:
C0428791
Disease or Syndrome
Deposition of calcium salts in the aortic valve.
Mitral valve calcification
MedGen UID:
181575
Concept ID:
C0919718
Disease or Syndrome
Abnormal calcification of the mitral valve.
Coronary artery calcification
MedGen UID:
345985
Concept ID:
C1611184
Pathologic Function
Calcification, that is, pathological deposition of calcium salts, affecting the coronary arteries.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Ear malformation
MedGen UID:
75618
Concept ID:
C0266589
Congenital Abnormality
An abnormality of the ear.
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Back pain
MedGen UID:
2530
Concept ID:
C0004604
Sign or Symptom
Acute or chronic pain located in the posterior regions of the THORAX; LUMBOSACRAL REGION; or the adjacent regions.
Abnormality of the urinary system
MedGen UID:
867444
Concept ID:
C4021821
Disease or Syndrome
An abnormality of the urinary system.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Acute or chronic inflammation of JOINTS.
Back pain
MedGen UID:
2530
Concept ID:
C0004604
Sign or Symptom
Acute or chronic pain located in the posterior regions of the THORAX; LUMBOSACRAL REGION; or the adjacent regions.
Arthropathy
MedGen UID:
7190
Concept ID:
C0022408
Disease or Syndrome
An abnormal structure or form of the joints, i.e., one or more of the articulations where two bones join.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Abnormally increased curvature of the thoracic portion of the spine.
Intervertebral disc degeneration
MedGen UID:
102357
Concept ID:
C0158266
Disease or Syndrome
Any disease of a degenerative nature that affects the intervertebral disc.
Aortic valve calcification
MedGen UID:
140899
Concept ID:
C0428791
Disease or Syndrome
Deposition of calcium salts in the aortic valve.
Mitral valve calcification
MedGen UID:
181575
Concept ID:
C0919718
Disease or Syndrome
Abnormal calcification of the mitral valve.
Thickened Achilles tendon
MedGen UID:
214714
Concept ID:
C0919997
Disease or Syndrome
An abnormal thickening of the Achilles tendon.
Coronary artery calcification
MedGen UID:
345985
Concept ID:
C1611184
Pathologic Function
Calcification, that is, pathological deposition of calcium salts, affecting the coronary arteries.
Vertebral fusion
MedGen UID:
480139
Concept ID:
C3278509
Anatomical Abnormality
A developmental defect leading to the union of two adjacent vertebrae.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Alkaptonuria in Orphanet.

Recent clinical studies

Etiology

Milan AM, Hughes AT, Davison AS, Devine J, Usher J, Curtis S, Khedr M, Gallagher JA, Ranganath LR
Ann Clin Biochem 2017 May;54(3):323-330. Epub 2017 Mar 16 doi: 10.1177/0004563217691065. PMID: 28081634
Nemethova M, Radvanszky J, Kadasi L, Ascher DB, Pires DE, Blundell TL, Porfirio B, Mannoni A, Santucci A, Milucci L, Sestini S, Biolcati G, Sorge F, Aurizi C, Aquaron R, Alsbou M, Lourenço CM, Ramadevi K, Ranganath LR, Gallagher JA, van Kan C, Hall AK, Olsson B, Sireau N, Ayoob H, Timmis OG, Sang KH, Genovese F, Imrich R, Rovensky J, Srinivasaraghavan R, Bharadwaj SK, Spiegel R, Zatkova A
Eur J Hum Genet 2016 Jan;24(1):66-72. Epub 2015 Mar 25 doi: 10.1038/ejhg.2015.60. PMID: 25804398Free PMC Article
Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, Briggs MC, Bygott H, Psarelli EE, Cox TF, Gallagher JA, Jarvis JC, van Kan C, Hall AK, Laan D, Olsson B, Szamosi J, Rudebeck M, Kullenberg T, Cronlund A, Svensson L, Junestrand C, Ayoob H, Timmis OG, Sireau N, Le Quan Sang KH, Genovese F, Braconi D, Santucci A, Nemethova M, Zatkova A, McCaffrey J, Christensen P, Ross G, Imrich R, Rovensky J
Ann Rheum Dis 2016 Feb;75(2):362-7. Epub 2014 Dec 4 doi: 10.1136/annrheumdis-2014-206033. PMID: 25475116
Steven RA, Kinshuck AJ, McCormick MS, Ranganath LR
J Laryngol Otol 2015 Oct;129(10):1004-8. doi: 10.1017/S0022215115002315. PMID: 26446762
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. PMID: 23357094

Diagnosis

Roca B, Roca M, Monferrer R
Conn Med 2016 Mar;80(3):139-41. PMID: 27169295
Gallagher JA, Dillon JP, Sireau N, Timmis O, Ranganath LR
Semin Cell Dev Biol 2016 Apr;52:53-7. Epub 2016 Feb 16 doi: 10.1016/j.semcdb.2016.02.020. PMID: 26891864
Steven RA, Kinshuck AJ, McCormick MS, Ranganath LR
J Laryngol Otol 2015 Oct;129(10):1004-8. doi: 10.1017/S0022215115002315. PMID: 26446762
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
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. PMID: 23357094

Therapy

Milan AM, Hughes AT, Davison AS, Devine J, Usher J, Curtis S, Khedr M, Gallagher JA, Ranganath LR
Ann Clin Biochem 2017 May;54(3):323-330. Epub 2017 Mar 16 doi: 10.1177/0004563217691065. PMID: 28081634
Mistry JB, Jackson DJ, Bukhari M, Taylor AM
Clin Rheumatol 2016 Jul;35(7):1849-56. Epub 2015 Oct 16 doi: 10.1007/s10067-015-3091-y. PMID: 26474772
Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, Briggs MC, Bygott H, Psarelli EE, Cox TF, Gallagher JA, Jarvis JC, van Kan C, Hall AK, Laan D, Olsson B, Szamosi J, Rudebeck M, Kullenberg T, Cronlund A, Svensson L, Junestrand C, Ayoob H, Timmis OG, Sireau N, Le Quan Sang KH, Genovese F, Braconi D, Santucci A, Nemethova M, Zatkova A, McCaffrey J, Christensen P, Ross G, Imrich R, Rovensky J
Ann Rheum Dis 2016 Feb;75(2):362-7. Epub 2014 Dec 4 doi: 10.1136/annrheumdis-2014-206033. PMID: 25475116
Ranganath LR, Timmis OG, Gallagher JA
J Inherit Metab Dis 2015 Sep;38(5):787-9. doi: 10.1007/s10545-015-9888-7. PMID: 26280757
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. PMID: 24575791

Prognosis

Nemethova M, Radvanszky J, Kadasi L, Ascher DB, Pires DE, Blundell TL, Porfirio B, Mannoni A, Santucci A, Milucci L, Sestini S, Biolcati G, Sorge F, Aurizi C, Aquaron R, Alsbou M, Lourenço CM, Ramadevi K, Ranganath LR, Gallagher JA, van Kan C, Hall AK, Olsson B, Sireau N, Ayoob H, Timmis OG, Sang KH, Genovese F, Imrich R, Rovensky J, Srinivasaraghavan R, Bharadwaj SK, Spiegel R, Zatkova A
Eur J Hum Genet 2016 Jan;24(1):66-72. Epub 2015 Mar 25 doi: 10.1038/ejhg.2015.60. PMID: 25804398Free PMC Article
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
Aquaron RR
J Inherit Metab Dis 2011 Dec;34(6):1115-26. Epub 2011 Sep 17 doi: 10.1007/s10545-011-9392-7. PMID: 21927854
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. PMID: 21748407
Zatkova A
J Inherit Metab Dis 2011 Dec;34(6):1127-36. Epub 2011 Jul 1 doi: 10.1007/s10545-011-9363-z. PMID: 21720873

Clinical prediction guides

Thorpe SD, Gambassi S, Thompson CL, Chandrakumar C, Santucci A, Knight MM
J Cell Physiol 2017 Sep;232(9):2407-2417. Epub 2017 Mar 31 doi: 10.1002/jcp.25839. PMID: 28158906Free PMC Article
Nemethova M, Radvanszky J, Kadasi L, Ascher DB, Pires DE, Blundell TL, Porfirio B, Mannoni A, Santucci A, Milucci L, Sestini S, Biolcati G, Sorge F, Aurizi C, Aquaron R, Alsbou M, Lourenço CM, Ramadevi K, Ranganath LR, Gallagher JA, van Kan C, Hall AK, Olsson B, Sireau N, Ayoob H, Timmis OG, Sang KH, Genovese F, Imrich R, Rovensky J, Srinivasaraghavan R, Bharadwaj SK, Spiegel R, Zatkova A
Eur J Hum Genet 2016 Jan;24(1):66-72. Epub 2015 Mar 25 doi: 10.1038/ejhg.2015.60. PMID: 25804398Free PMC Article
Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, Briggs MC, Bygott H, Psarelli EE, Cox TF, Gallagher JA, Jarvis JC, van Kan C, Hall AK, Laan D, Olsson B, Szamosi J, Rudebeck M, Kullenberg T, Cronlund A, Svensson L, Junestrand C, Ayoob H, Timmis OG, Sireau N, Le Quan Sang KH, Genovese F, Braconi D, Santucci A, Nemethova M, Zatkova A, McCaffrey J, Christensen P, Ross G, Imrich R, Rovensky J
Ann Rheum Dis 2016 Feb;75(2):362-7. Epub 2014 Dec 4 doi: 10.1136/annrheumdis-2014-206033. PMID: 25475116
Hughes AT, Milan AM, Davison AS, Christensen P, Ross G, Gallagher JA, Dutton JJ, Ranganath LR
Ann Clin Biochem 2015 Sep;52(Pt 5):597-605. Epub 2015 Jan 27 doi: 10.1177/0004563215571969. PMID: 25628464
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. PMID: 24575791

Recent systematic reviews

Lindner M, Bertelmann T
BMC Ophthalmol 2014 Jan 30;14:12. doi: 10.1186/1471-2415-14-12. PMID: 24479547Free PMC Article
Ozmanevra R, Güran O, Karatosun V, Günal I
Eklem Hastalik Cerrahisi 2013;24(3):169-72. PMID: 24191883
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. 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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