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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

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 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 GeneReviews]
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.  https://ghr.nlm.nih.gov/condition/alkaptonuria

Clinical features

Coronary artery calcification
MedGen UID:
345985
Concept ID:
C1611184
Pathologic Function
Calcification, that is, pathological deposition of calcium salts, affecting the coronary arteries.
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Back pain
MedGen UID:
2530
Concept ID:
C0004604
Sign or Symptom
If you've ever groaned, Oh, my aching back!, you are not alone. Back pain is one of the most common medical problems, affecting 8 out of 10 people at some point during their lives. Back pain can range from a dull, constant ache to a sudden, sharp pain. Acute back pain comes on suddenly and usually lasts from a few days to a few weeks. Back pain is called chronic if it lasts for more than three months. Most back pain goes away on its own, though it may take awhile. Taking over-the-counter pain relievers and resting can help. However, staying in bed for more than 1 or 2 days can make it worse. . If your back pain is severe or doesn't improve after three days, you should call your health care provider. You should also get medical attention if you have back pain following an injury. Treatment for back pain depends on what kind of pain you have, and what is causing it. It may include hot or cold packs, exercise, medicines, injections, complementary treatments, and sometimes surgery. NIH: National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Thickened Achilles tendon
MedGen UID:
214714
Concept ID:
C0919997
Disease or Syndrome
An abnormal thickening of the Achilles tendon.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Ear malformation
MedGen UID:
75618
Concept ID:
C0266589
Congenital Abnormality
An abnormality of the ear.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Thickened Achilles tendon
MedGen UID:
214714
Concept ID:
C0919997
Disease or Syndrome
An abnormal thickening of the Achilles tendon.

Term Hierarchy

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

Recent clinical studies

Etiology

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
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. PMID: 22100375Free PMC Article

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

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
Arnoux JB, Le Quan Sang KH, Brassier A, Grisel C, Servais A, Wippf J, Dubois S, Sireau N, Job-Deslandre C, Ranganath L, de Lonlay P
J Inherit Metab Dis 2015 Sep;38(5):791-6. Epub 2015 Apr 10 doi: 10.1007/s10545-015-9844-6. PMID: 25860819
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

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
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. PMID: 24373924

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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