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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
SNOMED CT: Alkaptonuria (360378009); 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); HGD-gene related homogentisate 1,2-dioxygenase deficiency (360378009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HGD (3q13.33)
 
Monarch Initiative: MONDO:0008753
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 dark urine or urine that turns dark on standing, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Ochronosis generally occurs after age 30 years; arthritis often begins in the third decade. Other manifestations can include pigment in the sclera, ear cartilage, and skin of the hands; aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation; renal stones; prostate stones; and hypothyroidism. [from GeneReviews]
Authors:
Wendy J Introne  |  Monique Perry  |  Marcus Chen   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 MedlinePlus Genetics
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://medlineplus.gov/genetics/condition/alkaptonuria

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Low back pain
MedGen UID:
7389
Concept ID:
C0024031
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the lower back.
Diminished physical functioning
MedGen UID:
1785731
Concept ID:
C5539751
Finding
A reduction in the ability to perform activities of daily living as compared to previous abilities because of functional deficits due to illness. The 36-item Short Form (SF-36) health survey questionnaire is one of many methods used to measure patients' perceptions of diminished physical functioning.
Nephrolithiasis
MedGen UID:
98227
Concept ID:
C0392525
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
Dark urine
MedGen UID:
604849
Concept ID:
C0426396
Finding
An abnormal dark color of the urine.
Decreased glomerular filtration rate
MedGen UID:
163428
Concept ID:
C0853068
Finding
An abnormal reduction in the volume of fluid filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time.
Elevated urinary homogentisic acid
MedGen UID:
1789056
Concept ID:
C5539768
Finding
An increased amount of homogentisic acid in the urine.
Limitation of knee mobility
MedGen UID:
866903
Concept ID:
C4021259
Finding
An abnormal limitation of knee joint mobility.
Aortic aneurysm
MedGen UID:
362
Concept ID:
C0003486
Disease or Syndrome
Aortic dilatation refers to a dimension that is greater than the 95th percentile for the normal person age, sex and body size. In contrast, an aneurysm is defined as a localized dilation of the aorta that is more than 150 percent of predicted (ratio of observed to expected diameter 1.5 or more). Aneurysm should be distinguished from ectasia, which represents a diffuse dilation of the aorta less than 50 percent of normal aorta diameter.
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
An accumulation of calcium and phosphate in arteries with mineral deposits in the intimal or medial layer of the vessel wall in a coronary artery.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Dark cerumen
MedGen UID:
1053180
Concept ID:
CN376539
Finding
Abnormally dark color of cerumen (earwax), which is a waxy substance secreted in the ear canal that normally has a brown, orange, red, yellowish or gray.
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Inflammation of a joint.
Arthropathy
MedGen UID:
7190
Concept ID:
C0022408
Disease or Syndrome
Any disorder of the joints.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Intervertebral disk degeneration
MedGen UID:
102357
Concept ID:
C0158266
Disease or Syndrome
The presence of degenerative changes of intervertebral disk.
Thickened Achilles tendon
MedGen UID:
214714
Concept ID:
C0919997
Finding
An abnormal thickening of the Achilles tendon.
Limited shoulder movement
MedGen UID:
341979
Concept ID:
C1851313
Finding
A limitation of the range of movement of the shoulder joint.
Limited hip movement
MedGen UID:
343601
Concept ID:
C1851542
Finding
A decreased ability to move the femur at the hip joint associated with a decreased range of motion of the hip.
Vertebral fusion
MedGen UID:
480139
Concept ID:
C3278509
Anatomical Abnormality
A developmental defect leading to the union of two adjacent vertebrae.
Brown pigmentation of the conjunctiva
MedGen UID:
1052890
Concept ID:
CN376961
Finding
Deposition of brown pigmentation in the conjunctiva.
Ochronosis disorder
MedGen UID:
45177
Concept ID:
C0028817
Disease or Syndrome
Brown or blue-gray discoloration of the skin that can present on the axillary and inguinal areas, face, palms or soles. In addition, blue-black discoloration can be apparent on skin overlying cartilage in which the pigment is deposited, such as the ears. This is a characteristic manifestation of alkaptonuria, which is an autosomal recessively inherited deficiency of homogentisic acid oxidase that results in accumulation of homogentisic acid in collagenous structures. The sclerae are also typically involved.
Pigmentation of the sclera
MedGen UID:
347969
Concept ID:
C1859882
Finding

Term Hierarchy

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

Professional guidelines

PubMed

Spiga O, Cicaloni V, Dimitri GM, Pettini F, Braconi D, Bernini A, Santucci A
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Recent clinical studies

Etiology

Ather N, Roberts WC
Cardiovasc Pathol 2020 Sep-Oct;48:107219. Epub 2020 Mar 7 doi: 10.1016/j.carpath.2020.107219. PMID: 32473412
Thimmapuram R, Bandettini WP, Shanbhag SM, Yu JH, O'Brien KJ, Gahl WA, Introne WJ, Chen MY
Mol Genet Metab 2020 Aug;130(4):289-296. Epub 2020 May 18 doi: 10.1016/j.ymgme.2020.05.006. PMID: 32466960
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Diagnosis

Bernardini G, Braconi D, Zatkova A, Sireau N, Kujawa MJ, Introne WJ, Spiga O, Geminiani M, Gallagher JA, Ranganath LR, Santucci A
Nat Rev Dis Primers 2024 Mar 7;10(1):16. doi: 10.1038/s41572-024-00498-x. PMID: 38453957
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Therapy

Häberle J
Lancet Diabetes Endocrinol 2020 Sep;8(9):732-733. Epub 2020 Aug 18 doi: 10.1016/S2213-8587(20)30222-9. PMID: 32822593
Ather N, Roberts WC
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Dance A
Nature 2016 Sep 8;537(7619):S52-3. doi: 10.1038/537S52a. PMID: 27602739
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Dermatol Online J 2010 Nov 15;16(11):6. PMID: 21163157

Prognosis

Shepherd RF, Kerns JG, Ranganath LR, Gallagher JA, Taylor AM
Calcif Tissue Int 2021 Sep;109(3):291-302. Epub 2021 Aug 21 doi: 10.1007/s00223-021-00896-3. PMID: 34417863Free PMC Article
Thimmapuram R, Bandettini WP, Shanbhag SM, Yu JH, O'Brien KJ, Gahl WA, Introne WJ, Chen MY
Mol Genet Metab 2020 Aug;130(4):289-296. Epub 2020 May 18 doi: 10.1016/j.ymgme.2020.05.006. PMID: 32466960
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Clinical prediction guides

Davison AS, Norman BP
Adv Clin Chem 2023;114:47-81. Epub 2023 Mar 28 doi: 10.1016/bs.acc.2023.02.005. PMID: 37268334
Shepherd RF, Kerns JG, Ranganath LR, Gallagher JA, Taylor AM
Calcif Tissue Int 2021 Sep;109(3):291-302. Epub 2021 Aug 21 doi: 10.1007/s00223-021-00896-3. PMID: 34417863Free PMC Article
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Thimmapuram R, Bandettini WP, Shanbhag SM, Yu JH, O'Brien KJ, Gahl WA, Introne WJ, Chen MY
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Recent systematic reviews

Ishack S, Lipner SR
Int J Dermatol 2022 Jun;61(6):675-684. Epub 2021 Sep 6 doi: 10.1111/ijd.15878. PMID: 34486734
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