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Synonyms:AKU, alcaptonuria; homogentisic acid oxidase deficiency; ochronosis
This is an autosomal recessive condition of homogentisic acid oxidase deficiency, resulting from a set of inherited alleles on chromosome 3 (3q21-q23). A whole spectrum of mutations has been identified.[1, 2] It was first described by Garrod in 1902 and was one of the first clinical descriptions to be identified as autosomal recessive. It has also been diagnosed in the mummy of Harwa dating from 1500 BC.
There is an underlying defect of tyrosine metabolism causing accumulation of homogentisic acid. This is rapidly cleared by the kidney but, if the urine is left standing, it is oxidised to form a pigmented polymer that colours the urine black. The kidneys keep blood levels of homogentisic acid very low but over time homogentisic acid is deposited in cartilage throughout the body and it is converted to the polymer. As the polymer accumulates within cartilage, over the course of many years, the normally transparent tissues become slate blue but this does not occur before adulthood.
Expression of the disease is multifactorial. A slightly raised occurrence of HLA-DR7 has been found. The disease loosens the cross-linking between collagen fibres and much of the pathology results from this.
Deposits of pigmented polymers of homogentisic acid occur in many tissues, including cartilage, tendons, nail beds, eyelids, cheeks, axillae, genital regions, eardrums, larynx and buccal mucosa. The name alkaptonuria originates from the dark colour of the urine due to the high level of 2,5-dehydroxyphenylacetic acid from the oxidation and polymerisation of the homogentisic acid.
Autopsy findings show that early changes include chondrocyte necrosis, pigment deposition in the cardiovascular system and fibrolipid components of atheromatous plaques. Pigmentation of the aortic and mitral valve cusps and valve rings is a result of intracellular and extracellular pigment deposition and is associated with calcification and clinically significant aortic stenosis.
It occurs in 1:100,000 to 1:250,000 live births in most European countries. There is an exceptionally high incidence in Slovakia at 1:19,000 but only about 10 of the chromosomal variations are present. This suggests inbreeding in a restricted gene pool. There is no difference in incidence between the sexes except that males tend to present sooner with more severe disease.
Symptoms of arthritis in the spine, hips and knees, starting around the age of 30 are common, if not universal.
It may be identified in infancy because nappies stain black but very often this is overlooked or ignored. The diagnosis should, however, always be borne in mind in children with darkening urine, as it may be the only sign of the condition and early treatment may prevent the onset of many complications. In the fourth decade of life, signs of pigment deposition called ochronosis begin. The slate blue, grey, or black discoloration of sclerae and ear cartilage is characteristic of widespread staining of the body tissues but, particularly, cartilage. Hips, knees and intervertebral discs are most affected and the disease may resemble rheumatoid arthritis (RA); however, calcification in these sites gives a radiological picture that is more consistent with osteoarthritis (OA).
Calcification may be palpable, especially in the pinna. Joint mobility declines and ankylosis may occur, especially in the spine with fusion of one or more discs. Disc herniation may occur. Joint effusions, especially in the knee are common and range of movement is restricted. Pigmentation of joints and tendons may be noticed at operation. There may be disease of the mitral or aortic valves and calcification of coronary arteries.
- Many conditions can cause dark urine, usually due to blood; however, urine that looks normal on passing then turns dark on standing is more unusual. The best known alternative diagnosis is acute intermittent porphyria.
- Joint disease may resemble RA or OA.
- Pain and stiffness of the back suggest ankylosing spondylitis.
- Rheumatic heart disease and mitral valve insufficiency may need to be excluded.
- Chromatographic examination of urine. This is the standard diagnostic test. Homogentisic acid can be identified using gas chromatography–mass spectroscopy. Plasma can also be used. There are reducing substances but not glucose present.
- X-ray of the lumbar spine. This may show disc degeneration with calcification.
- Chest X-ray. This is advisable if the condition is suspected, to exclude aortic or mitral valve involvement.
- CT scanning. This should be performed in patients over the age of 55 to rule out coronary artery calcification.
- Polymerase chain reaction (PCR) can identify gene mutations in DNA extracted from blood. .
If the disease is diagnosed in infancy, attempts are made to reduce progression. There have been no controlled trials but it is reasonable to restrict protein in the diet to reduce tyrosine and phenylalanine. The value of persisting with this regime into adulthood is dubious. In older children and adults vitamin C, up to 1 g daily, is said to retard the conversion of homogentisic acid to the polymer that is deposited in tissues. Nitisinone is an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid. Use has been reported to reduce excretion of the product but long-term safety is unproven.[13, 14]
Disc degeneration leads to a stiff spinal column with loss of normal lordosis. Disc herniation may need surgical excision. Degeneration in the shoulders, knees and hips leads to pain, effusions and loose bodies. Joint replacement may be required. The symphysis pubis tends to be affected but not the sacroiliac joints. Kidney stones may form. The aorta is calcified which tends to weaken it. Cardiovascular problems occur due to interference with collagen. This is the usual cause of death.
Life expectancy is normal but there is considerable morbidity, with significant pain beginning as early as the age of 30. Slow degeneration of the spinal discs and the large joints are the main problems, with subsequent loss of agility and mobility.
It is not possible to identify heterozygous carriers yet and prenatal screening is not available. Testing for carriers with a tyrosine load may give results but, as some have 50% of normal enzyme activity, it is unsatisfactory. It is common to find a negative family history of the condition.
Further reading and references
Rodriguez JM, Timm DE, Titus GP, et al; Structural and functional analysis of mutations in alkaptonuria. Hum Mol Genet. 2000 Sep 229(15):2341-50.
Vilboux T, Kayser M, Introne W, et al; Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum Mutat. 2009 Sep 4.
KNOX WE; Sir Archibald Garrod's inborn errors of metabolism. II. Alkaptonuria. Am J Hum Genet. 1958 Jun10(2):95-124.
Stenn FF, Milgram JW, Lee SL, et al; Biochemical identification of homogentisic acid pigment in an ochronotic egyptian mummy. Science. 1977 Aug 5197(4303):566-8.
Roth KS; Alkaptonuria. eMedicine, 2009.
Aliberti G, Proietta M, Pulignano I, et al; HLA antigens in alkaptonuric patients. Panminerva Med. 2001 Sep43(3):145-8.
Murray JC, Lindberg KA, Pinnell SR; In vitro inhibition of chick embryo lysyl hydroxylase by homogentisic acid. A proposed connective tissue defect in alkaptonuria. J Clin Invest. 1977 Jun59(6):1071-9.
Helliwell TR, Gallagher JA, Ranganath L; Alkaptonuria--a review of surgical and autopsy pathology. Histopathology. 2008 Nov53(5):503-12. Epub 2008 Mar 8.
Zatkova A, de Bernabe DB, Polakova H, et al; High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots. Am J Hum Genet. 2000 Nov67(5):1333-9. Epub 2000 Oct 2.
Peker E, Yonden Z, Sogut S; From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol. 2008 Nov-Dec74(6):700.
de Haas V, Carbasius Weber EC, de Klerk JB, et al; The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis. 1998 Dec21(8):791-8.
Morava E, Kosztolanyi G, Engelke UF, et al; Reversal of clinical symptoms and radiographic abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem. 2003 Jan40(Pt 1):108-11.
Suwannarat P, O'Brien K, Perry MB, et al; Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun54(6):719-28.
Phornphutkul C, Introne WJ, Perry MB, et al; Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26347(26):2111-21.
Hegedus ZL; The probable involvement of soluble and deposited melanins, their intermediates and the reactive oxygen side-products in human diseases and aging. Toxicology. 2000 Apr 14145(2-3):85-101.