Alkaptonuria

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) There are about 70 chromosomal variations. It is classified by OMIM as #203500.¹ It was first described by Garrod in 1902 and was one of the first clinical descriptions to be identified as an autosomal recessive.² It has also been diagnosed in the mummy Harwa dating from 1500BC.³

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 oxidized 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.⁴

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 oxidisation and polymerisation of the homogentisic acid.³

Expression of the disease is multifactorial. A slightly raised occurrence of HLA-DR7 has been found.⁵

The disease loosens the cross linking between collagen fibres and much of the pathology results from this.⁶

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.⁷ 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.

Symptoms⁴

Symptoms of arthritis in the spine, hips and knees, starting around the age of 30 is common if not universal.

Signs

It may be identified in infancy because nappies stain black but very often this is overlooked or ignored. 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 but calcification in these sites gives a radiological picture that is more consistent with osteoarthritis. 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, but urine that looks normal on passing then turn dark on standing is more unusual. The best known alternative diagnosis is acute intermittent porphyria.
• Joint disease may resemble rheumatoid arthritis or osteoarthritis.
• 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. The homogentisic acid produces a false positive for glucose on testing the urine with Clinitest tablets (no longer prescribable on the NHS) but there is no reaction with glucose oxidase strips.⁸ There are reducing substances but not glucose present.
• X-ray of the lumbar spine This may show disc degeneration with calcification.
• Chest Xray This is advisable if the condition is suspected, to exclude exclude aortic or mitral valve involvement.
• CT scanning This should be performed in patients over 55 to rule out coronary artery calcification.

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.⁹ 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.¹⁰ 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.^11,12

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 lead 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.¹³ 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.⁴ It is common to find a negative family history of the condition.