Alkaptonuria is caused by the deficiency of a single enzyme called homogentisate 1,2 dioxygenase. This is responsible for the degradation of homogentisic acid (HGA) to maleylacetoacetic acid via the degradation of tyrosine. It occurs at a frequency of about 1 in 250,000 to 1 in 1,000,000. It is autosomal recessive in inheritance, and is a classical example of an inborn error of metabolism.

Clinical Features

The three major features of alkaptonuria include:

• Homogentisic acid in the urine, which is oxidized by air to benzoquinoneacetate polymers and causes darkening of the urine on standing. This may be noticed in infants and leads to the diagnosis of this disorder in childhood in a fifth of cases.
• Ochronosis or bluish-black pigmentation of connective tissue occurs, usually after the age of 30, and is apparent as discoloration of the ears and eyes as well as of various body fluids.
• Arthritis involving the spine as well as large joints occurs, typically in the twenties, because of the deposition of the polymer within the cartilage and subchondral bone. This typically causes severe and progressive discoloration of the joint, which may lead to disability.

Other features may also arise, including:

• Calcification or regurgitation of the mitral and aortic valve
• Aortic dilatation
• Renal calculi
• Prostate stones

Inheritance

Alkaptonuria is an autosomal recessive disorder and thus each child in a family has a one-in-four chance of getting two copies of the defective gene and being clinically affected. The carrier rate is 50% (receiving only one defective copy), and these individuals have no symptoms. 25% of offspring may be free of disease both clinically and on genetic testing.

Diagnosis and Management

Alkaptonuria is diagnosed by detecting HGA in urine using gas chromatography-mass spectrometry, and is confirmed by genetic testing to identify a recessive mutation on the HGD gene.

Management is symptomatic and may include:

• Palliation of joint pain
• Physical therapy to strengthen the muscles and maintain flexibility
• Occupational therapy to help the patient remain independent and carry out activities of daily living
• Joint replacements when needed
• Treatment of renal and prostate calculi
• Aortic valve replacement if required

Regular monitoring is necessary to identify the presence of aortic dilatation, valve disease, and coronary calcification. This may require various imaging techniques. Joint stress, such as high-impact sports or heavy manual work should be avoided. Family screening and early intervention may help reduce or prevent complications in other relatives.

Newer Treatments

Newer therapies are being developed, including liver transplants, which can prevent HGA formation. Another avenue is the use of a herbicide (NTBC), which inhibits an enzyme involved in the synthesis of HGA. This drug has been used to treat hereditary tyrosinemia type 1, but may cause corneal irritation in the presence of elevated tyrosine levels in blood. This may be prevented by a low-tyrosine diet. Other potentially serious hematologic and neurologic complications are also known to occur with the use of this drug, preventing its widespread adoption.

The feasibility of replacing the missing enzyme is being discussed, but the difficulty of successfully targeting the specific site of replacement in the liver is huge, and failure will lead to catastrophic consequences by promoting the buildup of the toxic molecule succinlylacetate, known to cause mutations and cancers.

Thus, the riddle of treating alkaptonuria remains by and large an unsolved one, and most therapies are stopgap responses to solve crises as they arise.