Alkaptonuria
Alkaptonuria is a rare inherited genetic disorder which is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase ; if a person inherits an abnormal copy from both parents, the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.
Apart from treatment of the complications, the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more common in Slovakia and the Dominican Republic.
Signs and symptoms
Patients with black bone disease are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear and other cartilage, and the sclera and corneal limbus of the eye.After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees. The pain can be severe to the point that interferes with activities of daily living and may affect ability to work. Joint-replacement surgery is often necessary at a relatively young age. In the longer term, the involvement of the spinal joints leads to reduced movement of the rib cage and can affect breathing. Bone mineral density may be affected, increasing the risk of bone fractures, and rupture of tendons and muscles may occur.
Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases, valve replacement may be necessary. Irregularities in the heart rhythm and heart failure affect a significant proportion of people with alkaptonuria. Hearing loss affects 40% of people. Also, a propensity to developing kidney stones exists, and eventually also gallstones and stones in the prostate and salivary glands can occur.
Pathophysiology
All people carry in their DNA two copies of the gene HGD, which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase which can normally be found in numerous tissues in the body. In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme. HGD mutations are generally found in certain parts, but a total of over 100 abnormalities has been described throughout the gene. The normal HGD enzyme is a hexamer that are organized in two groups of three and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme. Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of HGD from a single parent is associated with alkaptonuria; other mechanisms or defects in other genes possibly are responsible in those cases.The HGD enzyme is involved in the metabolism of the aromatic amino acids phenylalanine and tyrosine. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as hormones, melanin, and certain proteins, but the vast majority is unused and is metabolized through a group of enzymes that eventually generate acetoacetate and malate. In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid into 4-maleylacetoacetate, and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.
The homogentisic acid is converted to the related substance benzoquinone acetic acid which forms polymers that resemble the skin pigment melanin. These are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis ; ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.
Diagnosis
If the diagnosis of alkaptonuria is suspected, it can be confirmed or excluded by collecting urine for 24 hours and determining the amount of homogentisic acid by means of chromatography. No assay of HGA in blood has been validated. The Genetic Testing Registry is used for maintaining information about the genetic test for alkaptonuria.The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones.
Treatment
No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of ascorbic acid or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment does not have definitively proven effectiveness and protein restriction has not shown to be effective in clinical studies.Several studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA. Nitisinone has been used for some time at much higher doses in the treatment of type I tyrosinemia. Nitisinone treatment has been shown to cause a larger than 95% reduction in plasma and urinary HGA. The main drawback is accumulation of tyrosine, the long-term risks of which are unknown; a particular concern exists about damage to the cornea of the eye. Long-term use requires frequent monitoring for complications.
Prognosis
Alkaptonuria does not appear to affect life expectancy, although the last study on the topic is from 1985. The main impact is on quality of life; many people with alkaptonuria have disabling symptoms such as pain, poor sleep, and breathing symptoms. These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50–55 years.Epidemiology
In most ethnic groups, the prevalence of alkaptonuria is between 1:100,000 and 1:250,000. In Slovakia and the Dominican Republic, the disease is much more common, with prevalence estimated at 1:19,000 people. As for Slovakia, this is not the result of a single mutation, but due to a group of 12 mutations in specific "hot spots" of the HGD gene. The Slovakian clustering probably arose in a small area in the northwest of the country and spread after the 1950s due to migration.History
Alkaptonuria was one of the four diseases described by Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis with the accumulation of alkaptans in 1902, and his views on the subject, including its mode of heritance, were summarized in a 1908 Croonian Lecture at the Royal College of Physicians.The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958. The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.
A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.