Information on the following diseases can be found in the Related Disorders section of this report:

• None

Individuals with alkaptonuria develop dark discolorations (ochronosis) of the nose, outer ears, and outer membrane covering the eyes (sclera). These discolorations usually begin to appear at the age of 20 to 30. The urine may be dark in color, or may darken upon exposure to air. In some cases, perspiration may become darkened and individuals may have stained clothing in the armpit area.

Later, affected individuals generally develop stiffness, pain, and restricted motion in the hips, knees and shoulders. As the disease progresses, freedom of movement is more severely restricted because of lack of mobility of the spine. Back pain is often present. The earlobe thickens as the cartilage becomes harder and the middle and inner ear structures become darkened. Some affected individuals may experience degeneration of the valves of the heart, especially the aortic valve. Individuals with alkaptonuria, who also have kidney disease, tend to get symptoms earlier and their symptoms tend to be more severe. This is due to an impaired excretion of homogentisic acid.

Alkaptonuria is inherited as an autosomal recessive trait that has been mapped to the long arm of the third chromosome (3q), and 30 different mutations have been defined. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.

Alkaptonuria affects males and females in equal numbers, although symptoms tend to be more severe in males and most severe in those individuals with impaired kidney function. Although all ethnic groups are affected, alkaptonuria occurs in an unusually high number of people in Czechoslovakia and the Dominican Republic.

The prevalence of alkaptonuria is estimated at 1 in 250,000 people in the United States.

Symptoms of the following disorders can be similar to those of alkaptonuria. Comparisons may be useful for a differential diagnosis.

Ankylosing spondylitis is a progressive inflammatory disease that typically becomes evident during early to mid adulthood. The disease is characterized by inflammation (arthritis), stiffness, and pain of various joints of the spine and potential loss of spinal mobility. It may involve joints between the spine and the pelvis, known as the sacroiliac joints; joints within the spinal column of the lower back (lumbar spine), the upper back (thoracic spine), and the neck (cervical spine) to varying degrees; as well as joints of the limbs, particularly the legs. Progression may spontaneously subside at any stage of involvement; however, in some individuals, all regions of the spinal column may eventually become involved. Many affected individuals develop lower back and hip pain that may be more severe at night and after rest. In addition, there is often associated stiffness of affected regions in the morning. In some cases, those with involvement of joints joining the ribs with the spine (costovertebral joints) may have a limited ability to expand the chest to take a deep breath. In addition, in some affected individuals, other associated findings may include recurrent inflammation of the colored region of the eyes (acute iritis), leakage of the aortic valve resulting in a backflow of blood into the lower left chamber (ventricle) of the heart (aortic insufficiency or regurgitation), and/or other abnormalities. The exact cause of ankylosing spondylitis is not known. However, researchers suggest that genetic, immunologic, and/or environmental factors may play some role. (For more information on this disorder, choose "ankylosing spondylitis" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis is made by measurement of homogentisic acid in the urine and characteristic radiographic changes to the spine. Homegentisic acid turns black upon exposure to oxygen or alkali treatment.

Treatment
Individuals with alkaptonuria are counseled to avoid occupations in which the large joints and spine are subjected to stress. There have been attempts to prevent symptoms by consuming a diet low in tyrosine or high in ascorbic acid. These regimens have had no effect on the disorder. Other treatment is symptomatic and supportive. Anti-inflammatory medication may be used to treat pain. Joint and aortic valve replacement may provide symptomatic relief.

Genetic counseling may be of benefit for affected individuals and their families.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Researchers at the National Institutes of Health conducted a natural history study aimed at enhancing the general understanding of alkaptonuria. Findings published by this multi-institutional team include that significant events or complications occurred at the following mean ages: joint replacement, 55 years; kidney stones, 64 years; cardiac valve involvement, 54 years; and coronary artery calcification, 59 years. Among those in the study, the disease tended to increase in severity after age 30 and this process was more rapid among men than among women. These and other findings, reported in the New England Journal of Medicine, have added to the general understanding of this disease and its impact on those affected.

In 2001, nitisinone (Orfadin) received orphan drug status from the Food and Drug Administration (FDA). This drug, which has been approved for treating the metabolic disorder tyrosinemia type I, is now being studied as a possible treatment for alkaptonuria.

In an earlier study, nitisinone was shown to have promise for reducing accumulations of homogentisic acid in alkaptonuria patients. Additional study is needed to determine the safety and long-term effectiveness of nitisinone in treating individuals affected by alkaptonuria.

An observational clinical trial is in progress (2006) sponsored by the National Human Genome Research Institute (NHGRI). Patients between 30 and 80 years of age who have alkaptonuria may be eligible to participate. For information, go to www.clinicaltrials.gov or contact the NIH Patient Recruitment Office listed above.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 203500; Last Update: 4/14/2000.

Introne WJ, Gahl WA. Alkaptonuria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:431.

Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1108.

Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:1371-82.

REVIEW ARTICLES
Lubics A, et al. Extensive bluish gray skin pigmentation and severe arthropathy. Endogenous ochronosis (alkaptonuria). Arch Dermatol. 2000;136:551-52.

JOURNAL ARTICLES
Suwannarat P, O’Brien K, Perry MB, et al. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005;54:719-28.

Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. New Engl J Med. 2002;347:2711-121.

Hamdi N, et al. Ochronotic arthropathy: case report and review of the literature. Int Orthop. 1999;23:122-25.

Cheskes J, et al. Ocular manifestations of alkaptonuric ochronosis. Arch Ophthalmol. 2000;118:724-25.

Aynaci O, et al. Bilateral hip arthroplasty for ochronotic arthropathy. Clin Rheumatol. 2000;19:150-02.

Kramer KE, et al. Exogenous ochronosis. J AM Acad Dermatol. 2000;42:869-71.

Casselamn F, et al. Aortic stenosis in endogenous ochronosis. J Heart Valve Dis. 1999;8:445-46.

Felbor U, et al. Ocular ochronosis in alkaptonuria patients carrying mutations in the homogentisate 1,2-dioxygenase gene. Br J Ophthalmol. 1999;83:680-83.