NORD gratefully acknowledges Wendy J. Introne, MD, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Although alkaptonuria is a genetic disorder, noticeable symptoms usually do not appear until adulthood. Symptoms are generally slowly progressive. The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air. However, since this change often takes several hours, it often goes unnoticed. During infancy, diapers may be stained black (from urine exposure to air), although this is often missed or ignored.
The first noticeable signs and symptoms of alkaptonuria usually do not develop until approximately 30 years of age and are due to chronic accumulation of homogentisic acid in connective tissue, especially cartilage. Affected individuals develop a condition called ochronosis, in which connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid. In many individuals, cartilage within the ear may become thickened, irregular and discolored blue, grey or black. Eventually, this discoloration may be apparent on the skin overlying the cartilage. In many cases, the whites of the eyes (sclera) also become discolored. However, this pigmentation does not interfere with vision.
In addition to cartilage, homogentisic acid accumulates in other connective tissue including tendons and ligaments and even bone. Over time, affected tissue becomes discolored, brittle and weak. Affected individuals may develop abnormalities affecting the tendons including thickened Achilles tendons and inflammation of the tendons (tendonitis). Affected tendons and ligaments may be particularly susceptible to rupturing. Eventually, discoloration of tendons may become visible on the overlying skin.
Long-standing alkaptonuria leads to chronic joint pain and inflammation (arthritis), especially in the spine and large joints (ochronotic arthropathy). Arthritis can be severe and disabling. Low back pain and stiffness are common symptoms and are sometimes seen before the age of 30. Discs between the vertebrae flatten and calcify. Eventually, vertebrae or other bones may fuse causing stiffening or immobility of affected joints (ankylosis). Spinal involvement may lead to abnormal outward curvature of the spine causing hunching of the back (kyphosis) and loss of height. The hip, knees and shoulders are commonly affected as well. Joint mobility is usually diminished and fluid buildup in affected joints (effusions) may also occur. Joint abnormalities are progressive and may eventually necessitate a joint replacement. Joint disease in alkaptonuria tends to begin earlier and progress more rapidly in males than females.
Less often, additional symptoms may occur in alkaptonuria. Although these symptoms occur less often than the main symptoms of alkaptonuria, they occur with greater frequency than would be expected in the general population. Such symptoms include kidney stones, which develop in 50 percent of affected individuals over 64 years of age. Men with alkaptonuria may also develop prostate stones. Passage of these black stones can be extremely painful.
In some individuals, heart disease may develop due to the accumulation of homogentisic acid within the aortic or mitral valves. This accumulation causes thickening of the valves and narrowing (stenosis) of the openings of the valves. Occasionally, the narrowing is severe enough that the aortic valve needs to be replaced. The aortic valve connects the lower left chamber (main pumping chamber) of the heart with the aorta (the main artery of the body). The mitral valve is located between the left upper and left lower chambers of the heart. Affected individuals may develop calcification of the valves and/or backflow of blood back through the affected valves (regurgitation), which can lead to reduced blood flow throughout the body. Widening (dilation) of the aorta may also occur. In some cases, calcification of the small blood vessels that supply blood and oxygen to the heart (coronary blood vessels) may also occur.
Alkaptonuria does not cause developmental delays or cognitive impairment and does not appear to affect life span. However, chronic pain and mobility issues can develop.
Alkaptonuria is caused by mutation of the homogentisate 1,2-dioxygenase (HGD) gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal 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 for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the HGD gene is located on the long arm (q) of chromosome 3 (3q13.33). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q13.33” refers to band 13.33 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The HGD gene contains instructions for creating (encoding) an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential for the breakdown of homogentisic acid. Mutations of the HGD gene result in deficient levels of functional homogentisate 1,2-dioxygenase, which, in turn, leads to excess levels of homogentisic acid. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to a slate blue or black. Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.
Alkaptonuria affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. More than 1,000 cases have been reported in the medical literature. The exact incidence of alkaptonuria is unknown. In the United States it is estimated to occur in 1 in 250,000-1,000,000 live births. Alkaptonuria has been reported in all ethnic groups. Areas with increased frequencies of the disorder have been identified in Slovakia, the Dominican Republic and Germany.
The diagnosis of alkaptonuria is made upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Identification of vastly elevated levels of homogentisic acid in the urine is indicative of alkaptonuria. Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms.
Clinical Testing and Work-up
Elevated amounts of homogentisic acid in the urine can be detected by gas chromatography-mass spectrometry analysis. Various imaging techniques can be used to determine the presence and extent of joint and spinal disease or the involvement of the aortic or mitral valves.
Molecular genetic testing, which can detect mutations in the HGD gene, is available on a clinical basis.
In individuals over 40, echocardiography may be recommended to detect potential cardiac complications such as aortic dilation or calcification or regurgitation of the aortic or mitral valves. With echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion.
Computed tomography (CT) scan may be recommended to detect coronary artery calcification.
The treatment of alkaptonuria is aimed at the specific symptoms that are present in each individual. Individuals with alkaptonuria often receive anti-inflammatory medications to treat joint pain. In severe cases, stronger medications such as narcotics may be recommended. Pain management is tailored to each individual’s specific case and requires long-term follow up and adjustment.
Some individuals with alkaptonuria will benefit from physical and occupational therapy, which can help maintain the strength and flexibility of muscles and joints. Genetic counseling may be of benefit for affected individuals and their families.
Some individuals with alkaptonuria require surgical intervention. Approximately half of individuals with alkaptonuria will require hip, knee or shoulder joint replacement, often by 50-60 years of age. Infrequently, individuals require spinal surgery, including fusion and/or removal of the lumber discs. Surgery to replace the aortic or mitral valves may also be necessary. In some cases, chronic and painful kidney or prostate stones may require surgical intervention or preventive (prophylactic) therapy.
Dietary restrictions have generally proven ineffective. Severe restriction of protein intake is required and has proven difficult for individuals to maintain over a long period of time. In addition, long-term, severe restriction of protein intake can be associated with complications.
In older children and adults, high-doses of vitamin C have also been used to treat alkaptonuria because it hinders the accumulation and deposition of homogentisic acid. However, long-term use of vitamin C has generally proven ineffective and definite clinical studies on its efficacy are lacking.
Activities that place significant physical stress to the spine and joints such as high impact sports or heavy manual labor should be avoided.
Researchers are studying the use of a drug known as nitisinone (Orfadin®) as a potential treatment for alkaptonuria. Nitisinone, which received orphan drug status in 2001 from the Food and Drug Administration (FDA), has been approved for the treatment of a metabolic disorder known as tyrosinemia. In earlier studies, nitisinone was shown to significantly reduce accumulations of homogentisic acid in individuals with alkaptonuria. However, more research is necessary to determine whether nitisinone given to younger patients can prevent the symptoms of alkaptonuria as well as to determine the long-term safety and effectiveness of the drug for individuals with alkaptonuria.
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 web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about alkaptonuria:
Wendy J Introne, MD
National Human Genome Research Institute
National Institutes of Health
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