Alkaptonuria

BACKGROUND

Alkaptonuria is caused by a defect, or mutation, in the HGD gene. This gene provides instructions for making an enzyme called homogentisic acid oxidase (HGAO). Normally, HGAO helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Patients with alkaptonuria do not have enough HGAO. As a result, a substance called homogentisic acid, which is produced when phenylalanine and tyrosine are improperly broken down, accumulates in the body.

Excess homogentisic acid accumulates in the blood and is deposited in connective tissues, such as those found in and around joints. By age 40, patients develop ochronosis, a blue-black discoloration of connective tissue, including bone, cartilage, and skin, caused by deposits of ochre-colored pigment. Over time, a buildup of this substance causes cartilage and heart valves to become brittle and weakened. Buildup of homogentisic acid in the joints leads to arthritis.

Homogentisic acid is also excreted in urine, making the urine turn dark when exposed to air. Dark staining of the diapers sometimes can indicate alkaptonuria in infants, but most patients are not aware they have the disease until they are 30 to 40 years of age. Males tend to have an earlier onset of arthritic symptoms with a greater degree of severity than females, although the reason for this difference is unclear. Alkaptonuria is not life-threatening. Patients typically require lifelong treatment to manage symptoms, but they are expected to live relatively normal, healthy lives. Treatment may include dietary modifications and anti-inflammatory medications.

Alkaptonuria is usually diagnosed based on symptoms of joint discomfort and skin discoloration. The diagnosis is confirmed by verifying family history of the disease, examining skin cells under a microscope, and testing the urine for homogentisic acid. A high urinary level of homogentisic acid is defined as greater than 4-8 grams in a 24-hour period. Homogentisic acid is not normally excreted in the urine of healthy individuals at all. Because many patients do not show dark urine, looking for high levels of homogentisic acid in the body fluids of all patients with osteoarthritis is recommended.

Because alkaptonuria is inherited, the only known risk factor is a family history of the disorder. Men and women are affected in equal numbers. The prevalence is estimated to be about one in 250,000 people worldwide. It is difficult to estimate the number of cases of alkaptonuria because newborn screening for alkaptonuria is not widely practiced and some people who have a mutation that causes the disorder do not show symptoms.

RISK FACTORS

General: Because alkaptonuria is inherited, the only known risk factor is a family history of the disorder. Men and women are affected in equal numbers. The prevalence is estimated to be about one in 250,000 people worldwide. It is difficult to estimate the number of cases of alkaptonuria because newborn screening for alkaptonuria is not widely practiced and some people that have a mutation that causes the disorder do not show symptoms.

Ethnicity: Although a rare disorder, the frequency of alkaptonuria is higher in certain populations. It is more common in certain areas of Slovakia where it affects approximately one in 19,000 people. It is also more common in the Dominican Republic, but the prevalence there is not known.

Autosomal recessive inheritance: Alkaptonuria is inherited in an autosomal recessive manner. Genes are inherited on alleles, or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because alkaptonuria is an autosomal recessive disorder, an individual must inherit two mutated alleles of the disease-causing gene to have the disease. Individuals who possess only one mutated allele do not experience symptoms, but are referred to as "carriers" because they have the ability to pass the mutated gene on to their offspring.

If only one parent is a carrier, there is a 50% chance with each birth that the child will become a carrier but a 0% chance of actually inheriting the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will not inherit either mutated allele. If both parents have the disease, there is a 100% chance that their offspring will have the disease.

CAUSES

General: A defect, or mutation, in the HGD gene causes alkaptonuria. The HGD gene provides instructions for making an enzyme called homogentisic acid oxidase (HGAO). More than 80 different mutations associated with alkaptonuria have been identified in the HGD gene.

Normally, HGAO helps to break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Patients with alkaptonuria do not have enough HGAO. As a result, a substance called homogentisic acid accumulates in the body. Homogentisic acid is produced when phenylalanine and tyrosine are improperly broken down.

Excess homogentisic acid accumulates in the blood and is deposited slowly throughout life in connective tissues. By age 40, the result is ochronosis, a blue-black discoloration of connective tissue, including bone, cartilage, and skin, caused by deposits of ochre-colored pigment. Over time, a buildup of this substance causes cartilage and heart valves to become weak and brittle. In addition, the buildup of homogentisic acid in the joints leads to arthritis. Homogentisic acid is also excreted in the urine, making it turn dark when exposed to air.

Autosomal recessive inheritance: Alkaptonuria is inherited, meaning it is passed down from parents to their children. Genes are inherited on alleles, or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because alkaptonuria is an autosomal recessive disorder, an individual must inherit two mutated alleles to have the disease. However, individuals who possess only one mutated allele do not experience symptoms but are referred to as "carriers" because they have the ability to pass the mutated gene on to their offspring. If only one parent is a carrier, then there is a 50% chance with each birth that the child will become a carrier but a 0% chance of actually inheriting the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will not inherit either mutated allele. If both parents have the disease, there is a 100% chance that their offspring will have the disease.

SIGNS AND SYMPTOMS

General: In patients with alkaptonuria, a substance called homogentisic acid accumulates in the blood and is very slowly deposited in bones, connective tissues, and urine. Dark staining of the diapers can sometimes indicate alkaptonuria in infants, but most patients are not aware they have the disease until they are 30 to 40 years of age. Males tend to have an earlier onset and greater severity of arthritic symptoms than females, although the reason for this difference is unclear. Life expectancy is normal, although aging with alkaptonuria is associated with progressive disability related to arthritis.

Black urine: Urine from patients with alkaptonuria may turn brownish black when exposed to air. Parents of children in diapers may notice this symptom. However, a significant number of people with alkaptonuria do not have black urine.

Heart: The aortic and mitral heart valves, which control blood flow to the body, are most affected by the accumulation of homogentisic acid, which causes these valves to calcify or harden by age 60. Homogentisic acid deposits also can lead to the formation of atherosclerotic plaques, hard spots in arteries that contain cholesterol and fat, which can lead to coronary artery disease.

Joints: Many alkaptonuria patients eventually experience progressively worsening arthritis, especially of the spine, hips, shoulders, and knees. The buildup of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria. Onset of pain in the chest and lower back at about age 30 is common. Individuals may also develop osteoarthritis, is a degenerative joint disease associated with painful joints, and arthropathy, or diseased joints.

Deposits of homogentisic acid cause cartilage to become brittle and eventually break apart. Other deposits cause buildups of calcium, or calcifications, which may feel hard in the discolored areas, particularly in the cartilage of the ear. Spontaneous fusion of one or more vertebrae, the bones of the spine, may occur. The Achilles tendon may also be affected and may be more prone to tearing.

Ochronosis: Ochronosis is a buildup of dark pigment caused by the accumulation of homogentisic acid in connective tissues such as cartilage and skin. This blue-black pigmentation usually appears after age 30 in various organs such as the eyes, skin, tendons, and joints. This discoloration may cause a history of dark urine. A slate blue, gray, or black discoloration of sclera, a part of the eye, and ear cartilage indicates widespread staining of the body tissues, particularly cartilage.

Skin: Individuals with alkaptonuria may have a blue-black speckled discoloration of the skin later in life. This is most noticeable in areas where the body is exposed to the sun and where sweat glands are located. Sweat can actually stain clothes brown. The ears, teeth, and sclera may appear grayish blue. However, vision is not usually affected.

Other: In men, the prostate is often affected. Deposits of homogentisic acid can form stones in the prostate and kidney. A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black depending on the amount of tyrosine and phenylalanine in the diet after several hours.

DIAGNOSIS

General: Usually a physician can diagnose alkaptonuria based on symptoms of joint discomfort and skin discoloration. The diagnosis is confirmed by verifying family history of the disease, examining skin cells under a microscope, and testing the urine. A high urinary level of homogentisic acid is defined as greater than 4-8 grams in a 24-hour period. Homogentisic acid is not normally excreted in the urine of healthy individuals at all. Because many patients do not show dark urine, looking for high levels of homogentisic acid in all patients with osteoarthritis is recommended.

Black urine: Urine from patients with alkaptonuria may turn brownish black when exposed to air. Parents of children in diapers may notice this symptom. However, a significant number of people with alkaptonuria do not have black urine.

Chromatography: Diagnostic testing can be performed on a blood sample using paper chromatography and thin layer chromatography. Chromatography is a laboratory method used to separate parts of complex mixtures by measuring how quickly they travel when a liquid is wicked up a surface, such as paper (paper chromatography) or a thin layer of silicon on a plate of glass (thin layer chromatography). In healthy subjects, homogentisic acid is absent in both blood and plasma. In alkaptonuria patients, plasma levels are 6.6 micrograms per milliliter of plasma on average, and urine levels are on average 3.12 micromoles per micromole of creatinine.

Genetic testing: If the specific mutation that causes alkaptonuria within a particular family is known, the DNA from an individual can be tested to look for the presence of that specific mutation. This is done by analyzing a blood sample.

Mass spectroscopy: Abnormally high levels of homogentisic acid can be identified in urine using mass spectroscopy. Mass spectrometry is an analytical technique that identifies the chemical composition of a sample by measuring the electrical charge and weight of tiny particles.

Prenatal testing: If the specific mutation that causes alkaptonuria within a particular family is known, the DNA from an individual can be tested to look for the presence of that specific mutation in a developing fetus. The cells for this type of testing can be obtained from chorionic villus sampling (CVS), amniocentesis, or blood collected from the umbilical cord. All prenatal tests carry the risk of miscarriage and the risks and results should be discussed with a genetic counselor.

During amniocentesis, a long, thin needle is inserted through the abdominal wall into the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. The fluid is then analyzed for mutations associated with alkaptonuria. During CVS, a small piece of tissue (chorionic villi) is removed from the placenta during early pregnancy. Depending on where the placenta is located, CVS can be performed through the cervix or through the abdomen. The tissue sample is then analyzed for mutations associated with alkaptonuria.

X-rays: X-rays can help identify complications such as degeneration or fusion of vertebrae (bones of the spine), especially in the lower back. Chest X-rays can check for the hardening of heart valves.

COMPLICATIONS

Arthritis: Many alkaptonuria patients eventually experience progressively worsening arthritis, especially of the spine, hips, shoulders, and knees. The buildup of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria. Onset of pain in the chest and lower back around age 30 is common. Osteoarthritis, a degenerative joint disease associated with painful joints, is a common form of arthritis in alkaptonuria patients.

Breathing: An accumulation of homogentisic acid in the cartilage of the larynx (voice box), the trachea (windpipe), and the bronchi (air passages to the lungs) causes these tissues to become weak and brittle. This is common and may interfere with breathing and speech.

Heart: Because homogentisic acid can build up on the heart valves, there is a risk of coronary artery disease and heart attack later in life. In some cases, patients will require heart valve replacement.

Other: The central nervous system, which includes the brain and spinal cord, and endocrine organs, which make hormones, also may be affected. In men, the prostate is often affected. Deposits of homogentisic acid can form stones in the prostate and kidney. Vertebrae, the bones of the spine, may deteriorate or fuse together.

TREATMENT

General: Although there is currently no known cure for alkaptonuria, treatment can help reduce symptoms. Patients may consult with a team of doctors, including a geneticist, a neurosurgeon, an orthopedist, and a cardiologist.

Diet: Diets low in protein, especially in the amino acids phenylalanine and tyrosine, can help reduce levels of homogentisic acid, thereby lessening the amount deposited in body tissues. Whether starting this dietary restriction early in life prevents or minimizes complications later is not known, but such an approach is reasonable.

Medications: Patients with arthritis may take nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen to relieve pain and inflammation. Commonly used over-the-counter NSAIDs include ibuprofen (Advil© or Motrin©) and naproxen sodium (Aleve©). Higher strength formulations of these drugs are also available by prescription. Commonly prescribed NSAIDs include diclofenac (Cataflam© or Voltaren©), nabumetone (Relafen©), and ketoprofen (Orudis©). NSAIDs may be taken by mouth, injected into a vein, or applied to the skin. Patients with more severe arthritis symptoms may benefit from the selective COX-2 inhibitor called celecoxib (Celebrex©). This medication is taken by mouth daily to reduce the pain and inflammation associated with arthritis.

There has been some research of limited use of the insecticide nitisinone, an inhibitor of the enzyme homogentisic acid oxidase (HGAO), which plays a role in the formation of homogentisic acid. In patients with alkaptonuria, a faulty HGAO enzyme causes buildup of homogentisic acid, whereas nitisinone treatment shuts down the HGAO enzyme entirely, preventing formation of homogentisic acid. Urinary homogentisic acid excretion was shown to be reduced but the safety of prolonged use is uncertain. The main side effect of nitisinone is eye irritation.

Surgery: Older individuals may require back surgery to correct fusion of vertebrae, the bones of the spine. Joint replacement surgery (e.g., for the hip, knee, and shoulder) is often necessary at a relatively young age. At least half of all patients with alkaptonuria undergo joint replacement by age 60.

Vitamin C: Some patients benefit from high doses of vitamin C (ascorbic acid). This vitamin has been shown to reduce the buildup of homogentisic acid in the cartilage of the ears, which may indicate that there is less homogentisic acid in the rest of the body and may slow the progression of arthritis. Vitamin C, up to 1 gram per day, is recommended for older children and adults. The mild antioxidant nature of ascorbic acid helps to slow the production of homogentisic acid.

INTEGRATIVE THERAPIES

Note: Currently, there are limited scientific data on the use of integrative therapies for the treatment or prevention of alkaptonuria. The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies.

Unclear or conflicting scientific evidence:

Vitamin C (ascorbic acid): Vitamin C (ascorbic acid) is a vitamin the body needs to form collagen in bones, cartilage, muscle, and blood vessels. It also helps the body absorb iron. Vitamin C is found in foods such as fruits and vegetables, especially citrus fruits (e.g., oranges and grapefruit). Alkaptonuria is a disorder characterized by the absence of the enzyme homogentisic acid oxidase, which causes accumulation of homogentisic acid in the blood and urine. Limited research reports that daily high-dose vitamin C may provide symptomatic relief by preventing the buildup of homogentisic acid and slowing the progression of complications of this disorder. Additional evidence is merited in this area.

Vitamin C is generally considered safe in amounts found in foods. Vitamin C supplements are also generally considered safe in most individuals if taken in recommended doses. It is recommended to avoid high doses of vitamin C with glucose 6-phosphate dehydrogenase deficiency, kidney disorders or stones, cirrhosis (inflammation of the liver), gout (foot inflammation), or paroxysmal nocturnal hemoglobinuria (bleeding disorder). Vitamin C intake from food is generally considered safe if pregnant or breastfeeding. It is unclear whether vitamin C supplements in doses higher than dietary reference intake recommendations are safe for pregnant or breastfeeding women. Vitamin C is naturally found in breast milk.

PREVENTION

There are currently no known methods of preventing alkaptonuria. Individuals with a genetic predisposition for developing this disorder can take steps to slow disease progression, such as eating healthy foods and exercising regularly. High-protein diets should be avoided. People with a family history of alkaptonuria should also visit their doctors regularly to determine whether they are at risk of developing symptoms.

Genetic counseling: Genetic counselors help individuals, families, and couples affected by or at risk for alkaptonuria work through the process of genetic testing for the disease. Genetic counseling also helps individuals, families, and couples as they plan to have a baby. Because many affected individuals are asymptomatic, all siblings of a newly diagnosed patient should be tested.

Prenatal testing: If the specific mutation that causes alkaptonuria within a particular family is known, the DNA from an individual can be tested to look for the presence of that specific mutation. The cells for this type of testing can be obtained from chorionic villus sampling, amniocentesis, or blood collected from the umbilical cord. All prenatal tests carry the risk of miscarriage.

During amniocentesis, a long, thin needle is inserted through the abdominal wall into the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. The fluid is then analyzed for mutations associated with alkaptonuria. During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta during early pregnancy. Depending on where the placenta is located, CVS can be performed through the cervix or through the abdomen. The tissue sample is then analyzed for mutations associated with alkaptonuria.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

• Alkaptonuria Society. www.alkaptonuria.info. Accessed August 7, 2008.
• Genetics Home Reference. http://ghr.nlm.nih.gov. Accessed August 7, 2008.
• National Heart, Lung, and Blood Institute. www.nhlbi.nih.gov. Accessed August 7, 2008.
• Natural Standard: The Authority on Integrative Medicine. Copyright © 2008. www.naturalstandard.com. Accessed August 7, 2008.
• Perry MB, Suwannarat P, Furst GP, et al. Musculoskeletal findings and disability in alkaptonuria. J Rheumatol. 2006 Nov;33(11):2280-5. View abstract
• Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21. View abstract
• Prasad C, Galbraith PA. Sir Archibald Garrod and alkaptonuria -'story of metabolic genetics'. Clin Genet. 2005 Sep;68(3):199-203. View abstract
• Rodr©guez JM, Timm DE, Titus GP, et al. Structural and functional analysis of mutations in alkaptonuria. Hum Mol Genet. 2000 Sep 22;9(15):2341-50. View abstract
• Verma SB. Early detection of alkaptonuria. Indian J Dermatol Venereol Leprol. 2005 May-Jun;71(3):189-91. View abstract

Copyright © 2011 Natural Standard (www.naturalstandard.com)

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