Alkaptonuria
Alkaptonuria is a rare inherited disorder characterized by the body's inability to properly metabolize the amino acid tyrosine, leading to a buildup of homogentisic acid (HGA). This accumulation results in distinctive symptoms, such as urine that turns black upon exposure to air, a consequence of HGA oxidation. The disorder follows an autosomal recessive inheritance pattern, meaning that an individual must inherit two defective copies of the HGD gene, one from each parent, to manifest the disease. While alkaptonuria is largely uncommon globally, it is more frequently observed in populations from Slovakia and the Dominican Republic.
Individuals with alkaptonuria may experience additional health issues, including joint pain, darkened tissues (known as ochronosis), and potential damage to heart valves due to HGA deposits. Diagnosis typically involves detecting elevated HGA levels in urine or blood, often initiated by the observation of discolored urine. Treatment options are limited; however, the medication nitisinone has shown promise in reducing HGA levels and slowing disease progression. As the disorder is genetically inherited, families with a history of alkaptonuria face a 25% chance of having another affected child in subsequent pregnancies.
Alkaptonuria
ALSO KNOWN AS: Black urine disease; AKU; alcaptonuria; homogentisate oxidase deficiency; homogentisic aciduria
DEFINITION: Alkaptonuria is an inherited autosomal recessive disorder of the degradative metabolism of the amino acid tyrosine. It results in a buildup of homogentisic acid (HGA), a metabolic product of tyrosine, some of which is excreted in urine. Patients' urine turns black when exposed to air from the oxidation of HGA.
Risk Factors
To have the disorder, a person must have received one defective copy of the HGD gene, which directs production of the enzyme homogentisate 1,2-dioxygenase, from each parent. The disorder is present from birth and is largely unaffected by treatment or lifestyle. The disease incidence is very rare, except in people whose ancestry derives from Slovakia or the Dominican Republic.
Etiology and Genetics
In 1902, the physician Archibald E. Garrod called alkaptonuria an “inborn error of metabolism,” meaning an inherited disorder of normal metabolism. This statement for the first time linked human disease with the recently rediscovered rules for the inheritance of traits in pea plants, originally discovered by Gregor Mendel in 1865. Among the hundreds of human genetic diseases that also fit this description are phenylketonuria, galactosemia, and Tay-Sachs disease. Though the terms “gene,” “DNA,” and “enzyme” were unknown in 1902, Garrod correctly implied that a single human gene determined the enzymatic ability to metabolize “alkapton” (now called homogentisic acid) and that the disease was caused by a defect in the gene. By 1908, Garrod had further identified albinism, cystinuria, and pentosuria as human inborn errors of metabolism analogous to alkaptonuria.
Alkaptonuria is caused by the inherited inability to convert homogentisic acid (HGA), a degradative metabolic intermediate of tyrosine, to its product 4-maleylacteoacetate. The conversion normally occurs mostly in the liver. In persons with alkaptonuria, accumulation of HGA in the liver leads to excretion into the blood and ultimately into the urine. HGA deposits may occur in joints and other tissues over time. The enzyme homogentisate 1,2-dioxygenase is responsible for the metabolic conversion. It is encoded by the HGD gene on the long arm of chromosome 3, band 3q13.33. The enzyme is inactive in persons with alkaptonuria as a consequence of defective alleles (gene copies) of the HGD gene, one from each parent. Parents may carry one defective copy of the gene and still not have the disorder if their other HGD allele functions normally.
The HGD gene has been cloned and sequenced. Mutations in the form of altered DNA sequence of the coding portion of the HGD gene, leading to amino acid substitutions that alter and inactivate the homogentisate 1,2-dioxygenase protein, have been identified in persons with alkaptonuria. Mutations at different locations in the HGD gene have been found in alkaptonurics living in the United States, Slovakia, Spain, Finland, Iraq, and Turkey, clearly indicating that the mutations, and thus the disease, have independently arisen multiple times in human history.
In most of the world, the incidence of alkaptonuria is between 1 in 250,000 and 1 in 1 million births, as reported by geneticists Wendy Introne and William Gahl. The defective gene frequency is highest in populations whose ancestry derives from Slovakia and the Dominican Republic. In Slovakia and the Dominican Republic, the disease occurs about once in every 19,000 births, according to A. Zatkova et al.
Symptoms
The primary symptom of the disease is urine that turns black shortly after excretion. Discolored urine may be the only sign in infants and young children. HGA is colorless, but air oxidation leads to a melanin-like dark pigment. Other signs and symptoms, especially in older children and adults, derive from HGA deposits in cartilage (ochronosis) and include dark earlobes, dark sclera of the eyes, joint and lower back pain, and kidney stones. HGA deposits damage cartilage, and joint deposits can cause osteoarthritis. Deposits may also damage heart valves.
Screening and Diagnosis
Infants may be diagnosed because of a black or brown urine-stained diaper. Confirmation requires measuring significant HGA levels in blood plasma or urine. As with many genetic disorders, one aid in diagnosis is another person in the same family or a close relative who has the disease.
Treatment and Therapy
Alkaptonuria is difficult to treat. Administration of the herbicide nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (an enzyme that also generates HGA), is the most effective form of treatment available. Nitisinone can slow or even prevent the progression of alkaptonuria by decreasing serum and urinary homogenistic acid levels. Beyond nitisinone, treatment options are limited. Dietary restriction of phenylalanine (as for phenylketonuria) and tyrosine has been tried. Large doses of ascorbic acid (vitamin C) have been tried on the idea that the vitamin can help prevent HGA deposits. Joint stiffness can be delayed by low- or moderate-impact exercise and physical training. Surgery can replace knee, hip, and shoulder joints damaged by arthritis in older adults. Monitoring can be done to check for cardiac or urologic complications.
Prevention and Outcomes
Parents who already have a child with alkaptonuria are identified as a “couple at risk,” as each subsequent pregnancy has a 25 percent chance of producing another child with the disease. Prenatal diagnosis and, if desired, abortion are feasible options for these couples. Because the disease is so rare, prevention by routine genetic testing to identify couples at risk is not feasible in most populations.
Bibliography
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Zatkova, Andrea. "An Update on Molecular Genetics of Alkaptonuria (AKU)." Journal of Inherited Metabolic Disease 34.6 (2011): 1127–36. MEDLINE Complete. Web. 15 Jan. 2016.