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A study on how homogentisic acid accumulates in the body Alkaptonuria was first identified and described by Sir Archibald Edward Garrod as a human inborn error of metabolism in 1902.It is an autosomal recessive disorder in which the lack of homogentisic oxidase blocks the metabolism of phenylalanine-tyrosine at the level of homogentisic acid. Thus, homogentisic acid accumulates in the body. A large amount is excreted, imparting a black color to the urine if allowed to stand and undergo oxidation. MORPHOLOGY The retained homogentisic acid selectively binds to collagen in connective tissues, tendons, and cartilage, imparting to these tissues a blue-black pigmentation (ochronosis) most evident in the ears, nose, and cheeks. Alkaptonuria has several characteristic symptoms; Urine that darkens on standing, ochronosis in certain tissues and, degenerative arthropathy resulting from ochronosis in joint tissues. The joints most affected are those of the thigh, hips, and knees, whereas the ankles and wrists are usually much less involved. This variability in arthropathy may be related to load bearing. Ochronotic arthopathies have a large number of presentations, including limitations of movement of the shoulder, hip and knee. The intervertebral discs often show degeneration and can cause pain. Cardiovascular symptoms include effects on the mitral and aortic valves. Overall, patients suffering from Alkaptonuria-induced Ochronosis can experience a lot of pain, incapacity and disability. The most serious consequences of ochronosis, however, stem from deposits of the pigment in the articular cartilages of the joints. In some obscure manner, the pigmentation causes the cartilage to lose its normal resiliency and become brittle and fibrillated. Wear and tear of this erosion of this abnormal cartilage leads to denudation of the subchondral bone, and often tiny fragments of the fibrillated cartilage are driven into the underlying bone, worsening the damage. Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid. Hepatic homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolizes homogentisic acid into 4-maleylacetoacetate.Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified. GENETICS: Generally Alkaptonuria is transmitted as an autosomal recessive trait. Archibald Edward Garrod’s suggestion that the disorder results from absence of the enzyme that catalyzes the oxidation of HGA, gave rise to the one geneone enzyme hypothesis, leading to the notion of inborn errors of metabolism and the field of biochemical genetics. It has been demonstrated that mutations of the Alkaptonuria gene, located on chromosome 3q21-23 in humans, leads to the production of an inactive HGAO protein. Pollak et al used homozygosity mapping to locate the Alkaptonuric gene to 3q2 in a 16cM region. In 1996, Fernandez- Canon et al cloned the gene for Homogentisate 1,2-dioxygenase (HGD, EC 184.108.40.206), and they demonstrated that HGD harbors the mutation that co-segregates with the disease and provided biochemical evidence that at least one of these missense mutations is a loss of function mutation. Mutations in the HFD genes cause Alkaptonuria because the HGD gene provides instructions for making an enzyme called Homegentisate oxidase. This enzyme helps break down the amino acids phenylalanine and tyrosine, which are important building blocks of proteins. Mutations in the HGD gene impair the enzymes role in this process. As a result, a substance called Homogentisic acid, which is produced as phenylalanine and tyrosine are broken down accumulates in the body. Excess Homogentisic acid and related compounds are deposited in connective tissues which cause cartilage and skin to darken. Over time, a buildup of this substance in the joints leadsto arthritis. Homogentisic acid is also excreted in urine, making the urine dark when exposed to air. MODE OF INHERITANCE:(RISK TO FAMILY MEMBERS) PARENTS OF A PROBAND: a) The parents of an affected child are obligate heterozygotes and therefore carry out mutant alleles. b) Heterozygotes (carriers) are asymptomatic. SIBLINGS OF A PROBAND: At conception, each sibling of an affected individual has 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being normal and not a carrier. Once an at-risk siblings is known to be unaffected, the chance of his/her being a carrier is 2/3. OFFSPRINGS OF A PROBAND: The offsprings of an individual with alkaptonuria are obligate heterozygotes (carriers) for a mutant allele causing Alkaptonuria. CARRIER DETECTION: MOLECULAR GENETIC TESTING: Carrier testing for at risk family members is possible if the disease- causing mutations in the family have been identified. BIOCHEMICAL TESTING:Biochemical genetic testing is not reliable as a method of carrier detection. DIAGNOSIS: The diagnosis of Alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography- mass spectrometry analysis (urine test). The amount of HGA excreted per day in individuals with Alkaptonuria is usually between one and eight grams. Blood plasma test can also be used for the diagnosis of Alkaptonuria. In healthy subjects, homogentisic acid is absent in blood, but in Alkaptonuria patients, the levels of homogentisic acid in plama may be up to 6.6micrograms/ml. Other complications of the disease like Arthritis, discoloration of the sclera, ear cartilage pigmentation, skin discoloration etc… may also help in the diagnosis of ALkaptonuria. SYMPTOMS: The symptoms of Alkaptonuria vary from one person to another.These symptoms described here are generally seen to some degree. Most young people have few oor no symptoms other than the discoloration of their urine, which turns black when left to stand in air. Narrowing and calcification of intervertebral spaces Calcification of the blood vessels: aorta, coronary arteries, mitral and aortic valves etc… Pigmentation in the eye Pigmentation in the ear Prostate and kidney stones Black pigment deposition in cartilage, connective tissue, and the main joints (hips, shoulders, elbows, knees, spine) Progressive arthritis TREATMENT: GENERAL: Although there is currently no known cure for Alkaptonuria, treatment can help reduce symptoms. Patients may consult with team of doctors, including a geneticist, a neurosurgeon, an orthopedist, and a cardiologist. This is because of the several complications involved in Alkaptonuria. 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. MEDICATIONS: *Patients with arthritis may take nonsteroidal anti-infalmatory drugs (NSAIDs) or acetaminophen to relieve pain and inflammation. Commonly used over-the –counter NSAIDs include Ibuprofen (Advil or Motrin) and naproxen sodium (Aleve). NSAIDs may be taken by mouth, injected into the vien, 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 arthritis. *Vitamin C, as much as 1g/d, is recommended for older children and adults. The mold antioxidant nature of ascorbic acid helps to retard the process of conversion of homogentisate to the polymeric material that is deposited in the cartilaginous tissues. *Limited use of nitisinone, an inhibitor of the enzyme 4hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid, has been reported. Urinary homogentisate excretion was markedly reduced, but safety of prolonged use is still an open question. SURGICAL: Older individuals may require removal of lumbar discs with fusion and Hip, shoulder or knee joint replacement may be necessary. CASE STUDY: A 45 year-old white woman presented with a three year history of bluish discoloration of her ears. The patient had noted a bluish-black staining of the armpit areas of her clothing for the prior 6 months. A review of systems and past medical history were significant for a history of constant right lower back pain and bilateral knee pain for approximately 1 year. A review of medications revealed dialy use of conjugated estrogens and multivitamins and intermittent use of ibuprofen. The patients parents were not known to be consanguineous. Mucocutaneous examination was significant for bluish-black patches on the ears in areas overlying cartilage. Larger bluish patches were also noted in the axillary vaults. Cardiac, ophthalmologic examinations were defected to some extent. Orthopedic evaluation revealed limited spinal range of motion. Examination of lumbosacral xrays revealed marked degenerative disc disease at the T12-S1 level and anterior osteophytosis at the T 11-L2 levels. Complete blood plasma test has elevated Homogentisic acid. A urine sample darkened upon standing. A qualitative assay for urinary Homogentisic acid was positive (Fishberg test)(Fishberg EH. The instantaneous diagnosis of alkaptonuria on a single drop of urine. JAMA 1942; 119:882).