Alkaptonuria is one of a rare autosomal recessive genetic disorder, which results from the deficiency of homogentisate 1,2 dioxygenase (HGD). HGD gene is expressed in the liver, kidney, prostate, small intestine, and colon. This enzyme plays a role in the metabolism of tyrosine that converts homogentisic acid (HGA) into malate and acetoacetate. In the absence of HGD, homogentisic acid produced in excess by the liver oxidizes into ochronotic pigment polymer. Accumulation of this pigment in various tissues leads to systemic disease. This process is called ochronosis.
Alkaptonuria was amongst the first genetic disorders in humans that found to follow the principles of Mendelian recessive inheritance. Historically, in 1908 it was used by Archibald Garrod in his Croonian lectures to illustrate the principles behind "inborn errors of metabolism." However, the Egyptian mummy Harwa believed to be the first clinical case of Alkaptonuria dating back as far as 1500 BC. The term alkaptonuria originated from the Arabic word "alkali." Also, Boedeker created the name in 1859 after he noticed unusual decreasing properties in patient urine. In 1866 ochronosis was discovered by Virchow, who noticed under microscopy when HGA pigment appeared to be a pale brownish yellow color (ochre-like).
Homogentisate 1,2 dioxygenase (HGD) expresses in various tissues in the body such as the kidney, liver, small intestine. HGD plays an important role in the tyrosine pathway by converting homogentisic acid (HGA) to maleylacetoacetate. HGD is a 445 amino based protein mapped to chromosome 3q13.33. Mutation in the HGD gene leads to a deficiency of the HGD enzyme resulting in the accumulation of homogentisic acid (HGA).
These mutations occur in specific parts of the exons. The normal HGD has a six subunit called a hexamer arranged in two trimers, each containing an iron atom. Various mutations may affect the function, structure, or solubility of HGD. Rarely, this genetic disorder can be inherited in an autosomal dominant manner; other defects in other genes probably are responsible in these cases.
Alkaptonuria is a rare disease with worldwide prevalence. The global prevalence of alkaptonuria is 1 per 100,000 to 250,000. The prevalence of the disease in the United States is 1 case in one million population. According to the AKU Society and the DevelopAKUre Consortium, the number of alkaptonuria patients in the U.S. is 92. It is mainly reported in the Dominican Republic and Slovakia. It appears in all races with slightly more occurrence in the African population. The disease affects both men and women equally, although the disease severity is more in men.
The homogentisic acid oxidase is involved in the metabolism of the tyrosine and phenylalanine. Tyrosine is mainly necessary for specific functions, such as melanin, hormone, and several proteins, but the most majority is unused and finally generates acetoacetate and malate. In AKU, the HGD cannot form 4-maleylacetoacetate from homogentisic acid; therefore, the level of homogentisic acid in the blood will rise 100 times than normal, even though the kidneys eliminate a plentiful amount. The HGD converts to benzoquinone acetic acid, which produces polymers that match the skin pigment melanin. These accumulate in the collagen. This process of deposition is called ochronosis. Ochronotic pigment deposits bind to connective tissues of various organs leading to the destruction of joints, valves, and intima of vessels.
The pathological effects of ochronosis include arthritis, increased incidence of renal, prostatic, gall bladder stones, ruptures of muscle, tendons, and ligaments.
Histopathological examination shows hyperkeratosis, hypergranulosis with fibro-elastic degeneration of collagen. Increased levels of homogentisic acid (HMA) shows intracellular and extracellular ochronotic pigmentation on electron microscopy.
Alkaptonuria is an autosomal recessive disorder; familial genetic analysis shows no other affected member. The typical presentation of alkaptonuria is the darkening of the urine upon standing for longer time or dark urine stains on the diaper to the oxidation and polymerization of homogentisic acid; this could be the only feature suggestive of alkaptonuria in the pediatric age group. A significant amount of people with AKU may not present with black urine, which can be unreliable. The most frequent symptoms are one of the arthritic features confined mainly to the spine, hips, and knees. Practically all people with AKU eventually experience Arthritis. The onset of lumbar back pain, thoracic back pain, or both is frequent, especially around age 30. Progressive kyphoscoliosis, reduced disc space, spinal stenosis, and compressive myelopathy can occur with advancing age.
Alkaptonuria has multiple clinical spectrums. Ochronosis, homogenistic aciduria, and ochronotic osteoarthropathy are called the triad of alkaptonuria. Ochronosis commonly presents in the third or fourth decade, which develops as the deposition of benzoquinone acetate in both extra- and intra-cellularly connective tissue. Finally, ochronotic arthropathy develops as an accumulation of Homogentisinic acid polymer within hyaline articular cartilage.
The diagnosis and evaluation of AKU can be established based on the severity scoring system.
AKU Severity Score Index (AKUSSI): is a clinical scoring system of an objective measurement of severity. It is based on a quantitative validated multidisciplinary assessment.
The clinical objectives include,
Despite being one of the first discovered genetic disorders that are supposed to follow Mendelian law, to date, there is no effective treatment for AKU. Therefore, the management of alkaptonuria remains palliative, which includes pain control, physiotherapy, and joints surgery. Additionally, the main focus of the treatment is to reduce the deposition of HGA.
Commonly recommended therapy involves ascorbic acid, which known as vitamin C due to the effect on reducing the conversion of homogentisic acid to benzoquinone acetic acid by oxidation. However, it does not affect the urinary excretion of homogentisic acid.
Low Protein Diet
A low protein diet can reduce tyrosine load and reduce the severity of the disease, but compliance with dietary requirements is not easy. Efficacy is unproven.
Many studies have suggested that nitisinone, a triketone herbicide has a significant impact on the treatment of AKU. The enzyme 4-hydroxyphenylpyrvute dioxygenase believed to play a role in converting the hydroxyphenylpyruvate to HGA. Therefore, nitisinone inhibits the conversion of tyrosine to homogentisic acid. Also, nitisinone therapy(2 mg/day )has shown to produce a reduction in urinary and plasma HGA larger than 95% hence, increase the levels of tyrosine in the body. Other serious side effects associated with raised plasma tyrosine levels rather than corneal irritation include leukopenia, thrombocytopenia, and porphyria.
This disorder does not seem to affect life expectancy. However, the significant impact is on the patient's quality of life; for example, lots of people with AKU have experienced symptoms such as lack of sleep, pain, and difficulty breathing. These features begin in the fourth decade.
Patient awareness is a crucial element of patient care. Education about the disorder process, signs, and symptoms to lifestyle and diet modification, including a low protein diet, lifestyle counseling may improve long-term outcomes in people with AKU. Also, referred for genetic counseling for all family members is very important. Some of the patients may need surgical interventions like knee and hip replacement, which can significantly improve the quality of life.
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