ALKAPTONURIA
editAlkaptonuria (black urine disease, black bone disease, or alcaptonuria) is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine, which occur in protein. It is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase; if a person inherits abnormal copies from each parent (it is a recessive condition) the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over thirty years old, although the dark discoloration of the urine is present from birth.
Symptoms
editPatients with black bone disease are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear as well as other cartilage, and the sclera and corneal limbus of the eye.
Other symptoms of alkaptonuria include:
- dark spots in the sclera (white) of your eyes
- thickened and darkened cartilage in your ears
- blue speckled discoloration of your skin, particularly around sweat glands
- dark-colored sweat or sweat stains
- black earwax
- kidney stones and prostate stones
- arthritis (especially hip and knee joints)
Diagnosis
editAlkaptonuria should be suspected in individuals with any of the following major features:
- Dark urine or urine that turns dark on standing. Oxidation of homogentisic acid (HGA) excreted in the urine produces a melanin-like product and causes the urine to turn dark on standing. Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent. However, darkening may not occur for several hours after voiding and many individuals never observe any abnormal color to their urine.
diagnosis - Ochronosis (bluish-black pigmentation of connective tissue). Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis .
- Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision.
- Ear cartilage pigmentation is seen in the concha and antihelix. The cartilage is slate blue or gray and feels irregular or thickened. Calcification of the ear cartilage may be observed on radiographs.
- Pigment also appears in cerumen and in perspiration, causing discoloration of clothing.
- A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger.
- Arthritis, often beginning in the spine and resembling ankylosing spondylitis in its large-joint distribution. Radiographs of the spine showing flattened and calcified intervertebral disks are pathognomonic. Findings include degeneration of the intervertebral disks followed by disk calcification and eventually fusion of the vertebral bodies. Osteophyte formation and calcification of the intervertebral ligaments also occur. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and osteophyte formation. Enthesopathy can be seen at the muscle insertions.
Pathophysiology
edit
Chemical skeletal formula of homogentisic acid, which accumulates in the body fluids of people with alkaptonuria.
Every person carries in their DNA two copies (one received from each parent) of the gene HGD, which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase (HGD) which can normally be found in numerous tissues in the body (liver, kidney, small intestine, colon and prostate). In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme. HGD mutations are generally found in certain parts (exons 6, 8, 10 and 13) but a total of over 100 abnormalities have been described throughout the gene. The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an iron atom. Different mutations may affect the structure, function or solubility of the enzyme. Very occasionally the disease appears to be transmitted in an autosomal dominant fashion, where a single abnormal copy of HGD from a single parent is associated with alkaptonuria; it is possible that other mechanisms or defects in other genes are responsible in those cases. Pathophysiology of alkaptonuria, which is due to the absence of functional homogentisate dioxygenase in the liver. The HGD enzyme in involved in the metabolism (chemical processing) of the aromatic amino acids phenylalanine and tyrosine. Normally these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions such as hormones (e.g. thyroxine, the thyroid hormone), melanin (the dark pigment in the skin and hair) and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a group of enzymes that eventually generate acetoacetate and malate. In alkaptonuria the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into 4-maleylacetoacetate, and homogentisic acid levels in the blood are a hundredfold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.
The homogentisic acid is converted to the related substance benzoquinone acetic acid (BQA) which forms polymers that resemble the skin pigment melanin. These are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.
Treatment
editThere’s no specific treatment for alkaptonuria.
You may be put on a low-protein diet. Your doctor may also recommend large doses of ascorbic acid, or vitamin C, to slow down the accumulation of homogentisic acid in your cartilage.However, long-term use of vitamin C has generally proven ineffective for treating this condition.
Other treatments for alkaptonuria are focused on preventing and relieving possible complications, such as:
- arthritis
- heart disease
- kidney stones
Several recent studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme, 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA. Nitisinone has been used for some time at much higher doses in the treatment of type I tyrosinemia. Nitisinone treatment has been shown to cause a larger than 95% reduction in plasma and urinary HGA. The main drawback is accumulation of tyrosine, the long-term risks of which are unknown; there is a particular concern about damage to the cornea of the eye. Long-term use would require frequent monitoring for complications.
Management
edit- Treatment of manifestations: Management of joint pain tailored to the individual; physical and occupational therapy to help maintain muscle strength and flexibility; knee, hip, and shoulder replacements when needed; surgical intervention for prostate stones and renal stones as needed; aortic stenosis may necessitate valve replacement.
- Surveillance: In individuals older than age 40 years, echocardiography to detect aortic dilation, aortic or mitral valve calcification, and stenosis; CT to detect coronary artery calcification.
- Agents/circumstances to avoid: Physical stress to the spine and large joints, including heavy manual labor or high-impact sports, to try to reduce progression of severe arthritis.
- Evaluation of relatives at risk: Testing for the presence of elevated urinary HGA in sibs of affected individuals allows for early diagnosis and intervention to prevent secondary complications.
Outlook
editThe life expectancy for people with alkaptonuria is fairly normal.
However, the disease puts you at much higher risk of certain disorders, including:
- arthritis in your spine, hips, shoulders, and knees
- tearing of your Achilles tendon
- hardening of your heart’s aortic and mitral valves
- hardening of your coronary arteries
- kidney and prostate stones
References
edithttps://ghr.nlm.nih.gov/condition/alkaptonuria#genes
