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Alkaptonuria (AKU) is a rare inherited genetic disorder of tyrosine metabolism characterized by the triad of Homogentisic aciduria, ochronosis and arthritis. It is one of the conditions in which Mendelian recessive inheritance was proposed. It was also one of the four inborn errors of metabolism described by Garrod.
The most obvious sign in adults is a thickening and blue-black discoloration of the ear cartilage. This blue-black discoloration of connective tissue (including bone, cartilage, and skin) is caused by deposits of yellow or ochre-colored pigment, and is called Ochronosis.
The condition is rare, affecting one in 250,000 to one million people worldwide. In US, the incidence is 1 case per 4 million populations.
AKU is an autosomal recessive disorder, caused due to deficiency of Homogentisic acid oxidase (HGAO) which catalyzes the conversion of HGA (also called alkaptone) to maleyl acetoacetate (Figure-1). Inability to convert homogentisic acid to maleylacetoacetic acid results in accumulation of the former. Homogentisic acid is subsequently converted to benzoquinone acetic acid and spontaneously polymerized (Figure-1).
In the absence of the enzyme HGAO, Homogentisic acid and benzoquinone acetic acid (BQA) build up in the body (Figure-1). Homogentisic acid is rapidly cleared in the kidney and excreted.
Although homogentisic acid blood levels are kept very low through rapid kidney clearance, over time homogentisic acid is deposited in cartilage throughout the body and is converted to the pigment like polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues. As the polymer accumulates within cartilage, a process that takes many years, the normally transparent tissues become slate blue, an effect ordinarily not seen until adulthood.
The earliest sign of the disorder is the tendency for diapers to stain black. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of pigment like polymer material into collagenous tissues occurs.
In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear.
The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative of widespread staining of the body tissues, particularly cartilage. The hips, knees, and intervertebral joints are affected most commonly and show clinical symptoms resembling rheumatoid arthritis. Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected joints.
Most patients don’t have any symptoms throughout childhood or early adult life and it is not until they reach their 40’s that other signs of the disease start appearing.
- One of the earliest signs is thickening of the ear cartilage (the pinna feels noticeably thickened and flexible). In addition the skin turns a blue-black color (Figure-2)
Figure-2- Showing blackening of the ear cartilage
- Earwax is often reddish-brown or jet-black.
- Bones and cartilage of the lower back, knees, shoulders and hips are most affected. Firstly patients suffer low back pain with stiffness, followed by knee, shoulder and hip pain over the next 10 years. Cartilage becomes brittle and can break apart easily. In some cases this leads to spinal injuries such as prolapsed intervertebral discs.
- Deposits around the trachea, larynx and bronchi may cause shortness of breath and difficulty breathing.
- Deposits around the heart and blood vessels can calcify and lead to atherosclerotic plaques.
- Pigmentation of the sclera of the eye usually occurs early on. This does not affect vision but appears as brown or grey deposits on the surface of the eye (Figure-3)
Figure-3- Showing black spots on the sclera
- Skin color changes are most apparent on areas exposed to the sun and where sweat glands are found (Figure-4)
Figure-4- Showing blackening of the skin
- Urine exposed to air can become dark; this is useful for diagnosing young children using diapers. The urine is malodorous.
Figure-5- Showing the darkening of urine on standing.
Presumptive diagnosis can be made by adding sodium or potassium hydroxide to urine and observing the formation of a dark brown to black pigment on the surface layer of urine within 30 minutes to 1 hour.
The fresh urine of an alkaptonuric appears normal but starts darkening on exposure to the air. This is caused by oxidation and polymerization of the HGA that speeds up on alkalization. Hence, (strongly) acidic urine may not darken for many hours on standing. This may be one of the reasons why darkening of the urine may not be noted in an affected child and the diagnosis is delayed until adulthood when arthritis or ochronosis appears.
HGA is a strong reducing substance that produces a positive reaction with Benedict’s and Fehling’s reagent. With Fehling’s (FeCl3) reagent, it gives transient blue-green Color.
The diagnosis of alkaptonuria is confirmed by measurement of HGA concentration in the urine by paper and thin layer chromatography and photometry.
HGA is not elevated in the blood but excreted in the urine in heavy amounts – as much as 4-8gm / day.
Alkaptonuria is a life long disease. There is no cure for the condition.Prevention is not possible and the treatment is aimed at ameliorating symptoms. Reducing intake of the amino acids phenylalanine and tyrosine to the minimum required to sustain health (phenylalanine is an essential amino acid) can help slow the progression of the disease. Vitamin C has been found to slow down the conversion of homogentisic acid to the polymeric deposits in cartilage and bone. A dose of up to 1g/day is recommended for older children and adults.
Medical therapy is used to ameliorate the rate of pigment deposition. This minimizes articular and cardiovascular complications in later life.
Reduction of phenylalanine and tyrosine has reportedly reduced homogentisic acid excretion. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable.
Life expectancy is normal although patients may be at increased risk of heart conditions and may require surgical treatments for spine, hip, knee and shoulder joint problems. Exogenous cutaneous Ochronosis has been successfully treated by laser.
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