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Alkaptonuria
Updated: Apr 27, 2009
Introduction
Background
Alkaptonuria is one of 4 disorders originally defined as an inborn error of metabolism by Archibald Garrod in his Croonian Lectures of 1902.1 The hallmark of the disease is passage of urine that becomes black when left standing. Garrod identified a familial pattern of inheritance and concluded that an inherited biochemical abnormality must result in the passage of an abnormal intermediate in the urine. That Garrod conceived of an intermediate is remarkable given that virtually nothing was known of serial biochemical reactions in the metabolic disposal of nutrient substances at that time.
Pathophysiology
The defect lies in the catabolic pathway of tyrosine, which contains a parahydroxylated ring structure. In a poorly understood complex reaction, the enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the ring. The product, homogentisic acid, is actually ortho-meta- dihydroxyphenylacetic acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase (HGO) forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted.
Upon contact with air, homogentisic acid is oxidized to form a pigmentlike polymeric material responsible for the black color of standing urine. 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 pigmentlike polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues. As the polymer accumulates within cartilage, a processthat 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 pigmentlike polymer material into collagenous tissues occurs.
In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear.
Upon microscopic examination, amber-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).
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. Because of calcifications that occur in these sites, however, the radiologic picture is more consistent with osteoarthritis.
Despite many speculations that this polymer deposition is associated with cardiac pathology, no reports of mortality directly related to the homozygous state for alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis.
Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although no correlation has so far been made between the molecular nature of the HGO mutation and its clinical phenotype, the wide variability of mutational phenomena could certainly help explain the clinical variability in this disease. Approximately 70 separate mutations have thus far been reported.
Frequency
United States
As Garrod suggested, alkaptonuria is an autosomal recessive genetic trait, although an autosomal dominant transmission pattern in 3 generations in a nonconsanguineous family has been reported.2 The true frequency of alkaptonuria cannot be given with certainty for numerous reasons. These include the fact that newborn screening for alkaptonuria is much less widely practiced than that for phenylketonuria. Guidelines for phenylketonuria screening have been well established.3 Also, some carriers express 50% or more of normal enzyme activity and do not manifest abnormal findings even with tyrosine loading. To further complicate this picture, reports in the literature indicate wide variability in incidence, particularly where gene pools are highly restricted. In certain areas, an incidence rate as high as 1 in every25,000 live birthshas been reported; worldwide it is certainly far lower.
Mortality/Morbidity
Life expectancy is normal; however, associated morbidity can be significant. Early involvement of the intervertebral discs at the thoracic and lumbar levels is very common, occurring in approximately 50% of affected individuals. Typically, significant back pain begins from age 30 years. The large joints (knee, shoulder and hip) are very frequently involved; at least half of all patients undergo joint replacement by the middle of the sixth decade of life. Achilles tendon involvement is also common and may result in tearing. Involvement of the aortic leaflets, mitral valve leaflets, or both is common, and calcifications of the coronary arteries occurs in one half of all patients prior to age 60 years.
Sex
The distribution of this disease is equal in males and females because it is an autosomal recessive or autosomal dominant trait. Males tend to have an earlier onset of arthritic symptoms with a greater degree of severity than females, although the reason for this difference is unclear.
Age
Because alkaptonuria is a genetic disorder, the deficiency of the HGO enzyme is present from conception. Clinical symptoms, aside from dark-stained diapers, are generally present only after the third decade of life.
Clinical
History
- Because alkaptonuria is usually autosomal recessive, a family pedigree, in all likelihood, reveals no other affected individuals. However, because many individuals are asymptomatic, the low frequency of affected family members may be due to a lack of ascertainment.
- Despite the intrinsic biochemical defect and the expectation that all affected individuals should excrete urine that becomes black when left standing, a significant number of people with alkaptonuria do not present with this clinical finding.
- The most common history is one of arthritic symptoms confined chiefly to the spine, hips, and knees. Virtually all people with alkaptonuria eventually experience arthritis. Onset of thoracic back pain, lumbar back pain, or both around age 30 years is frequent.
Physical
- Slate blue or gray discoloration may be found in the sclerae or ear cartilage.
- Calcifications may be palpable in the discolored areas, particularly in the cartilage of the ear.
- Joint mobility diminishes, as in osteoarthritis. Ankylosis may be present. Spontaneous fusion of one or more discs may occur, with consequent diminished spinal flexion. Joint effusions, particularly in the knee are common and range of motion may be significantly diminished.
- Signs of aortic or mitral valvulitis may be present.
Causes
- 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. Deposition of the polymer in association with cartilage is the initiating pathophysiologic cause of the arthritis.
- Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected joints.
- Exogenous agents including quinacrine (Atabrine), carbolic acid, and hydroquinone have been reported to cause an ochronotic picture without the joint disease. All have been reversible.
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| References |
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References
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Oexie K, Engel K, Tinschert S, et al. Three-generational alkaptonuria in a non-consanguineous family. J Inherit Metab Dis. Dec/2008;Epub:Epub.
US Preventive Services Task Force. Screening for phenylketonuria (PKU): US Preventive Services Task Force Reaffirmation recommendation. Ann Fam Med. Mar-Apr 2008;6(2):166. [Medline].
Peker E, Yonden Z, Sogut S. From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol. Nov-Dec 2008;74(6):700. [Medline].
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O'Brien W, La Du BN, Bunim JJ. Biochemical, pathological and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: review of the world literature (1584-1962). Am J Med. 1963;34:813-38.
Perry MB, Suwannarat P, Furst GP, Gahl WA, Gerber LH. Musculoskeletal findings and disability in alkaptonuria. J Rheumatol. Nov 2006;33(11):2280-5. [Medline].
Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. N Engl J Med. Dec 26 2002;347(26):2111-21. [Medline].
Suwannarat P, O'Brien K, Perry MB, et al. Use of nitisinone in patients with alkaptonuria. Metabolism. Jun 2005;54(6):719-28. [Medline].
Vavuranakis M, Triantafillidi H, Stefanadis C, Toutouzas P. Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome. Cardiology. 1998;90(4):302-4. [Medline].
Watts RW, Watts RA. Alkaptonuria: a 60-yr follow-up. Rheumatology (Oxford). Feb 2007;46(2):358-9. [Medline].
Wolff JA, Barshop B, Nyhan WL, et al. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res. Aug 1989;26(2):140-4. [Medline].
Further Reading
Keywords
alkaptonuria, ochronosis, alcaptonuria, homogentisuria, dark urine, inborn error of metabolism, IEM, Croonian lectures, abnormal intermediate, homogentisic acid oxidase, homogentisate, vitamin C, arthritis, osteoarthritis, rheumatoid arthritis, ankylosis, dark stained diapers, coronary artery disease, myocardial infarction, phenylketonuria, treatment, diagnosis, joint effusion, aortic valvulitis, mitral valvulitis
