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Alkaptonuria

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Aug 07, 2015
 

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.

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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.[2, 3]

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 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 pigmentlike polymer material into collagenous tissues occurs.

In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear. See the image below.

Upon microscopic examination, amber-colored, oval- 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. Recently, ocular pigment deposition has been recognized, with adverse implications for vision.[4]  

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.[5]

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.

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Epidemiology

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.[6] 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.[7]

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 every 25,000 live births has 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.

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Contributor Information and Disclosures
Author

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

References
  1. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. 1902 [classical article]. Yale J Biol Med. 2002 Jul-Aug. 75(4):221-31. [Medline].

  2. Lodh M, Kerketta JA. Early diagnosis of co-existent ß-thalassemia and alkaptonuria. Indian J Hum Genet. 2013 Apr. 19(2):259-61. [Medline]. [Full Text].

  3. Zatkova A, Sedlackova T, Radvansky J, Polakova H, Nemethova M, Aquaron R, et al. Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. JIMD Rep. 2012. 4:55-65. [Medline]. [Full Text].

  4. Lindner M, Bertelmann T. On the ocular findings in ochronosis: a systematic review of literature. BMC Ophthalmology. January 2014. 14:12. [Medline].

  5. Lok ZS, Goldstein J, Smith JA. Alkaptonuria-associated aortic stenosis. J Card Surg. 2013 Jul. 28(4):417-20. [Medline].

  6. Oexie K, Engel K, Tinschert S, et al. Three-generational alkaptonuria in a non-consanguineous family. J Inherit Metab Dis. Dec/2008. Epub:Epub.

  7. US Preventive Services Task Force. Screening for phenylketonuria (PKU): US Preventive Services Task Force Reaffirmation recommendation. Ann Fam Med. 2008 Mar-Apr. 6(2):166. [Medline].

  8. Peker E, Yonden Z, Sogut S. From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol. 2008 Nov-Dec. 74(6):700. [Medline].

  9. de Haas V, Carbasius Weber EC, de Klerk JB, et al. The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis. 1998 Dec. 21(8):791-8. [Medline].

  10. Ffolkes LV, Brull D, Krywawych S, Hayward M, Hughes SE. Aortic stenosis in cardiovascular ochronosis. J Clin Pathol. 2007 Jan. 60(1):92-3. [Medline].

  11. Fisher AA, Davis MW. Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res. 2004 Nov. 2(4):209-15. [Medline].

  12. Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: review of the literature. Rheumatol Int. 2005 Mar. 25(2):81-5. [Medline].

  13. Levine HD, Parisi AF, Holdsworth DE, Cohn LH. Aortic valve replacement for ochronosis of the aortic valve. Chest. 1978 Oct. 74(4):466-7. [Medline].

  14. Lorenzini S, Mannoni A, Selvi E. Alkaptonuria. N Engl J Med. 2003 Apr 3. 348(14):1408; author reply 1408. [Medline].

  15. Mayatepek E, Kallas K, Anninos A, Muller E. Effects of ascorbic acid and low-protein diet in alkaptonuria. Eur J Pediatr. 1998 Oct. 157(10):867-8. [Medline].

  16. 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.

  17. Perry MB, Suwannarat P, Furst GP, Gahl WA, Gerber LH. Musculoskeletal findings and disability in alkaptonuria. J Rheumatol. 2006 Nov. 33(11):2280-5. [Medline].

  18. Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26. 347(26):2111-21. [Medline].

  19. Suwannarat P, O'Brien K, Perry MB, et al. Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun. 54(6):719-28. [Medline].

  20. 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].

  21. Watts RW, Watts RA. Alkaptonuria: a 60-yr follow-up. Rheumatology (Oxford). 2007 Feb. 46(2):358-9. [Medline].

  22. 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. 1989 Aug. 26(2):140-4. [Medline].

 
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Upon microscopic examination, amber-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).
 
 
 
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