VOLUME 18 | ISSUE 5 | SEPTEMBER 1998

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Alkaptonuria: Case Report and Review of the Literature

M. Al-Essa, MD; L. Al-Shamsan; M.S. Rashed, PhD; P.T. Ozand, md, PhD

From the Departments of Pediatrics and Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

How to cite this article:

M Al-Essa, L Al-Shamsan, MS Rashed, PT Ozand, Alkaptonuria: Case Report and Review of the Literature. 1998; 18(5): 442-444

 

 

Alkaptonuria (McKusick 203500) is a rare metabolic disease characterized by a triad of homogentisic aciduria, arthritis and ochronosis. It enjoys the historic distinction of being one of the first conditions in which mendelian recessive inheritance was proposed and is also one of the conditions in the charter of group of inborn errors of metabolism.1 It is of interest to note that the disease was identified in 1500 BC in an ancient Egyptian mummy.2 The manifestations are urine that turns dark on standing and alkalinization due to excretion of excessive amounts of homogentisic acid, large joint arthritis and black ochronotic pigmentation of cartilage and collagenous tissue. This disease is unusually frequent in Slovakia3 and the Dominican Republic.4

 

More than 126 patients have been reported from Czechoslovakia,5 108 from Germany, and 90 from the United States. In countries of the Middle East, the disease was first reported from Lebanon in 19586 and from Sudan in 1965.7 Two adult patients, one Saudi and one Yemeni, have also been reported from Saudi Arabia.8,9 We report the first Saudi child with presymptomatic alkaptonuria, who was diagnosed and treated at King Faisal Specialist Hospital and Research Centre, and we discuss the clinical aspect and management of this condition with a review of the relevant literature.

 

Case

Case Report

A 4-year-old boy of a first-degree consanguineous couple was noted by the parents to have darkening of the urine to an almost black color when it was left standing. He had a normal sibling and there were no other medical problems, in particular hemolytic anemia, in the family. Childhood growth and development were normal. Physical examination revealed a healthy child with normal growth parameters. In particular, there was no abnormal pigmentation of the sclera, conjunctiva, cornea and ear cartilage. Joint examinations were normal as well. The patient's urine appeared normal during voiding, however, it turned black on standing in room temperature (Figure 1). Regular laboratory investigations were normal and skeletal survey showed no degenerative changes. The urine gas chromatography/mass spectrometry (GC/MS) showed a massive amount of homogentisic acid. He was started on Vitamin C (0.5 g/bid). Currently, the patient is asymptomatic and is under follow-up every six months in the Outpatient Clinic. After screening the close and extended family members, no other cases were identified.

Discussion

Alkaptonuria, or the excretion of urine which darkens on exposure to air, is an autosomal recessive disorder due to deficiency of homogentisic acid oxidase, an important enzyme in the catabolism of aromatic amino acids. It catalyzes the conversion of homogentisic acid to maleylacetoacetic, which is ultimately converted to fumaric and acetoacetic acid10 (Figure 2).

 

The urine of an alkaptonuric individual usually appears normal when passed. However, it starts to darken upon standing. This is caused by oxidation and polymerization of the homogentisic acid, and it is enhanced with an alkaline pH. Therefore, an acidic urine may not become dark even after many hours of standing. This is one of the reasons why darkening of the urine may perhaps never be noted in an affected person, and the diagnosis may be delayed until adulthood, when arthritis or ochronosis occurs.

 

Homogentisic acid is a strong reducing agent that produces a positive reaction with Fehling or Benedict reagent, a feature that was also recognized in 1859.11 The diagnosis is confirmed by measurement of homogentisic acid by enzymatic spectrophotometry,12 or by using gas liquid chromatography.13 The diagnosis could also be confirmed by the high-pressure liquid chromatography method for the quantitation of homogentisic acid and its derivative benzoquinone acetic acid.14 Measurement of this product by this method is used for therapy monitoring. Excretion of homogentisic acid in the urine is usually massive—as much as 4 to 8 g of this compound is excreted daily in the urine,15 and very little is found in the plasma.

 

Alkaptonuric patients are usually asymptomatic as children or young adults.16-18 When they get older, pigmentation of the sclera or the cartilage of the ear start to appear. Pigmentation may be seen in the teeth,19 buccal mucosa, and in the nails or the skin, giving these areas a dusty coloration. The widespread deposition of pigment in alkaptonuric patients is called ochronosis,20,21 a term used to describe the darkening of tissues, which is due to a slow accumulation of the black polymer of homogentisic acid in the cartilage and other mesenchymal tissues.

 

Arthritis is the only disabling effect of this condition, and occurs in almost all patients with advancing age.22,23 The earliest symptoms are usually in the hips, spine and knees, the large weight-bearing joints. The arthritis has the clinical characteristics of rheumatoid arthritis, however, the radiological picture is of severe osteoarthritis. In contrast to osteoarthritis, the large joints at the hip and shoulder are most commonly involved, whereas the sacroiliac joint may be spared. The degenerative changes in the lumbar spine are quite characteristic, with narrowing of joint spaces and fusion of vertebral bodies, resulting in marked limitations of motion with ultimate ankylosis. Ochronotic arthropathy in the hips and the knees may be so severe as to require total joint arthroplasty.24 The disease is more severe in men, although the incidence in the two sexes is equal.25

 

There is a high incidence of heart disease,26 commonly due to mitral and aortic valvulitis. Secondary calcification of the aortic valve may be so severe as to necessitate urgent aortic valve replacement.27Ischemic heart disease with ultimate myocardial infarction is a common cause of death.

 

Genetically, alkaptonuria is inherited as an autosomal recessive trait.26 Janocha et al.28 demonstrated linkage to microsatellite markers from proximal 3q. Markers on that chromosome were selected for study because of previously demonstrated homology of synteny with mouse chromosome 16.29 Independently, Pollak et al.30 used homozygosity mapping to locate the alkaptonuric gene to 3 q 2 in a 16-cM region. Sucrase-isomaltase deficiency31 and neonatal hyperparathyroidism32 could be co-inherited with alkaptonuria. In 1996, Fernandez-Canon et al. cloned the gene for homogentisate 1,2 dioxygenase (HGD,EC 1.13.11.5), and they demonstrated that HGD harbors the mutation that co-segregates with the disease and provided biochemical evidence that at least one of these missense mutations is a loss of function mutation.33

 

Treatment of alkaptonuric patients is a challenge for a pediatrician. No treatment has been completely successful. Dietary restrictions on the intake of tyrosine and phenylalanine substantially reduced the excretion of homogentisic acid, however, the long-term compliance with this diet is the major drawback of this approach.14 Homogentisic acid inhibits the growth of cultured human articular chondrocyte, and binds to connective tissue in rats.34 Ascorbic acid prevents these effects. Wolff et al. treated two adults with high doses of ascorbic acid. The level of excretion of homogentisic acid did not change, whereas its derivative, benzoquinone acetic acid, completely disappeared from the urine.14

References

1. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. Lancet 1902;II:1616-20.

2. Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A. Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science 1977;197:566-8.

3. Cervenansky J, Sitaj S, Urbanek T. Alkaptonuria and ochronosis. J Bone Joint Surg (abstract) 1959;41:1169-82.

4. Milch RA. Studies of alcaptonuria: inheritance of 47 cases in eight highly inter-related Dominican kindreds. Am J Hum Genet 1960;12:76-85.

5. O'Brien WM, La Du BN, Bunim JJ. Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: a review of world literature (1584-1962). Am J Med 1963;34:813-38.

6. Khachadurian A, Abu Feisal K. Alkaptonuria: report of a family with severe cases in four successive generations, with metabolic studies in one patient. J Chronic Dis 1958;7:455-65.

7. Salih MAM. Genetic disorders in Sudan. In: Teebi AS, Farag TI, editors. Genetic disorders among Arab populations. Oxford: Oxford University Press, 1997:322-40.

8. Kagalwalla YA. Alkaptonuria: a case report. Saudi Med J (letter) 1991;12:438-9.

9. Mohay-Ud-Din K. Alkaptonuria: a case report. Saudi Med J (letter) 1989;10:523-4.

10. La Du BN. Alcaptonuria. In: Stanbury JB, Wyngaarden JB, Frederickson DS, editors. The metabolic basis of inherited disease. 4th edition. New York: McGraw-Hill 1978:268-82.

11. Boedeker C. Ueber das alcapton: ein bietrag zur Frage: Welche Stoffe des Harns Können Kupferreduction bewirken? Z Rat Med 1859;7:130.

12. Seegmiller JE, Zannoni VG, Laster L, La Du BN. An enzymatic spectrophotometric method for the determination of homogentisic in plasma and urine. J Biol Chem 1961;236:774.

13. Hill A, Hoag GN, Zaleski WA. The investigation of aromatic acids in phenylketonuria, alkaptonuria and tyrosinosis using gas-liquid chromatography. Clin Chim Acta 1972;37:455-62.

14. 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;26:140-4.

15. Neuberger A, Rimington C, Wilson JMG. Studies on alcaptonuria II. Investigations on a case of human alcaptonuria. Biochem J 1947;41:438.

16. Bunim JJ, McGuire JS Jr, Hilbish TF, et al. Alcaptonuria, Clinical Staff Conference at the National Institutes of Health. Ann Intern Med 1957;47:1210.

17. Cooper PA. Alkaptonuria with ochronosis. Proc R Soc Med 1951;44:917.

18. Minno AM, Rogers JA. Ochronosis: report of a case. Ann Intern Med 1957;46:179.

19. Sickert RG, Gibilisco JA. Discoloration of the teeth in alkaptonuria (ochronosis) and Parkinsonism. Oral Surg Oral Med Oral Pathol 1970;29:197-9.

20. Wirchow R. Ein Fall von allgemeiner Ochronose der Knorpel und knorpelähnichlen Theile. Arch Pathol Anat 1866;37:212.

21. Osler W. Ochronosis: the pigmentation of cartilages, sclerotics, and skin in alkaptonuria. Lancet 1904; 1:10.

22. Yules JH. Ochronotic arthritis: report of a case. Bull N Engl Med Center 1957;16:168.

23. O'Brien WM, Banfield WG, Sokoloff L. Studies on the pathogenesis of ochronotic arthropathy. Arthritis Rheum 1961;4:137.

24. Carrier DA, Harris CM. Bilateral hip and bilateral knees arthroplasties in a patient with ochronotic arthropathy. Orthop Rev 1990;19:1005-9.

25. Harrold AJ. Alkaptonuric arthritis. J Bone Joint Surg 1956;38:532.

26. Hogben L, Worrall RI, Zieve I. The genetic basis of alkaptonuria. Proc R Soc Edinb (Biol) 1932;52:264.

27. Dereymaeker L, Van Parijs G, Bayart M, et al. Ochronosis and alkaptonuria: report of a new case with calcified aortic valve stenosis. Acta Cardiol 1990;45:87-92.

28. Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, Guénet JL, et al. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 1994;19:5-8.

29. Montagutelli X, Lalouette A, Coude M, Kamoun P, Forest M, Guénet JL. Aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16. Genomics 1994;19:9-11.

30. Pollak MR, Chou Y-H, Cerda JJ, et al. Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nature Genet 1993;5:201-4.

31. Garnica AD, Cerda JJ, Maenard D, et al. Alcaptonuria and sucrase-isomaltase deficiency in three offspring of a consanguineous marriage. Acta Vitaminol Enzymol 1981;3:157-69.

32. Steinmann B, Gnehm HE, Rao VH, et al. Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia. Helv Paediatr Acta 1984;39:171-86.

33. Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, et al. The molecular basis of alkaptonuria. Nature Genet 1996;14:19-24.

34. Stoner R, Blivaiss BB. Homogentisic acid metabolism: a 1,4 addition reaction to benzoquinone-1 acid with amino acids and other biological amines. Fed Proc 1965;24:656.

 

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