Correspondence

Alkaptonuria

N Engl J Med 2003; 348:1408April 3, 2003

Article

To the Editor:

In alkaptonuria, discussed by Phornphutkul et al. (Dec. 26 issue),1 tissue injury is induced by a product of the oxidation of homogentisic acid (HGA) — namely, benzoquinone acetic acid (BQA). The oxidation of HGA to BQA is catalyzed by polyphenol oxidase.2 Accordingly, therapy for alkaptonuria should be aimed at reducing BQA levels through the inhibition of 4-hydroxyphenyl-pyruvate dioxygenase (i.e., with the use of nitisinone). Nitisinone can reduce HGA production while increasing levels of plasma tyrosine and phenylalanine.1 Thus, measuring the BQA level during a trial with nitisinone would be helpful. As described by Wolff et al.,2 the evaluation of plasma tyrosine and urinary HGA accounts for a reduction in HGA production, but we can only presume that the BQA level has also decreased.

Therapy should also aim to inhibit the oxidation of HGA to BQA. This could be achieved with the use of antioxidants such as ascorbic acid; reducing HGA oxidation could increase urinary excretion of HGA.3 Furthermore, ascorbic acid has been shown to inhibit HGA polyphenol oxidase, with a consequent decrease in BQA synthesis.4 Long-term clinical studies are needed to establish the exact role of antioxidant compounds in preventing or slowing the progression of alkaptonuria.

Sauro Lorenzini, B.S.
University of Siena, 53100 Siena, Italy
lorenzini@unisi.it

Alessandro Mannoni, M.D.
Azienda Sanitaria di Firenze, 50100 Florence, Italy

Enrico Selvi, M.D.
University of Siena, 53100 Siena, Italy

4 References

1. 1

   Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. N Engl J Med 2002;347:2111-2121
   Full Text | Web of Science | Medline

2. 2

   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;26:140-144
   CrossRef | Web of Science | Medline

3. 3

   Forslind K, Wollheim FA, Akesson B, Rydholm U. Alkaptonuria and ochronosis in three siblings: ascorbic acid treatment monitored by urinary HGA excretion. Clin Exp Rheumatol 1988;6:289-292
   Web of Science | Medline

4. 4

   Zannoni VG, Lomtevas N, Goldfinger S. Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 1969;177:94-105
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree that measurement of BQA in patients with alkaptonuria who are being treated with nitisinone would be of interest. However, both HGA and BQA undergo binding by connective-tissue macromolecules.1 Hence, HGA, from which all presumably toxic products derive, appears to be a reasonable marker of the efficacy of nitisinone.

The benefits of vitamin C in patients with alkaptonuria remain uncertain.2 In 1988, Forslind et al.3 concluded that “ascorbic acid is not effective in the treatment of symptomatic ochronosis.” In addition, because ascorbic acid serves as a cofactor for 4-hydroxyphenylpyruvate dioxygenase, the vitamin may increase production of HGA in alkaptonuria. Inhibition of HGA polyphenol oxidase was demonstrated with the use of 10 mM ascorbic acid,1 a concentration that is impossible to achieve in vivo. Furthermore, the large doses of ascorbic acid actually used in alkaptonuria might contribute to the formation of renal oxalate stones in patients with this disorder, who are already at increased risk for kidney stones.2 We believe that, rather than pursuing a controlled trial of ascorbic acid treatment in patients with alkaptonuria, efforts are better spent in blocking the formation of HGA itself.

Chanika Phornphutkul, M.D.
Brown University, Providence, RI 02903

Wendy J. Introne, M.D.
16 Perriwinkle Way, Webster, NY 14580

William A. Gahl, M.D., Ph.D.
National Human Genome Research Institute, Bethesda, MD 20892-1851
bgahl@helix.nih.gov

3 References

1. 1

   Zannoni VG, Lomtevas N, Goldfinger S. Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim Biophys Acta 1969;177:94-105
   CrossRef | Web of Science | Medline

2. 2

   La Du BN. Alkaptonuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 2. New York: McGraw-Hill, 2001:2109-23.
   

3. 3

   Forslind K, Wollheim FA, Akesson B, Rydholm U. Alkaptonuria and ochronosis in three siblings: ascorbic acid treatment monitored by urinary HGA excretion. Clin Exp Rheumatol 1988;6:289-292
   Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   L. Tinti, A. M. Taylor, A. Santucci, B. Wlodarski, P. J. Wilson, J. C. Jarvis, W. D. Fraser, J. S. Davidson, L. R. Ranganath, J. A. Gallagher. (2011) Development of an in vitro model to investigate joint ochronosis in alkaptonuria. Rheumatology 50:2, 271-277
   CrossRef

2. 2

   Laura Tinti, Adriano Spreafico, Daniela Braconi, Lia Millucci, Giulia Bernardini, Federico Chellini, Giovanni Cavallo, Enrico Selvi, Mauro Galeazzi, Roberto Marcolongo, James A. Gallagher, Annalisa Santucci. (2010) Evaluation of antioxiodant drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model. Journal of Cellular Physiology 225:1, 84-91
   CrossRef

3. 3

   D. Braconi, M. Laschi, L. Amato, G. Bernardini, L. Millucci, R. Marcolongo, G. Cavallo, A. Spreafico, A. Santucci. (2010) Evaluation of anti-oxidant treatments in an in vitro model of alkaptonuric ochronosis. Rheumatology 49:10, 1975-1983
   CrossRef