Alkaptonuria: Leading to the Treasure in Exceptions
The brilliant geneticist, William Bateson, a formidable English experimentalist, was the first to recognize the nature of the “inborn” in Archibald Garrod’s errors of metabolism. Bateson’s advice to young scientists: “Treasure your exceptions!” summarizes much of the vigorous empiricism associated with the study of rare disorders.
The first inborn error of metabolism to be so recognized was alkaptonuria, and it is only recently that a proper understanding of this condition as a disease, rather than a biochemical curiosity, has emerged. Abnormal excretion of the reactive tyrosine metabolite, homogentisic acid, not only provides a tangible biomarker of alkaptonuria, but also a focus for detailed mechanistic understanding.
Currently, there is no proven treatment for alkaptonuria but emergence of orphan drug legislation internationally has promoted the licensing of nitisinone (Orfadin™) for an equally rare disorder of tyrosine metabolism – hereditary tyrosinaemia type 1. Nitisinone, a triketone competitive inhibitor of a proximal step leading to the formation of homogentisic acid, has potent therapeutic effects in hereditary tyrosinemia and rapidly ameliorates the primary biochemical abnormality in patients with alkaptonuria.
Here, we discuss the context in which nitisinone should be further explored for the treatment of alkaptonuria. This exceptional disease is a paradigm case, which opens up unusual opportunities for basic and applied research. In modern times, it also shows how the conflation of orphan drug legislation and the emerging power and commitment of patient organizations can synergize effectively to advance basic research and therapeutic development in ultra-orphan diseases.
KeywordsFabry Disease Inborn Error Homogentisic Acid Orphan Medicinal Product Acute Porphyria
- Bacon F (1620) Francis Bacon: the new Organon, or true directions for the interpretation of nature (Novum Organum). In: Jardine L, Silverthorne M (eds) (2000) Aphorisms, Book II, Chap. 29. Cambridge University Press, Cambridge, pp 102–221Google Scholar
- Bateson W (1908) The methods and scope of genetics, Inaugural Lecture delivered 23 Oct 1908. Cambridge University Press, CambridgeGoogle Scholar
- Bateson W (1913) Mendel’s principles of heredity, Chaps 4, 5 and 12. Cambridge University Press, Cambridge, pp. 77–87, 88–106, 212–216, 221Google Scholar
- Beadle GW (1958) Genes and chemical reactions in Neurospora. In: Nobel Lectures including presentation speeches and laureates’ biographies. Physiology or Medicine, 1942–1962. Elsevier, Amsterdam, pp 587–597Google Scholar
- Dolgin E (2010) Big pharma moves from ‘blockbusters’ to ‘niche busters’. Nat Med 16:837Google Scholar
- European Committee for Orphan Medicinal Products (2011) European regulation on orphan medicinal products: 10 years of experience and future perspectives. Nat Rev Drug Discov 10:341–349Google Scholar
- Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S (1996) The molecular basis of alkaptonuria. Nat Genet 14:19–24. http://www.findakure.org/contact_us.php. Accessed 31 May 2011
- Garrod AE (1902) The incidence of alkaptonuria: a study in chemical individuality. Lancet 2:1616–1620Google Scholar
- Garrod AE (1909) Inborn errors of metabolism; the Croonian Lectures delivered before the Royal College of Physicians of London, in June, 1908. Henry Frowde, Hodder and Stoughton, Oxford University Press, LondonGoogle Scholar
- Garrod AE (1924) The debt of science to medicine, Harveian oration, before the Royal College of Physicians on St Luke’s Day 1924. Clarendon, Oxford University, 30pGoogle Scholar
- Garrod AE (1931) The inborn factors in disease. Clarendon, Oxford University, London, p 65Google Scholar
- Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O’Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab, E-pub, May, 6Google Scholar
- Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL (1998) From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4- trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis 42:498–506CrossRefGoogle Scholar
- Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In:Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The metabolic and molecular bases of inherited disease (OMMBID), Chap 79, 8th edn. McGraw- Hill, New York, pp 1777–1805. http://www.ommbid.com. Modified 2002
- Miyamoto BE, Kakkis ED (2011) The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases. Orphanet J Rare Dis 6:49Google Scholar
- Saunders ER, Bateson W (1902) The facts of Heredity in the light of Mendel’s discovery. Report of the Evolution Committee of the Royal Society 1:135Google Scholar
- Saunders ER, Punnett RC, Bateson W (1905) Further experiments on inheritance in sweet peas and stocks. Proc R Soc Lond B 77:236–238Google Scholar
- Saunders ER, Punnett RC, Bateson W (1906) Experimental studies in the physiology of heredity. Report to the Evolution Committee of the Royal Society 3:2–11Google Scholar
- Saunders ER, Punnett RC, Bateson W (1908) Experimental studies in the physiology of heredity. Report to the Evolution Committee of the Royal Society 4:2–5Google Scholar
- Tatum EL (1958) A case history in biological research. In: Nobel Lectures including presentation speeches and laureates’ biographies. Physiology or Medicine, 1942–1962. Elsevier, Amsterdam. http://nobelprize.org/nobel_prizes/medicine/laureates/1958/. Accessed 9 July 2011
- Wheldale M (1915) The anthocyanin pigments of plants, 1st edn. Cambridge University Press, CambridgeGoogle Scholar
- Wills R (1847) The works of W. Harvey (Transl). Sydenham Society, London, p 616Google Scholar