Abstract
Increased circulating homogentisic acid in body fluids occurs in alkaptonuria (AKU) due to lack of enzyme homogentisate dioxygenase leading in turn to conversion of HGA to a pigmented melanin-like polymer, known as ochronosis. The tissue damage in AKU is due to ochronosis. A potential treatment, a drug called nitisinone, to decrease formation of HGA is available. However, deploying nitisinone effectively requires its administration at the most optimal time in the natural history. AKU has a long apparent latent period before overt ochronosis develops. The rate of change of ochronosis and its consequences over time following its recognition has not been fully described in any quantitative manner. Two potential tools are described that were used to quantitate disease burden in AKU. One tool describes scoring the clinical features that includes clinical assessments, investigations and questionnaires in 15 patients with AKU. The second tool describes a scoring system that only includes items obtained from questionnaires in 44 people with AKU. Analysis of the data reveals distinct phases of the disease, a pre-ochronotic phase and an ochronotic phase. The ochronotic phase appears to demonstrate an earlier slower progression followed by a rapidly progressive phase. The rate of change of the disease will have implications for monitoring the course of the disease as well as decide on the most appropriate time that treatment should be started for it to be effective either in prevention or arrest of the disease.
Similar content being viewed by others
References
Beck M (2006) The Mainz Severity Score Index (MSSI): development and validation of a system for scoring the signs and symptoms of Fabry disease. Acta Paediatr Suppl 451:43–46
Cox TF, Ranganath LR (2011) A quantitative assessment of alkaptonuria: testing the reliability of two disease severity scoring systems. JIMD (in press)
Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D et al (1996) The molecular basis of alkaptonuria. Nat Genet 14:19–24
Goodfellow RJ, Schwartz J, Leya F (2005) Black aorta: a rare finding at aortic valve replacement. J Invasive Cardiol 17:165–167
Grigg OA, Farewell VT, Spiegelhalter DJ (2003) Use of risk-adjusted CUSUM and RSPRT charts for monitoring in medical contexts. Stat Methods Med Res 12:147–170
Helliwell TR, Gallagher JA, Ranganath L (2008) Alkaptonuria - a review of surgical and autopsy pathology. Histopathol 53:503–512
LaDu BN (2001) Alkaptonuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The metabolic and molecular basis of inherited disease, vol. 2, 8th edn. McGraw-Hill, New York, pp 2109–2123
O’Brien WM, La Du BN, Bunim JJ (1963) Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy: review of world literature (1584–1962). Am J Med 34:813–838
Phornphutkul C, Introne WJ, Perry MB et al (2002) Natural history of alkaptonuria. N Engl J Med 347:2111–2121
Suwannarat P, O’Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA (2005) Use of nitisinone in patients with alkaptonuria. Metab Clin Exp 54:719–728
Wilke A, Steverding D (2009) Ochronosis as an unusual cause of valvular defect: a case report. J Med Case Rep 3:9302
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by: Ertan Mayatepek
Competing interest: None declared.
Rights and permissions
About this article
Cite this article
Ranganath, L.R., Cox, T.F. Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit Metab Dis 34, 1141–1151 (2011). https://doi.org/10.1007/s10545-011-9374-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-011-9374-9