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J Clin Pathol doi:10.1136/jclinpath-2012-200877
  • Acp best practice

Recent advances in management of alkaptonuria (invited review; best practice article)

  1. James A Gallagher2
  1. 1Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK
  2. 2Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, Institute for Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
  1. Correspondence to Prof L R Ranganath, Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, 4th Floor Duncan Building, Daulby St, Liverpool L7 8XP, UK; lrang{at}liv.ac.uk
  • Received 21 December 2012
  • Accepted 28 January 2013
  • Published Online First 13 March 2013

Abstract

Alkaptonuria (AKU) is an autosomal recessive condition arising as a result of a genetic deficiency of the enzyme homogentisate 1,2 dioxygenase and characterised by accumulation of homogentisic acid (HGA). Oxidative conversion of HGA leads to production of a melanin-like polymer in a process termed ochronosis. The binding of ochronotic pigment to the connective tissues of the body leads to multisystem disorder dominated by premature severe spondylo-arthropathy. Other systemic features include stones (renal, prostatic, salivary, gall bladder), renal damage/failure, osteopenia/fractures, ruptures of tendons/muscle/ligaments, respiratory compromise, hearing loss and aortic valve disease. Detection of these features requires systematic investigation. Treatment in AKU patients is palliative and unsatisfactory. Ascorbic acid, low protein diet and physiotherapy have been tried but do not alter the underlying metabolic defect. Regular surveillance to detect and treat complications early is important. Palliative pain management is a crucial issue in AKU. Timely spinal surgery and arthroplasty are the major treatment approaches at present. A potential disease modifying drug, nitisinone, inhibits 4-hydroxy-phenyl-pyruvate-dioxygenase and decreases formation of HGA and could prevent or slow the progression of disease in AKU. If nitisinone therapy is able to complement the biochemical ‘cure’ with improved outcomes, it will completely alter the way we approach the management of this disease. Greater efforts to improve recognition and registration of the disease will be worthwhile. Improved laboratory diagnostics to monitor the tyrosine metabolic pathway that includes plasma metabolites including tyrosine to monitor efficacy, toxicity and safety postnitisinone will also be required.


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