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.