Alkaptonuria: Leading to the Treasure in Exceptions

Abstract

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.

Redox proteomics gives insights into the role of oxidative stress in alkaptonuria

“…More recently, also on the basis of what was evaluated in an AKU mouse model [38,39], two new clinical trials, one in the USA and another in Europe, have been undertaken to evaluate the use of nitisinone in treating AKU and ochronoticosteo arthropathy. Although care should be taken about the right dose of drug to be administered to AKU patients and the most proper age to start the treatment [40], and also considering the fact that obviously the drug is not devoid of adverse effects [37], at the moment nitisinone is the most promising drug for the treatment of AKU.…”

Treatment of Nongout Joint Deposition Diseases: An Update

“…Yet, it remains debated especially since the only available randomized controlled trial including 40 patients, though well-tolerated, could not show any efficacy on the primary and secondary clinical outcomes [ 62 ]. However, some patients experienced clear improvement in joint symptoms and some authors suggest the need for further trials on nitisinone [ 63 ]. The study also suggested the importance of physical medicine.…”