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.