Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the
homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of
homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called
ochronosis. As a result, severe
arthropathy of large joints and
spondyloarthropathy with frequent fractures, ligament
ruptures, and
osteoporosis develops in AKU patients. Since 2020, the first-time treatment with
nitisinone has become available in the European Union.
Nitisinone significantly reduces HGA production and arrests
ochronosis in AKU patients. However, blocking of the
tyrosine metabolic pathway by the
drug leads to
tyrosine plasma and tissue concentrations increase. The
nitisinone-induced
hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall
protein intake reduces the risk of the keratopathy during
nitisinone-induced
hypertyrosinemia in AKU patients. The
low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and
weight gain due to increased energy intake from
carbohydrates and
fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to
nitisinone-induced
hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.