Suitability of nitisinone for alkaptonuria

Abstract

In many, but not all, genetic metabolic conditions, biochemical markers are used in the diagnosis and monitoring of patients. However, these markers are not always relevant for the pathogenesis of the respective conditions. For example, in the classical urea cycle disorder citrullinaemia type 1, 1 Diez-Fernandez C Rüfenacht V Häberle J Mutations in the human argininosuccinate synthetase (ASS1) gene, impact on patients, common changes, and structural considerations. Hum Mutat. 2017; 38: 471-484 Crossref PubMed Scopus (30) Google Scholar the metabolite citrulline, an amino acid, is greatly elevated in the blood and urine of affected patients but has no known role in the pathogenesis of the condition (but rather the accompanying hyperammonaemia). In other conditions, an abnormal metabolite is crucial for developing disease; for example, the phenolic acid homogentisic acid is markedly elevated in the blood and urine in alkaptonuria, a disorder of phenylalanine and tyrosine degradation. 2 Phornphutkul C Introne WJ Perry MB et al. Natural history of alkaptonuria. N Engl J Med. 2002; 347: 2111-2121 Crossref PubMed Scopus (443) Google Scholar , 3 Ranganath LR Cox TF Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit Metab Dis. 2011; 34: 1141-1151 Crossref PubMed Scopus (57) Google Scholar Importantly, this metabolite is not only elevated but also considered to be central to the many complications of alkaptonuria, which mainly occur in adulthood. Unfortunately, once these complications develop, the most prominent of which are damage to ochronotic tissue resulting in premature spondyloarthritis, tendon ruptures, cardiac valve disease, and nephropathy, they are irreversible. Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trialNitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. Full-Text PDF