Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient

Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features.

BackgroundAlkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment.MethodsAKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score.Results65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features.ConclusionsPCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics