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...

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Bibliographic Details
Published in:JIMD Reports, Volume 24 Volume 24, 2015-01, Vol.24, p.45-50
Main Authors: Keenan, Craig M, Preston, Andrew J, Sutherland, Hazel, Wilson, Peter J, Psarelli, Eftychia E, Cox, Trevor F, Ranganath, Lakshminarayan R, Jarvis, Jonathan C, Gallagher, James A
Format: Article
Language:English
Subjects:
Homogentisic Acid
Lifetime Treatment
Tibial Plateau
Tibiofemoral Joint
Tyrosinaemia Type
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Summary: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.
ISSN:2192-8304
2192-8312
DOI:10.1007/8904_2015_437