Nitisinone causes acquired tyrosinosis in alkaptonuria

For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence sugg...

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Bibliographic Details
Published in:Journal of inherited metabolic disease 2020-09, Vol.43 (5), p.1014-1023
Main Authors: Khedr, Milad, Cooper, Maggie S., Hughes, Andrew T., Milan, Anna M., Davison, Andrew S., Norman, Brendan P., Sutherland, Hazel, Jarvis, Jonathan C., Fitzgerald, Richard, Markinson, Louise, Psarelli, Eftychia‐Eirini, Ghane, Parisa, Deutz, Nicolaas E. P., Gallagher, James A., Ranganath, Lakshminarayan R.
Format: Article
Language:English
Subjects:
Alkaptonuria
Cognitive ability
nitisinone
Phenylalanine
pool size
tyrosinaemia
Tyrosine
tyrosinosis
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Summary:For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC‐induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight‐threatening keratopathy. In the context of a non‐lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l‐[13C9]tyrosine and l‐[d8]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P 
ISSN:0141-8955
1573-2665
DOI:10.1002/jimd.12229