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Hughes, JH, Wilson, PJM, Sutherland, H, Judd, S, Hughes, AT, Milan, AM, Jarvis, JC, Bou-Gharios, G, Ranganath, LR and Gallagher, JA (2020) Dietary restriction of tyrosine and phenylalanine lowers tyrosinaemia associated with nitisinone therapy of alkaptonuria. Journal of Inherited Metabolic Disease. pp. 1-10. ISSN 0141-8955
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Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.pdf - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview |
Abstract
BACKGROUND: Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. METHODS: Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. RESULTS: Elevated tyrosine (813μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3μmol/L, 274.8μmol/L and 144.3μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3μmol/L, 530.2μmol/L and 656.2μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (p=0.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700μmol/L. CONCLUSION: Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinaemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
| Item Type: | Article |
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| Uncontrolled Keywords: | 1103 Clinical Sciences |
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine |
| Divisions: | Sport & Exercise Sciences |
| Publisher: | Wiley |
| Related URLs: | |
| Date Deposited: | 29 Jan 2020 15:21 |
| Last Modified: | 04 Sep 2021 08:01 |
| DOI or ID number: | 10.1002/jimd.12172 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/12143 |
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