Hughes, Juliette H 
ORCID: 0000-0001-6155-4136, Wilson, Peter JM, Sutherland, Hazel, Judd, Shirley, Hughes, Andrew T, Milan, Anna M ORCID: 0000-0002-0452-2338, Jarvis, Jonathan C, Bou-Gharios, George, Ranganath, Lakshminarayan R and Gallagher, James A
(2020)
Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.
JOURNAL OF INHERITED METABOLIC DISEASE, 43 (2).
pp. 259-268.
|
Text
Hughes_et_al-2019-Journal_of_Inherited_Metabolic_Disease - pre-print.pdf - Author Accepted Manuscript Download (1MB) | Preview |
Abstract
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. 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 >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813 μmol/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 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | alkaptonuria, nitisinone, phenylalanine, protein, tyrosinemia, tyrosine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 12 Sep 2019 10:29 |
| Last Modified: | 19 Jan 2023 00:26 |
| DOI: | 10.1002/jimd.12172 |
| Open Access URL: | https://doi.org/10.1002/jimd.12172 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3054359 |
Dimensions
Dimensions
