Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria



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.

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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
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3054359