Temporal adaptations in the phenylalanine/tyrosine pathway and related factors during nitisinone-induced tyrosinaemia in alkaptonuria.

Ranganath, LR, Hughes, AT, Davison, AS, Khedr, M, Olsson, B, Rudebeck, M, Imrich, R, Norman, BP ORCID: 0000-0001-9293-4852, Bou-Gharios, G, Gallagher, JA ORCID: 0000-0002-0852-279X
et al (show 1 more authors) (2022) Temporal adaptations in the phenylalanine/tyrosine pathway and related factors during nitisinone-induced tyrosinaemia in alkaptonuria. Molecular genetics and metabolism. S1096-7192(22)00325-0-.

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<h4>Background</h4>Adaptations within the phenylalanine (PHE)/tyrosine (TYR) pathway during nitisinone (NIT) are not fully understood.<h4>Objective</h4>To characterise the temporal changes in metabolic features in NIT-treated patients with alkaptonuria.<h4>Patients and methods</h4>Serum (s) and 24-urine (u) homogentisic acid (sHGA, uHGA<sub>24</sub>), TYR (sTYR, uTYR<sub>24</sub>), PHE (sPHE, uPHE<sub>24</sub>), hydroxyphenylpyruvate (sHPPA, uHPPA<sub>24</sub>), hydroxyphenyllactate (sHPLA, uHPLA<sub>24</sub>) and sNIT were measured at baseline (V1) and until month 48 (V6) in 69 NIT-treated patients, recommended to reduce protein intake. The 24-h urine urea (uUREA<sub>24</sub>), creatinine (uCREAT<sub>24</sub>) and body weight were also measured. Amounts of tyrosine metabolites in total body water (TBW) were derived by multiplying the serum concentrations by 60% body weight, and sum of TBW and urine metabolites resulted in combined values (c).<h4>Results</h4>uUREA<sub>24</sub> and uCREAT<sub>24</sub> decreased between V1 and V6 during NIT, whereas body weight and sNIT increased. Linear regression coefficient between uUREA<sub>24</sub> and uCREAT<sub>24</sub> was extremely strong (R = 0.84). sPHE, TBWPHE and cPHE24 increased gradually from V1 to V6. A decrease in cTYR<sub>24</sub>/cPHE<sub>24,</sub> sTYR/sPHE and TBWTYR/TBWPHE was seen from V2 to V6. Serum, 24-urine and combined TYR, HPPA and HPLA either remained stable or decreased from V2 to V6.<h4>Discussion</h4>The gradual increase in PHE suggests adaptation to increasing TYR during NIT therapy. The decrease in protein intake resulted in decreased muscle mass and increased weight gain.<h4>Conclusion</h4>Progressive adaptation by decreasing PHE conversion to TYR occurs over time during NIT therapy. A low protein diet results in loss of muscle mass but also weight gain suggesting an increase in fat mass.

Item Type: Article
Additional Information: Source info: MGM-D-22-00117
Uncontrolled Keywords: Alkaptonuria, Homogentisic acid, Hydroxyphenyllactate, Hydroxyphenylpyruvate, Nitisinone, Phenylalanine, Tyrosinaemia, Tyrosine
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 18 Nov 2022 16:37
Last Modified: 01 Jun 2023 01:30
DOI: 10.1016/j.ymgme.2022.05.006
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166276