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

• Published in: Molecular genetics and metabolism 2022-06
• Main Authors: Ranganath, L.R., Hughes, A.T., Davison, A.S., Khedr, M., Olsson, B., Rudebeck, M., Imrich, R., Norman, B.P., Bou-Gharios, G., Gallagher, J.A., Milan, A.M.
• Format: Article
• Language: English
• Subjects: Alkaptonuria; Homogentisic acid; Hydroxyphenyllactate; Hydroxyphenylpyruvate; Nitisinone; Phenylalanine; Tyrosinaemia; Tyrosine
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2022.05.006

Adaptations within the phenylalanine (PHE)/tyrosine (TYR) pathway during nitisinone (NIT) are not fully understood. To characterise the temporal changes in metabolic features in NIT-treated patients with alkaptonuria. Serum (s) and 24-urine (u) homogentisic acid (sHGA, uHGA24), TYR (sTYR, uTYR24), PHE (sPHE, uPHE24), hydroxyphenylpyruvate (sHPPA, uHPPA24), hydroxyphenyllactate (sHPLA, uHPLA24) 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 (uUREA24), creatinine (uCREAT24) 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). uUREA24 and uCREAT24 decreased between V1 and V6 during NIT, whereas body weight and sNIT increased. Linear regression coefficient between uUREA24 and uCREAT24 was extremely strong (R = 0.84). sPHE, TBWPHE and cPHE24 increased gradually from V1 to V6. A decrease in cTYR24/cPHE24, 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. 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. 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. •Tyrosinaemia decreased over time in nitisinone-receiving patients.•No apparent increase in HPLA pathway was seen over time during nitisinone therapy.•A progressive increase in PHE over time potentially limiting tyrosinaemia was seen.•A biochemical state of relative phenylalaninaemia was seen during nitisinone therapy.•Despite decrease in muscle mass there was weight gain over time.