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. 2022 Aug 22;12(8):772.
doi: 10.3390/metabo12080772.

Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment

Lakshminarayan R Ranganath  1   2 , Anna M Milan  1 , Andrew T Hughes  1 , Andrew S Davison  1 , Milad Khedr  1 , Richard Imrich  3 , Mattias Rudebeck  4 , Birgitta Olsson  5 , Brendan P Norman  2 , George Bou-Gharios  2 , James A Gallagher  2
Affiliations

Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment

Lakshminarayan R Ranganath et al. Metabolites. .

Abstract

Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and the influence of gender in NIT-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24 h urine collected from patients treated with NIT during a 4-year randomized study in NIT vs. no-treatment controls (SONIA 2; Suitability Of Nitisinone In Alkaptonuria 2; EudraCT no. 2013-001633-41) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), TYR, PHE, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine in the NIT-group. All statistical analyses were post hoc. Keratopathy occurred in 10 out of 69 AKU patients, eight of them male. Thirty-five sampling points (serum and 24 h urine) were analysed in patients experiencing KP and 272 in those with no-KP (NKP) during NIT therapy. The KP group had a lower HPLA/TYR ratio and a higher TYR/PHE ratio compared with the NKP group (p < 0.05 for both). There were 24, 45, 100 and 207 sampling points (serum and 24 h urine) in the NIT group which were pre-NIT female, pre-NIT male, NIT female and NIT male, respectively. The PHE/TYR ratio and the HPLA/TYR ratio were lower in males (p < 0.001 and p < 0.01, respectively). In the KP group and in the male group during NIT therapy, adaptive responses to minimise TYR formation were impaired compared to NKP group and females, respectively.

Keywords: alkaptonuria; homogentisic acid; hydroxyphenyllactate; hydroxyphenylpyruvate; keratopathy; phenylalanine; sex; tyrosinaemia.

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Conflict of interest statement

L.R.R. received fees for lectures and consultations from Swedish Orphan Biovitrum; M.R. and B.O. are shareholders and were employees of Swedish Orphan Biovitrum (Sobi) at the time of the initial study. All other authors do not have any competing interests to declare. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Changes in sTYR and uTYR24, sPHE and uPHE24, and sHPLA and uHPLA24 in the nitisinone group of the SONIA 2. (p-values indicated for comparison between keratopathy and no-keratopathy sampling points where statistical significance was achieved; keratopathy sampling points n = 35; no-keratopathy sampling points n = 272) (data shown as boxplots with median) (statistical significance p expressed * < 0.05, ** < 0.01, and *** < 0.001 respectively).
Figure 2
Figure 2
Changes in sTYR/sPHE & uTYR24/uPHE24, and sHPLA/sTYR & uHPLA24/uTYR24 in the nitisinone group of the SONIA 2. (p-values indicated for comparison between keratopathy and no-keratopathy sampling points where statistical significance was achieved; keratopathy sampling points n = 35; no-keratopathy sampling points n = 272 (data shown as boxplots with median) (statistical significance p expressed * < 0.05, ** < 0.01 and *** < 0.001, respectively).
Figure 3
Figure 3
Changes in sTYR and uTYR24 and sPHE and uPHE24, in the nitisinone group of the SONIA 2. (p-values indicated for comparison between female pre-nitisinone (n = 24), male pre-nitisinone (n = 45), female nitisinone (n = 120), male pre-nitisinone (n = 225), sampling points where statistical significance was achieved) (data shown as boxplots with median) (statistical significance p expressed * < 0.05, ** < 0.01 and *** < 0.001, respectively).
Figure 4
Figure 4
Changes in sTYR/sPHE and uTYR24/uPHE24, and sHPLA/sTYR and uHPLA24/uTYR24, in the nitisinone group of the SONIA 2. (p-values indicated for comparison between female pre-nitisinone (n = 24), male pre-nitisinone (n = 45), female nitisinone (n = 120), male pre-nitisinone (n = 225), sampling points where statistical significance was achieved) (data shown as boxplots with median) (statistical significance p expressed * < 0.05, ** < 0.01 and *** < 0.001, respectively).
Figure 5
Figure 5
(A,B) A cartoon representation of changing relationships between PHE, TYR, HPPA and HPLA during NIT therapy. In A, the figure highlights the state of the pathway in NKP group, showing lesser conversion of PHE to TYR (solid black arrow) inhibited more by TYR (more prominent curved red arrow), and similarly more conversion of HPPA to HPLA (a straight solid red arrow) as well as lesser conversion from HPPA to TYR (a straight black arrow). In B, the figure highlights the state of the pathway in the KP group, showing greater conversion of PHE to TYR (thin solid black arrow) inhibited less by TYR (less prominent curved red arrow), as well as lesser conversion of HPPA to HPLA (a straight solid red arrow) and more conversion from HPPA to TYR (a straight black arrow).
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