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,
Anna M. Milan,
Andrew T. Hughes,
Andrew S. Davison,
Milad Khedr,
Richard Imrich,
Mattias Rudebeck,
Birgitta Olsson,
Brendan P. Norman,
George Bou-Gharios,
James A. Gallagher
Affiliations
Lakshminarayan R. Ranganath
Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, Liverpool L7 8XP, UK
Anna M. Milan
Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, Liverpool L7 8XP, UK
Andrew T. Hughes
Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, Liverpool L7 8XP, UK
Andrew S. Davison
Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, Liverpool L7 8XP, UK
Milad Khedr
Departments of Clinical Biochemistry and Metabolic Medicine, Liverpool University Hospitals NHS Foundation Trusts, Liverpool L7 8XP, UK
Richard Imrich
Biomedical Research Centre, Slovak Academy of Sciences, 831 01 Bratislava, Slovakia
Mattias Rudebeck
OnPoint Science AB, 111 29 Stockholm, Sweden
Birgitta Olsson
Garriguella AB, 179 62 Ekerö, Sweden
Brendan P. Norman
William Henry Duncan Building, Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK
George Bou-Gharios
William Henry Duncan Building, Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK
James A. Gallagher
William Henry Duncan Building, Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK
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 p 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.