Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Ranganath, L.; Milan, Anna M.; Hughes, Andrew T.; Davison, Andrew S.; Khedr, Milad; Norman, Brendan P.; Bou‐Gharios, George; Gallagher, James A.; Imrich, Richard; Arnoux, Jean Baptiste; Rudebeck, Mattias; Olsson, Birgitta

doi:10.1038/s41598-022-20424-z

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…Urine metabolite data from the time points in patients on nitisinone (visits 4 and 6 for treated patients) were compared against previous data obtained from the same samples by quantitative LC/MS [ 12 ]. The relationship between individual urine metabolites and degree of hypertyrosinaemia was investigated by comparing urine data with the corresponding serum tyrosine concentration (sTYR: µmol/L) using thresholds applied in previous analyses: <701, 701–900, 900–1100 and >1100 [ 31 ]. A total of 15 urine metabolites showed statistically significant differences between sTYR thresholds ( Figure 3 and Table S3 ).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

et al. 2022

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Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homogentisic acid (HGA), the active molecule in this disease. The aim of this research was to study the phe-tyr metabolic pathway and whether the metabolites upstream of HGA, increased in nitisinone-treated patients, also undergo phase 1 and 2 biotransformation reactions. Metabolomic analyses were performed on serum and urine from patients partaking in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the same patients at baseline (pre-nitisinone) then at 24 and 48 months on nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients N = 45 serum; 50 urine). Targeted feature extraction was performed to specifically mine data for the entire complement of theoretically predicted phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to phenylalanine-derived metabolites with known increases in phenylketonuria. In total, we observed 13 phase 1 and 2 biotransformation products from phenylalanine through to HGA. Each of these products were observed in urine and two were detected in serum. The derivatives of the metabolites upstream of HGA were markedly increased in urine of nitisinone-treated patients (fold change 1.2–16.2) and increases in 12 of these compounds were directly proportional to the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with serum tyrosine = 0.2–0.7). Increases in the urinary phenylalanine metabolites were also observed across consecutive visits in the treated group. Nitisinone treatment results in marked increases in a wider network of phe-tyr metabolites than shown before. This network comprises alternative biotransformation products from the major metabolites of this pathway, produced by reactions including hydration (phase 1) and bioconjugation (phase 2) of acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We propose that these alternative routes of phe-tyr metabolism, predominantly in urine, minimise tyrosinaemia as well as phenylalanaemia.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

et al. 2022

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“…Based on SONIA 2 results, where no dietetic management to enforce low-protein diet was used, approximately 15% of AKU patients on nitisinone develop keratopathy as an expected side effect (Ranganath et al 2020b). Therefore, monitoring of tyrosine plasma levels and low-protein diet has been recommended to maintain tyrosine plasma levels between 500 and 800 µmol/l, the range considered relatively safe in terms of the keratopathy risk (Ranganath et al 2022b). In the case of the keratopathy development, nitisinone treatment must be stopped and reintroduced only after symptoms have disappeared.…”

Section: Mechanism Of Nitisinone Actionmentioning

confidence: 99%

“…The rationale was that low-protein intake could delay clinical progression by lowering of HGA concentration. Currently, with the treatment available, the low-protein diet aims to minimize nitisinoneinduced hypertyrosinemia to minimize the risk of keratopathy; however, the low-protein diet is poorly tolerated by majority of AKU patients (Ranganath et al 2022b). The low compliance with low-protein diet in AKU patients often leads to increased tyrosine concentrations above 800 µmol/l increasing the risk of keratopathy development and therapy interruptions (Ranganath et al 2022c).…”

Section: Alkaptonuria Dietary Measures and Nutritional Therapymentioning

confidence: 99%

Nutritional interventions for patients with alkaptonuria: A minireview

Imrich

Zaťková

Lukáčová

et al. 2023

Endocrine Regulations

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Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.

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“…Nitisinone is a benzoylcyclohexane-1,3-dione that reversibly inhibits the enzyme before HGD, the 4-hydroxyphenylpyruvate dioxygenase (HPPD), hence reducing the production of homogentisic acid ( Figure 1 ). The effects of nitisinone treatment have been well characterized from a metabolomic point of view [ 23 , 26 , 27 , 28 ]. The main side effect of nitisinone administration is the elevation of plasma tyrosine levels analogous to tyrosinemia type 2, which might cause eye pathology in AKU patients [ 29 ]; moreover, the effect of nitisinone on already-developed ochronosis is limited [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Untargeted NMR Metabolomics Reveals Alternative Biomarkers and Pathways in Alkaptonuria

Grasso

Geminiani

Galderisi

et al. 2022

IJMS

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Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment.

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Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Cited by 6 publications

References 32 publications

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

Nutritional interventions for patients with alkaptonuria: A minireview

Untargeted NMR Metabolomics Reveals Alternative Biomarkers and Pathways in Alkaptonuria

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