Clinical and biochemical assessment of depressive symptoms in patients with Alkaptonuria before and after two years of treatment with nitisinone

Davison, Andrew S.; Harrold, Joanne A.; Hughes, Georgina; Norman, Brendan P.; Devine, J.; Usher, J.; Hughes, Andrew T.; Khedr, Milad; Gallagher, James A.; Milan, Anna M.; J.C.G., Halford; Ranganath, L.

doi:10.1016/j.ymgme.2018.07.008

Cited by 16 publications

(21 citation statements)

References 34 publications

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“…In this study no direct measurements of dopamine or serotonin were made in brain tissue, but they concluded that slower learning and cognitive difference in the mice studied were caused by HT1 and not by the treatment with nitisinone. We have also reported an increase in a urinary dopamine metabolite (3-MT) following nitisinone treatment in AKU patients (Davison et al 2018a , b ) and are in agreement that this is likely to reflect a change in peripheral metabolism of catecholamines.…”

Section: Discussionsupporting

confidence: 80%

“…In AKU there is uncertainty about whether the hypertyrosinaemia may alter neurotransmitter metabolism and specifically whether this may lead to depression or altered cognition through the mechanisms detailed above. Recently Davison et al ( 2018a ) concluded that treatment with nitisinone is unlikely to cause depression in patients with AKU in a study that assessed urinary neurotransmitter metabolite concentrations, in a cohort of patients with AKU. This study did show an increase in urinary 3-methoxytyramine (3-MT, dopamine metabolite) and a decrease in urinary 5-hydroxyindole acetic acid (serotonin metabolite) following treatment.…”

Section: Introductionmentioning

confidence: 99%

“…1), is being evaluated as a potential treatment (Ranganath et al 2016; Milan et al 2017; SONIA-2—ClinicalTrials.gov Identifier: NCT01916382). This drug acts to move the metabolic block in the tyrosine metabolic pathway resulting in a marked reduction in the circulating concentration of HGA and a consequential significant increase in tyrosine, creating a so called ‘pseudo type-3 Tyrosinaemia’ picture (Suwannarat et al 2005; Introne et al 2011; Olsson et al 2015; Ranganath et al 2016; Milan et al 2017; Davison et al 2018a, b, c). Hypertyrosinaemia has also been well documented in patients with Hereditary Tyrosinaemia type-1 (HT1, OMIM 276700) that are treated with nitisinone (Lindstedt et al 1992; Zeybek and Zubarioglu 2017; van Ginkel et al 2017).…”

Section: Introductionmentioning

confidence: 99%

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Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging

et al. 2019

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Objective Nitisinone induced hypertyrosinaemia is a concern in patients with Alkaptonuria (AKU). It has been suggested that this may alter neurotransmitter metabolism, specifically dopamine and serotonin. Herein mass spectrometry imaging (MSI) is used for the direct measurement of 2,4-diphenyl-pyranylium tetrafluoroborate (DPP-TFB) derivatives of monoamine neurotransmitters in brain tissue from a murine model of AKU following treatment with nitisinone. Methods Metabolite changes were assessed using MSI on DPP-TFB derivatised fresh frozen tissue sections directing analysis towards primary amine neurotransmitters. Matched tail bleed plasma samples were analysed using LC-MS/MS. Eighteen BALB/c mice were included in this study: HGD −/− (n = 6, treated with nitisinone – 4 mg/L, in drinking water); HGD −/− (n = 6, no treatment) and HGD +/− (n = 6, no treatment). Results Ion intensity and distribution of DPP-TFB derivatives in brain tissue for dopamine, 3-methoxytyramine, noradrenaline, tryptophan, serotonin, and glutamate were not significantly different following treatment with nitisinone in HGD −/− mice, and no significant differences were observed between HGD −/− and HGD +/− mice that received no treatment. Tyrosine (10-fold in both comparisons, p = 0.003; [BALB/c HGD −/− (n = 6) and BALB/c HGD +/− (n = 6) (no treatment) vs. BALB/c HGD −/− (n = 6, treated)] and tyramine (25-fold, p = 0.02; 32-fold, p = 0.02) increased significantly following treatment with nitisinone. Plasma tyrosine and homogentisic acid increased (9-fold, p = < 0.0001) and decreased (9-fold, p = 0.004), respectively in HGD −/− mice treated with nitisinone. Conclusions Monoamine neurotransmitters in brain tissue from a murine model of AKU did not change following treatment with nitisinone. These findings have significant implications for patients with AKU as they suggest monoamine neurotransmitters are not altered following treatment with nitisinone.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging

et al. 2019

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“…Nitisinone therapy in AKU and HT1 has long been associated with altered‐tyrosine metabolism, and so can be considered a “targeted effect.” More recently off targets effects of nitisinone have been reported due to its impact on tryptophan metabolism. A decrease in 5‐hydroxyindoleacetic acid (serotonin metabolite) has been reported in the cerebral spinal fluid and urine of patients with HT1 and AKU, respectively. Serum tryptophan itself has been shown not to change following treatment with nitisinone; in contrast, urinary tryptophan has been shown to decrease .…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms have been proposed for this including altered metabolism of the monoamine neurotransmitters . Davison et al demonstrated in a cohort of AKU patients that nitisinone therapy resulted in altered urinary excretion of dopaminergic and serotoninergic neurotransmitter metabolites. However, these findings are limited as they are not a direct reflection of neurotransmitter metabolism in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC‐QTOF‐MS

et al. 2019

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Background The homogentisic acid‐lowering therapy nitisinone is being evaluated for the treatment of alkaptonuria (AKU) at the National Centre for AKU. Beyond hypertyrosinemia, the wider metabolic consequences of its use are largely unknown. The aim of this work was to evaluate the impact of nitisinone on the serum metabolome of patients with AKU after 12 and 24 months of treatment. Methods Deproteinized serum from 25 patients with AKU (mean age[±SD] 51.1 ± 14.9 years, 12 male) was analyzed using the 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time‐of‐flight mass spectrometry (Agilent, UK). Raw data were processed using a batch targeted feature extraction algorithm and an accurate mass retention time database containing 469 intermediary metabolites (MW 72‐785). Matched entities (±10 ppm theoretical accurate mass and ±0.3 minutes retention time window) were filtered based on their frequency and variability (<25% CV) in group quality control samples, and repeated measures statistical significance analysis with Benjamini‐Hochberg false discovery rate adjustment was used to assess changes in metabolite abundance. Results Eight metabolites increased in abundance (log 2 fold change [FC] 2.1‐15.2, P < .05); 7 of 8 entities were related to tyrosine metabolism, and 13 decreased in abundance (log 2 FC 1.5‐15.5, P < .05); including entities related to tyrosine (n = 2), tryptophan (n = 3), xanthine (n = 2), and citric acid cycle metabolism (n = 2). Conclusions Evaluation of the serum metabolome of patients with AKU showed a significant difference in the abundance of several metabolites following treatment with nitisinone, including a number that have not been previously reported; several of these were not related to the tyrosine metabolic pathway. Synopsis Nitisinone therapy has a significant impact on several metabolites beyond the tyrosine metabolic pathway, several of which appear to be related to the redox state of the cell.

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Nitisinone causes acquired tyrosinosis in alkaptonuria

Khedr

Cooper

Hughes

et al. 2020

J of Inher Metab Disea

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For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC‐induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight‐threatening keratopathy. In the context of a non‐lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l‐[13C9]tyrosine and l‐[d8]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P < .001), suggesting that NTBC increases tyrosine not just in serum but also in tissues (ie, acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC‐related acquired tyrosinosis which should be overcome to ensure the safe use of NTBC in AKU.

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Clinical and biochemical assessment of depressive symptoms in patients with Alkaptonuria before and after two years of treatment with nitisinone

Cited by 16 publications

References 34 publications

Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging

Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging

Evaluation of the serum metabolome of patients with alkaptonuria before and after two years of treatment with nitisinone using LC‐QTOF‐MS

Nitisinone causes acquired tyrosinosis in alkaptonuria

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