Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria

Ranganath, L.; Milan, Anna M.; Hughes, Andrew T.; Khedr, Milad; Davison, Andrew S.; Shweihdi, Ella; Norman, Brendan P.; Hughes, Juliette H.; Bygott, Helen; Luangrath, Emily; Fitzgerald, Richard J.; Psarelli, Eftychia Eirini; Kan, Christa van; Laan, Dinny; Olsson, Birgitta; Rudebeck, Mattias; Mankowitz, Louise; Sireau, Nicolas; Arnoux, Jean Baptiste; Sang, Kim Hanh Le Quan; Jarvis, Jonathan C.; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Zaťková, Andrea; Glasová, H.; Stančík, Roman; Imrich, Richard; Rhodes, Nicholas P.; Gallagher, James A.

doi:10.1002/jimd.12181

Cited by 23 publications

(24 citation statements)

References 35 publications

(107 reference statements)

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“…27 Despite this increase in sNIT later on in SONIA 2, paradoxically sHGA did not decrease further; nitisinone has been shown to inhibit organic anion transporters and putative mediators of renal HGA excretion and may account for this effect at the higher dose (Figure S5 A–D). 28 …”

Section: Discussionmentioning

confidence: 99%

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

et al. 2021

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Background: Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared. Patients and methods: Sixty-nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24-h urine homogentisic acid (uHGA 24 ), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc. Results:The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x-axis was À132, À411, À295, and À 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p < 0.001) and the SONIA 2 (p < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively. Discussion: The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively. Conclusion: Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low-protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone.

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Section: Discussionmentioning

confidence: 99%

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

et al. 2021

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“…In serum, values were 7.6-82.4 µmol/L, and in urine 5,175--84,320 µmol/day, while normal urine values were 1.94±0.12 µmol/day or lower. 41 As mentioned earlier, in patients this variability does not reflect the differences in residual activity of the HGD enzyme due to different mutations. 20 It is believed that the variability depends mainly on daily intake of the proteins (in the diet) and on the effectiveness of renal excretion of accumulated HGA.…”

Section: Understanding the Process Of Ochronosis And Specific Featurementioning

confidence: 85%

“…Results of HGA measurements in 225 AKU patients from four recent clinical studies are summarized in Table 2. 41 Generally, there was large variation in plasma-and urine-HGA concentrations among alkaptonuric patients. In serum, values were 7.6-82.4 µmol/L, and in urine 5,175--84,320 µmol/day, while normal urine values were 1.94±0.12 µmol/day or lower.…”

Section: Understanding the Process Of Ochronosis And Specific Featurementioning

confidence: 94%

<p>Alkaptonuria: Current Perspectives</p>

Zaťková

Ranganath

Kádaši

2020

TACG

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The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.

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“…The markedly increased output of the HGA-glucuronide (FC = 5) and HGA-sulfate (FC = 9.3), as well as HGA (FC = 7.9), in AKU Hgd −/− mice has implications for the regulation of plasma HGA and products. Despite efficient renal excretion of HGA-related compounds in AKU, 17 the circulating HGA remains elevated; mean serum HGA concentration is 30 μ mol/L in untreated AKU 18 and <1.5 μ mol/L in healthy subjects. 19 , 20 The increased plasma HGA persists as the primary toxic agent in AKU; its oxidation produces ochronotic pigment, which becomes bound within the extracellular matrix of collagenous tissues.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

et al. 2022

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Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria

Abstract: Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria.

Cited by 23 publications

References 35 publications

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

<p>Alkaptonuria: Current Perspectives</p>

Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

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