Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

Stewart, Rosalind M K; Briggs, Michael; Jarvis, Jonathan C.; Gallagher, James A.; Ranganath, L.R.

doi:10.1007/8904_2014_307

Cited by 31 publications

(45 citation statements)

References 17 publications

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“…Tyrosinemia can cause eye and skin keratopathy in a minority of patients requiring a lower dose or cessation of nitisinone, or a strict low protein diet, to resolve symptoms. Low‐dose nitisinone, ranging from 0.5 to 2 mg daily, has caused eye complications in five reported AKU patients to date . Attempting to restrict dietary tyrosine and phenylalanine consumption, while taking nitisinone to keep HGA low, is the most logical approach to combat tyrosinemia.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, significant reductions in serum tyrosine (Figure 4) were seen in the 10 NAC patients observed (P = .002; twotailed Wilcoxon's signed rank test), with four patients reducing serum tyrosine <700 μmol/L. Three patients (Figure 4, dashed lines) reduced serum tyrosine (mean[range]) by 22 [18][19][20][21][22][23][24][25][26][27][28][29][30]% by advised protein restriction alone; the other seven patients required a combination of reduced protein intake with tyrosine/phenylalanine-free supplements to achieve a 33 % reduction. The initial tyrosine value for patients using amino acid supplements was with dietary restriction alone, with subsequent values using a combination of reduced protein intake and amino acid supplementation.…”

Section: Nac Dietary Intervention In Aku Patientsmentioning

confidence: 99%

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Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

Hughes

Wilson

Sutherland

et al. 2020

J of Inher Metab Disea

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Alkaptonuria (AKU) is caused by homogentisate 1,2‐dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone‐treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone‐treated AKU mice were fed tyrosine/phenylalanine‐free and phenylalanine‐free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre‐nitisinone, post‐nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine‐free amino acid supplements. Elevated tyrosine (813 μmol/L) was significantly reduced in nitisinone‐treated AKU mice fed a tyrosine/phenylalanine‐free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine‐free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine‐free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone‐induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.

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Section: Discussionmentioning

confidence: 99%

Section: Nac Dietary Intervention In Aku Patientsmentioning

confidence: 99%

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

Hughes

Wilson

Sutherland

et al. 2020

J of Inher Metab Disea

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“…The lack of a correlation between the serum tyrosine levels and the development of corneal opacities suggests that there may potentially be other factors involved, potentially patient specific, in producing adverse effects seen in individuals administered nitisinone [18].…”

Section: Discussionmentioning

confidence: 97%

Osteoarticular cells tolerate short-term exposure to nitisinone—implications in alkaptonuria

et al. 2015

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“…[28][29][30] Similar corneal opacities have been reported in AKU. 10,31 In all cases, the corneal opacities resolved upon cessation of NTBC and normalization of tyrosine concentrations. In addition, by measuring NTBC, the pharmacodynamics can be monitored.…”

mentioning

confidence: 89%

Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry

et al. 2015

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Background: Alkaptonuria is a rare debilitating autosomal recessive disorder of tyrosine metabolism, where deficiency of homogentisate 1,2-dioxygenase results in increased homogentisic acid. Homogentisic acid is deposited as an ochronotic pigment in connective tissues, especially cartilage, leading to a severe early onset form of osteoarthritis, increased renal and prostatic stone formation and hardening of heart vessels. Treatment with the orphan drug, nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase has been shown to reduce urinary excretion of homogentisic acid. Method: A reverse phase liquid chromatography tandem mass spectrometry method has been developed to simultaneously analyse serum homogentisic acid, tyrosine and nitisinone. Using matrix-matched calibration standards, two product ion transitions were identified for each compound (homogentisic acid, tyrosine, nitisinone) and their respective isotopically labelled internal standards ( 13 C 6 -homogentisic acid, d 2 -tyrosine, 13 C 6 -nitisinone). Results: Intrabatch accuracy was 94-108% for homogentisic acid, 95-109% for tyrosine and 89-106% for nitisinone; interbatch accuracy (n ¼ 20) was 88-108% for homogentisic acid, 91-104% for tyrosine and 88-103% for nitisinone. Precision, both intra-and interbatch were <12% for homogentisic acid and tyrosine, and <10% for nitisinone. Matrix effects observed with acidified serum were normalized by the internal standard (<10% coefficient of variation). Homogentisic acid, tyrosine and nitisinone proved stable after 24 h at room temp, three freeze-thaw cycles and 24 h at 4 C. The assay was linear to 500mol/L homogentisic acid, 2000mol/L tyrosine and 10mol/L nitisinone; increased range was not required for clinical samples and no carryover was observed. Conclusions:The method developed and validated shows good precision, accuracy and linearity appropriate for the monitoring of alkaptonuria patients, pre-and post-nitisinone therapy.

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Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

Cited by 31 publications

References 17 publications

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

Osteoarticular cells tolerate short-term exposure to nitisinone—implications in alkaptonuria

Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry

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