Serum Amino Acid Profiling in Patients with Alkaptonuria Before and After Treatment with Nitisinone

Davison, Andrew S.; Norman, Brendan P.; Smith, E. A.; Devine, J.; Usher, J.; Hughes, Andrew T.; Khedr, Milad; Milan, Anna M.; Gallagher, James A.; Ranganath, L.R.

doi:10.1007/8904_2018_109

Cited by 13 publications

(19 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the last two decades, there have been several reports on the use of nitisinone to treat AKU. Its inhibition of HPPD (Figure S1) has been shown to dramatically reduce the circulating concentration of HGA, but leads to marked hypertyrosinemia . Beyond hypertyrosinemia, there is very little reported on the biochemical consequences of nitisinone therapy.…”

Section: Discussionmentioning

confidence: 99%

“…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 . These differences may be explained by the fact that tryptophan is highly protein bound (~90%‐95%) and measurement in serum reflects total tryptophan and urinary tryptophan reflects free tryptophan.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment options for AKU are conservative in large focusing on supportive and palliative measures . The HGA lowering agent nitisinone (Figure S1) has been shown to completely prevent ochronosis in AKU mice and is being evaluated as a potential treatment in AKU patients; it is however not without its own challenges as it is well documented to result in significant hypertyrosinemia in AKU and hereditary tyrosinaemia type 1 (HT1, OMIM: 276700) . The consequences of this are largely unknown in AKU; in HT1 it has been suggested this may contribute to the neurodevelopmental delay that is frequently observed in children treated with nitisinone .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…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: 94%

“…Additional observational data of dietary intervention in AKU patients attending the National Alkaptonuria Centre (NAC; Liverpool, UK), where patients receive 2 mg nitisinone daily, are presented. At the NAC, serum tyrosine increases to a mean level of approximately 600 to 700 μmol/L with nitisinone, therefore patients are advised to restrict protein intake with guidance from a specialist dietician. We provide proof‐of‐concept that mechanisms reducing uptake of dietary tyrosine into the bloodstream would be effective.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma

et al. 2020

View full text Add to dashboard Cite

Background Alkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross‐sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning. Method Seventy‐four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7‐day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25‐hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti‐inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)—a validated measure of disease progression stratified by age. Results Fifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid‐upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as “clinically undernourished.” Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti‐inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score. Conclusion AKU patients are at risk of protein depletion associated with a “perfect storm” of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated.

show abstract

Serum Amino Acid Profiling in Patients with Alkaptonuria Before and After Treatment with Nitisinone

Cited by 13 publications

References 45 publications

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

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

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

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma

Contact Info

Product

Resources

About