Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model

Vliet, Danique van; Bruinenberg, Vibeke M.; Mazzola, Priscila Nicolao; Faassen, Martijn H. J. R. van; Blaauw, Pim de; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Heiner‐Fokkema, M. Rebecca; Zee, Eddy A. van der; Spronsen, Francjan J. van

doi:10.3945/ajcn.116.135996

Cited by 40 publications

(53 citation statements)

References 32 publications

(53 reference statements)

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“…These LNAA may compete with Phe at LAT1 to reduce Phe transport into brain, resulting in greater availability of Tyr and Trp for neurotransmitter synthesis. In support of this, specific supplementation with Leu and Ile has been shown to decrease Phe concentrations in the brain of PKU mice (29), and we have reported a 20% decrease in brain Phe concentrations in Pah enu2 mice fed diets comprised of GMP compared with amino acids (30). …”

Section: Discussionmentioning

confidence: 53%

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Ney

Murali

Stroup

et al. 2017

Molecular Genetics and Metabolism

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Background Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). Methods Subjects with PKU consumed a low-Phe diet combined with AA-MF and GMP-MF for 3 weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-hr urine samples. Results Intake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA- MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF. Conclusions The Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU.

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Section: Discussionmentioning

confidence: 53%

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Ney

Murali

Stroup

et al. 2017

Molecular Genetics and Metabolism

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“…Several monogenic metabolic disorders such as phenylketonuria are characterized by markedly abnormal plasma amino acids levels that result in toxic brain levels. While the mainstay of phenylketonuria treatment, for example, is the reduction of phenylalanine intake, recent investigations using animal models suggest that supplementation with large neutral amino acids that compete with the excessive levels of phenylalanine at the shared transport system may be an effective alternative treatment (Van Vliet et al., 2016). Although the magnitude of perturbation of brain amino acids would be expected to be less in persons with multifactorially determined obesity or metabolic syndrome than in classic monogenic metabolic disorders, a similar principle could apply to treating these patients and further work in this area appears warranted based on our findings.…”

Section: Resultsmentioning

confidence: 99%

Metabolomic analysis of obesity, metabolic syndrome, and type 2 diabetes: amino acid and acylcarnitine levels change along a spectrum of metabolic wellness

Libert

Nowacki

Natowicz

2018

PeerJ

110

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BackgroundMetabolic syndrome (MS) is a construct used to separate “healthy” from “unhealthy” obese patients, and is a major risk factor for type 2 diabetes (T2D) and cardiovascular disease. There is controversy over whether obese “metabolically well” persons have a higher morbidity and mortality than lean counterparts, suggesting that MS criteria do not completely describe physiologic risk factors or consequences of obesity. We hypothesized that metabolomic analysis of plasma would distinguish obese individuals with and without MS and T2D along a spectrum of obesity-associated metabolic derangements, supporting metabolomic analysis as a tool for a more detailed assessment of metabolic wellness than currently used MS criteria.MethodsFasting plasma samples from 90 adults were assigned to groups based on BMI and ATP III criteria for MS: (1) lean metabolically well (LMW; n = 24); (2) obese metabolically well (OBMW; n = 26); (3) obese metabolically unwell (OBMUW; n = 20); and (4) obese metabolically unwell with T2D (OBDM; n = 20). Forty-one amino acids/dipeptides, 33 acylcarnitines and 21 ratios were measured. Obesity and T2D effects were analyzed by Wilcoxon rank-sum tests comparing obese nondiabetics vs LMW, and OBDM vs nondiabetics, respectively. Metabolic unwellness was analyzed by Jonckheere-Terpstra trend tests, assuming worsening health from LMW → OBMW → OBMUW. To adjust for multiple comparisons, statistical significance was set at p < 0.005. K-means cluster analysis of aggregated amino acid and acylcarnitine data was also performed.ResultsAnalytes and ratios significantly increasing in obesity, T2D, and with worsening health include: branched-chain amino acids (BCAAs), cystine, alpha-aminoadipic acid, phenylalanine, leucine + lysine, and short-chain acylcarnitines/total carnitines. Tyrosine, alanine and propionylcarnitine increase with obesity and metabolic unwellness. Asparagine and the tryptophan/large neutral amino acid ratio decrease with T2D and metabolic unwellness. Malonylcarnitine decreases in obesity and 3-OHbutyrylcarnitine increases in T2D; neither correlates with unwellness. Cluster analysis did not separate subjects into discreet groups based on metabolic wellness.DiscussionLevels of 15 species and metabolite ratios trend significantly with worsening metabolic health; some are newly recognized. BCAAs, aromatic amino acids, lysine, and its metabolite, alpha-aminoadipate, increase with worsening health. The lysine pathway is distinct from BCAA metabolism, indicating that biochemical derangements associated with MS involve pathways besides those affected by BCAAs. Even those considered “obese, metabolically well” had metabolite levels which significantly trended towards those found in obese diabetics. Overall, this analysis yields a more granular view of metabolic wellness than the sole use of cardiometabolic MS parameters. This, in turn, suggests the possible utility of plasma metabolomic analysis for research and public health applications.

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“…The reduced expression of antioxidant systems that we observed could lead to a defect in maintenance of the redox homeostasis in response to elevation of ROS levels (superoxide and hydroxyl anions especially) responsible of cellular damages previously observed in PKU (Ercal et al 2002;Sitta et al 2009;Sanayama et al 2011). GPX glutathione peroxidase, GSR glutathione reductase, GSH reduced glutathione, GSSG oxidized glutathione, SOD superoxide dismutase, CAT catalase, TXN thioredoxins, GLRX glutaredoxins, PRDX peroxiredoxins (van Vliet et al 2016). Large neural amino acids supplementation could be an interesting alternative dietary treatment in patients with PKU (Andersen and Avins 1976).…”

Section: Discussionmentioning

confidence: 99%

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

et al. 2017

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Background: Several studies have highlighted disturbance of redox homeostasis in patients with phenylketonuria (PKU) which may be associated with neurological disorders observed in patients, especially during adulthood when phenylalanine restrictive diets are not maintained. The aim of this study was to assess the antioxidant profile in a cohort of PKU patients in comparison to the controls and to evaluate its relation to biochemical parameters especially phenylalaninemia. Methods:We measured RNA expression of 22 antioxidant genes and reactive oxygen species (ROS) levels in white blood cells of 10 PKU patients and 10 age-and gendermatched controls. We also assessed plasma amino acids, vitamins, oligo-elements, and urinary organic acids concentrations. Then we evaluated the relationship between redox status and biochemical parameters. Results: In addition to expected biochemical disturbances, we highlighted a significant global decrease of antioxidant genes expression in PKU patients in comparison to the controls. This global decrease of antioxidant genes expression, including various isoforms of peroxiredoxins, glutaredoxins, glutathione peroxidases, and superoxide dismutases, was significantly correlated to hyperphenylalaninemia. Conclusion: This study is the first to evaluate the expression of 22 antioxidant genes in white blood cells regarding biochemical parameters in PKU. These findings highlight the association of hyperphenylalaninemia with antioxidant genes expression. New experiments to specify the role of oxidative stress in PKU pathogenesis may be useful in suggesting new recommendations in PKU management and new therapeutic trials based on antioxidant defenses.

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Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model

Cited by 40 publications

References 32 publications

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Metabolomic analysis of obesity, metabolic syndrome, and type 2 diabetes: amino acid and acylcarnitine levels change along a spectrum of metabolic wellness

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

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