Metabolomic Insights into the Nutritional Status of Adults and Adolescents with Phenylketonuria Consuming a Low-Phenylalanine Diet in Combination with Amino Acid and Glycomacropeptide Medical Foods

Bridget M Stroup, Denise M Ney, Sangita G Murali, Frances Rohr, Sally T Gleason, Sandra C van Calcar, Harvey L Levy, Bridget M Stroup, Denise M Ney, Sangita G Murali, Frances Rohr, Sally T Gleason, Sandra C van Calcar, Harvey L Levy

Abstract

Background: Nutrient status in phenylketonuria (PKU) requires surveillance due to the restrictive low-Phe diet in combination with amino acid medical foods (AA-MF) or glycomacropeptide medical foods (GMP-MF). Micronutrient profiles of medical foods are diverse, and optimal micronutrient supplementation in PKU has not been established.

Methods: In a crossover design, 30 participants with PKU were randomized to consume AA-MF and Glytactin™ GMP-MF in combination with a low-Phe diet for 3 weeks each. Fasting venipunctures, medical food logs, and 3-day food records were obtained. Metabolomic analyses were completed in plasma and urine by Metabolon, Inc.

Results: The low-Phe diets in combination with AA-MF and GMP-MF were generally adequate based on Dietary Reference Intakes, clinical measures, and metabolomics. Without micronutrient supplementation of medical foods, >70% of participants would have inadequate intakes for 11 micronutrients. Despite micronutrient supplementation of medical foods, inadequate intakes of potassium in 93% of participants and choline in >40% and excessive intakes of sodium in >63% of participants and folic acid in >27% were observed. Sugar intake was excessive and provided 27% of energy.

Conclusions: Nutrient status was similar with AA-MF and Glytactin GMP-MF. More research related to micronutrient supplementation of medical foods for the management of PKU is needed.

Figures

Figure 1
Figure 1
Experimental design. AA-MF, amino acid medical foods; GMP-MF, glycomacropeptide medical foods.
Figure 2
Figure 2
Caloric contribution from carbohydrate, sugar, protein, fat, and saturated fat was calculated for the low-Phe diet in combination with AA-MF as a percentage of total energy intake (a). Macronutrient distribution was similar for GMP-MF (data not shown). Caloric contribution from macronutrients was compared to the age-appropriate AMDR (protein, carbohydrate, and fat) or the DGA (sugar and saturated fat) (b) for each participant to determine the percentage of subjects that were below or above the AMDR or DGA (c). Percentage of participants with inadequate and excessive macronutrient distributions were similar for GMP-MF (data not shown). AA-MF, amino acid medical food; AMDR, acceptable macronutrient distribution ranges; DGA, Dietary Guidelines for Americans; GMP-MF, glycomacropeptide medical foods; Sat. fat, saturated fat.
Figure 3
Figure 3
Urine metabolomics of sulfur-containing amino acid (Met and Cys) metabolism, n = 9. Values are means ± SE. Participants with PKU consumed significantly more Met and Cys from medical foods with AA-MF compared to GMP-MF, n = 8 (means ± SE; Met, g/d: AA-MF, 1.3 ± 0.2, versus GMP-MF, 0.9 ± 0.1, p=0.047; Cys, g/d: AA-MF, 2.5 ± 0.3, versus GMP-MF, 0.3 ± 0.007, p < 0.0001). Participants had higher urinary excretion of taurine and taurine-related metabolites (hypotaurine, cysteine sulfonate, cysteine, and cystathionine), possibly related to higher intakes of sulfur-containing amino acids and increased need to excrete sulfur. AA-MF, amino acid medical foods; GMP-MF, glycomacropeptide medical foods.

References

    1. Flydal M. I., Martinez A. Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life. 2013;65(4):341–349. doi: 10.1002/iub.1150.
    1. Vockley J., Andersson H. C., Antshel K. M., et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in Medicine. 2014;16(2):188–200. doi: 10.1038/gim.2013.157.
    1. Bilder D. A., Kobori J. A., Cohen-Pfeffer J. L., Johnson E. M., Jurecki E. R., Grant M. L. Neuropsychiatric comorbidities in adults with phenylketonuria: a retrospective cohort study. Molecular Genetics and Metabolism. 2017;121(1):1–8. doi: 10.1016/j.ymgme.2017.03.002.
    1. Singh R. H., Rohr F., Frazier D., et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genetics in Medicine. 2014;16(2):121–131. doi: 10.1038/gim.2013.179.
    1. Etzel M. R. Manufacture and use of dairy protein fractions. Journal of Nutrition. 2004;134(4):996S–1002S.
    1. Laclair C. E., Ney D. M., MacLeod E. L., Etzel M. R. Purification and use of glycomacropeptide for nutritional management of phenylketonuria. Journal of Food Science. 2009;74(4):E199–E206. doi: 10.1111/j.1750-3841.2009.01134.x.
    1. van Calcar S. C., MacLeod E. L., Gleason S. T., et al. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. American Journal of Clinical Nutrition. 2009;89(4):1068–1077. doi: 10.3945/ajcn.2008.27280.
    1. Ney D. M., Stroup B. M., Clayton M. K., et al. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial. American Journal of Clinical Nutrition. 2016;104(2):334–345. doi: 10.3945/ajcn.116.135293.
    1. Singh R. H., Cunningham A. C., Mofidi S., et al. Updated, web-based nutrition management guideline for PKU: an evidence and consensus based approach. Molecular Genetics and Metabolism. 2016;118(2):72–83. doi: 10.1016/j.ymgme.2016.04.008.
    1. Lammardo A. M., Robert M., Rocha J. C., et al. Main issues in micronutrient supplementation in phenylketonuria. Molecular Genetics and Metabolism. 2013;110:S1–S5. doi: 10.1016/j.ymgme.2013.08.008.
    1. Jans J. J., de Sain-van der Velden M. G. M., van Hasselt P. M., et al. Supplementation with a powdered blend of PUFAs normalizes DHA and AA levels in patients with PKU. Molecular Genetics and Metabolism. 2013;109(2):121–124. doi: 10.1016/j.ymgme.2013.03.006.
    1. Tanumihardjo S. A., Russell R. M., Stephensen C. B., et al. Biomarkers of nutrition for development (BOND)-vitamin A review. Journal of Nutrition. 2016;146(9):1816S–1848S. doi: 10.3945/jn.115.229708.
    1. Borel P. Factors affecting intestinal absorption of highly lipophilic food microconstituents (fat-soluble vitamins, carotenoids and phytosterols) Clinical Chemistry and Laboratory Medicine. 2003;41(8):979–994. doi: 10.1515/CCLM.2003.151.
    1. Jakeman S. A., Henry C. N., Martin B. R., et al. Soluble corn fiber increases bone calcium retention in postmenopausal women in a dose-dependent manner: a randomized crossover trial. American Journal of Clinical Nutrition. 2016;104(3):837–843. doi: 10.3945/ajcn.116.132761.
    1. Whisner C. M., Martin B. R., Nakatsu C. H., et al. Soluble corn fiber increases calcium absorption associated with shifts in the gut microbiome: a randomized dose-response trial in free-living pubertal females. Journal of Nutrition. 2016;146(7):1298–1306. doi: 10.3945/jn.115.227256.
    1. Fairweather-Tait S. J., Collings R., Hurst R. Selenium bioavailability: current knowledge and future research requirements. American Journal of Clinical Nutrition. 2010;91(5):1484S–1491S. doi: 10.3945/ajcn.2010.28674j.
    1. Öhrvik V. E., Büttner B. E., Rychlik M., Lundin E., Witthöft C. M. Folate bioavailability from breads and a meal assessed with a human stable-isotope area under the curve and ileostomy model. American Journal of Clinical Nutrition. 2010;92(3):532–538. doi: 10.3945/ajcn.2009.29031.
    1. Evans S., Daly A., MacDonald J., et al. The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge. Annals of Nutrition and Metabolism. 2014;65(1):42–48. doi: 10.1159/000363391.
    1. Demirdas S., van Spronsen F. J., Hollak C. E. M., et al. Micronutrients, essential fatty acids and bone health in phenylketonuria. Annals of Nutrition and Metabolism. 2017;70(2):111–121. doi: 10.1159/000465529.
    1. Vugteveen I., Hoeksma M., Bjorke Monsen A. L., et al. Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages. Molecular Genetics and Metabolism. 2011;102(1):13–17. doi: 10.1016/j.ymgme.2010.07.004.
    1. Pinto A., Almeida M. F., Ramos P. C., et al. Nutritional status in patients with phenylketonuria using glycomacropeptide as their major protein source. European Journal of Clinical Nutrition. 2017;71(10):1230–1234. doi: 10.1038/ejcn.2017.38.
    1. Wilson K., Charmchi P., Dworetzsky B. State Statutes and Regulations on Dietary Treatments of Disorders Identified Through Newborn Screening. Bethesda, MD, USA: American College of Medical Genetics & Genomics: Catalyst Center, Center for Advancing Health Policy & Practice, Boston University; 2016. pp. 1–80.
    1. Institute of Medicine. Dietary Reference Intake for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids (Macronutrients) Washington D.C., USA: The National Academies Press; 2005.
    1. U.S. Department of Health and Human Services and U.S. Department of Agriculture. Dietary Guidelines for Americans 2015–2020. 8th. 2015.
    1. Institute of Medicine. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, D.C., USA: The National Academies Press; 2006.
    1. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington D.C., USA: The National Academies Press; 2011.
    1. Ney D. M., Murali S. G., Stroup B. M., et al. Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Molecular Genetics and Metabolism. 2017;121(2):96–103. doi: 10.1016/j.ymgme.2017.04.003.
    1. Stroup B. M. Nutritional management of phenylketonuria with glycomacropeptide medical foods. Ann Arbor, MI, USA: ProQuest, order no. 10604680; 2017.
    1. Stroup B. M., Murali S. G., Nair N., et al. Dietary amino acid intakes associated with a low-phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects with phenylketonuria. Data in Brief. 2017;13:377–384. doi: 10.1016/j.dib.2017.06.004.
    1. Stroup B. M., Sawin E. A., Murali S. G., Binkley N., Hansen K. E., Ney D. M. Amino acid medical foods provide a high dietary acid load and increase urinary excretion of renal net acid, calcium, and magnesium compared with glycomacropeptide medical foods in phenylketonuria. Journal of Nutrition and Metabolism. 2017;2017:12. doi: 10.1155/2017/1909101.1909101
    1. Zeisel S. H. Choline: critical role during fetal development and dietary requirements in adults. Annual Review of Nutrition. 2006;26:229–250. doi: 10.1146/annurev.nutr.26.061505.111156.
    1. WHO. Geneva, Switzerland: United Nations University, World Health Organization; 2007. Protein and amino acid requirements in human nutrition. Tech. Rep. 935.
    1. Dominy J. E., Jr., Hwang J., Guo S., Hirschberger L. L., Zhang S., Stipanuk M. H. Synthesis of amino acid cofactor in cysteine dioxygenase is regulated by substrate and represents a novel post-translational regulation of activity. Journal of Biological Chemistry. 2008;283(18):12188–12201. doi: 10.1074/jbc.M800044200.
    1. Lowe N. M., Fekete K., Decsi T. Methods of assessment of zinc status in humans: a systematic review. American Journal of Clinical Nutrition. 2009;89(6):2040S–2051S. doi: 10.3945/ajcn.2009.27230g.
    1. Robert M., Rocha J. C., van Rijn M., et al. Micronutrient status in phenylketonuria. Molecular Genetics and Metabolism. 2013;110:S6–S17. doi: 10.1016/j.ymgme.2013.09.009.
    1. MacDonald A., Rocha J. C., van Rijn M., Feillet F. Nutrition in phenylketonuria. Molecular Genetics and Metabolism. 2011;104:S10–S18. doi: 10.1016/j.ymgme.2011.08.023.
    1. Fisberg R. M., da Silva-Femandes M. E., Fisberg M., José Schmidt B. Plasma zinc, copper, and erythrocyte superoxide dismutase in children with phenylketonuria. Nutrition. 1999;15(6):449–452. doi: 10.1016/S0899-9007(99)00082-9.
    1. Dobbelaere D., Michaud L., Debrabander A., et al. Evaluation of nutritional status and pathophysiology of growth retardation in patients with phenylketonuria. Journal of Inherited Metabolic Disease. 2003;26(1):1–11.
    1. Crujeiras V., Aldamiz-Echevarria L., Dalmau J., et al. Vitamin and mineral status in patients with hyperphenylalaninemia. Molecular Genetics and Metabolism. 2015;115(4):145–150. doi: 10.1016/j.ymgme.2015.06.010.
    1. Andrade F., López-Suárez O., Llarena M., Couce M. L., Aldámiz-Echevarría L. Influence of phenylketonuria’s diet on dimethylated arginines and methylation cycle. Medicine. 2017;96(27):p. e7392. doi: 10.1097/MD.0000000000007392.
    1. Dobrowolski S. F., Lyons-Weiler J., Spridik K., et al. Altered DNA methylation in PAH deficient phenylketonuria. Molecular Genetics and Metabolism. 2015;115(2-3):72–77. doi: 10.1016/j.ymgme.2015.04.002.
    1. Dobrowolski S. F., Lyons-Weiler J., Spridik K., Vockley J., Skvorak K., Biery A. DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAHenu2 mouse model of phenylketonuria. Molecular Genetics and Metabolism. 2016;119(1-2):1–7. doi: 10.1016/j.ymgme.2016.01.001.
    1. Colomé C., Artuch R., Vilaseca M. A., et al. Lipophilic antioxidants in patients with phenylketonuria. American Journal of Clinical Nutrition. 2003;77(1):185–188.
    1. Schulpis K. H., Tsakiris S., Karikas G. A., Moukas M., Behrakis P. Effect of diet on plasma total antioxidant status in phenylketonuric patients. European Journal of Clinical Nutrition. 2003;57(2):383–387. doi: 10.1038/sj.ejcn.1601529.
    1. Daly A., Evans S., Chahal S., Santra S., MacDonald A. Glycomacropeptide in children with phenylketonuria: does its phenylalanine content affect blood phenylalanine control? Journal of Human Nutrition and Dietetics. 2017;30(4):515–523. doi: 10.1111/jhn.12438.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe