Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria

Francesco Porta; Sara Giorda; Alberto Ponzone; Marco Spada

doi:10.1515/jpem-2020-0319

Article

Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria

Francesco Porta , Sara Giorda , Alberto Ponzone and Marco Spada

Published/Copyright: November 19, 2020

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 33 Issue 12

Abstract

Objectives

Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU).

Methods

We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6 ± 11.9 years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100 mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy.

Results

1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p<0.01); (2) the response to a Tyr loading test in PKU was normal, with basal Tyr concentrations reached within 12 h; (3) the diurnal metabolic profile in patients on slow-release amino acids therapy revealed higher morning fasting and nocturnal Tyr concentrations with respect to traditional therapy (p<0.01); (4) this picture was confirmed at follow-up, with normalization of morning fasting Tyr concentrations in patients on slow-release amino acids therapy (p<0.01) and unchanged Phe control (p=0.19).

Conclusions

Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.

Keywords: amino acids supplementation; diet; phenylalanine; phenylketonuria; tyrosine

Corresponding author: Francesco Porta, MD, PhD, Department of Pediatrics, University of Torino, Piazza Polonia 94, 10126, Torino, Italy, Phone: +39 011 313 5125, Fax: +39 011 313 5382, E-mail: francesco.porta@unito.it

Research funding: None declared.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Ethical statement: The study was conducted according to the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects.
Competing interests: Authors state no conflict of interest.

References

1. van Wegberg, AMJ, MacDonald, A, Ahring, K, Bélanger-Quintana, A, Blau, N, Bosch, AM, et al.. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 2017;12:162, https://doi.org/10.1186/s13023-017-0685-2.Search in Google Scholar PubMed PubMed Central

2. Weglage, J, Brämswig, JH, Koch, HG, Karassalidou, S, Ullrich, K. Growth in patients with phenylketonuria. Eur J Pediatr 1994;153:537–8, https://doi.org/10.1007/bf01957014.Search in Google Scholar PubMed

3. Macdonald, A, Daly, A, Davies, P, Asplin, D, Hall, SK, Rylance, G, et al.. Protein substitutes for PKU: what’s new? J Inherit Metab Dis. 2004;27:363–71. https://doi.org/10.1023/b:boli.0000031099.79046.65.10.1023/B:BOLI.0000031099.79046.65Search in Google Scholar PubMed

4. Manta-Vogli, PD, Dotsikas, Y, Loukas, YL, Schulpis, KH. The phenylketonuria patient: a recent dietetic therapeutic approach. Nutr Neurosci 2018:1–12.10.1080/1028415X.2018.1538196Search in Google Scholar PubMed

5. Pena, MJ, de Almeida, MF, van Dam, E, Ahring, K, Bélanger-Quintana, A, Dokoupil, K, et al.. Protein substitutes for phenylketonuria in Europe: access and nutritional composition. Eur J Clin Nutr 2016;70:785–9, https://doi.org/10.1038/ejcn.2016.54.Search in Google Scholar PubMed

6. van Spronsen, FJ, van Dijk, T, Smit, GP, van Rijn, M, Reijngoud, DJ, Berger, R, et al.. Large daily fluctuations in plasma tyrosine in treated patients ith phenylketonuria. Am J Clin Nutr. 1996;64:916–21, https://doi.org/10.1093/ajcn/64.6.916.Search in Google Scholar PubMed

7. van Spronsen, FJ, van Rijn, M, Bekhof, J, Koch, R, Smit, PG. Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets. Am J Clin Nutr 2001;73:153–7, https://doi.org/10.1093/ajcn/73.2.153.Search in Google Scholar PubMed

8. Cazzorla, C, Bensi, G, Biasucci, G, Leuzzi, V, Manti, F, Musumeci, A, et al.. Living with phenylketonuria in adulthood: the PKU ATTITUDE study. Mol Genet Metab Rep 2018;16:39–45, https://doi.org/10.1016/j.ymgmr.2018.06.007.Search in Google Scholar PubMed PubMed Central

9. Hochuli, M, Bollhalder, S, Thierer, C, Refardt, J, Gerber, P, Baumgartner, MR. Effects of inadequate amino acid mixture intake on nutrient supply of adult patients with phenylketonuria. Ann Nutr Metab 2017;71:129–35, https://doi.org/10.1159/000479746.Search in Google Scholar PubMed

10. Walkowiak, D, Bukowska-Posadzy, A, Kałużny, Ł, Ołtarzewski, M, Staszewski, R, Musielak, M, et al.. Therapy compliance in children with phenylketonuria younger than 5 years: a cohort study. Adv Clin Exp Med 2019;28:1385–91, https://doi.org/10.17219/acem/104536.Search in Google Scholar PubMed

11. Ferreira, BK, Rodrigues, MT, Streck, EL, Ferreira, GC, Schuck, PF. White matter disturbances in phenylketonuria: possible underlying mechanisms. J Neurosci Res 2020. https://doi.org/10.1002/jnr.24598.Search in Google Scholar PubMed

12. Porta, F, Mussa, A, Zanin, A, Greggio, NA, Burlina, A, Spada, M. Impact of metabolic control on bone quality in phenylketonuria and mild hyperphenylalaninemia. J Pediatr Gastroenterol Nutr 2011;52:345–50, https://doi.org/10.1097/mpg.0b013e3182093b32.Search in Google Scholar

13. Roato, I, Porta, F, Mussa, A, D’Amico, L, Fiore, L, Garelli, D, et al.. Bone impairment in phenylketonuria is characterized by circulating osteoclast precursors and activated T cell increase. PloS One 2010;5:e14167, https://doi.org/10.1371/journal.pone.0014167.Search in Google Scholar PubMed PubMed Central

14. Pena, MJ, Pinto, A, Daly, A, MacDonald, A, Azevedo, L, Rocha, JC, et al.. The use of glycomacropeptide in patients with phenylketonuria: a systematic review and meta-analysis. Nutrients 2018;10. https://doi.org/10.3390/nu10111794.Search in Google Scholar PubMed PubMed Central

15. Burlina, AP, Cazzorla, C, Massa, P, Polo, G, Loro, C, Gueraldi, D, et al.. Large neutral amino acid therapy increases tyrosine levels in adult patients with phenylketonuria: a long-term study. Nutrients 2019;11. https://doi.org/10.3390/nu11102541.Search in Google Scholar PubMed PubMed Central

16. Kumru, B, Ozturk Hismi, B, Kaplan, DS, Celik, H. Studying the effect of large neutral amino acid supplements on oxidative stress in phenylketonuric patients. J Pediatr Endocrinol Metab 2019;32:269–74, https://doi.org/10.1515/jpem-2018-0454.Search in Google Scholar PubMed

17. Ponzone, A, Porta, F, Mussa, A, Alluto, A, Ferraris, S, Spada, M. Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency. Metabolism 2010;59:645–52, https://doi.org/10.1016/j.metabol.2009.09.008.Search in Google Scholar PubMed

18. Porta, F, Spada, M, Ponzone, A. Early screening for tetrahydrobiopterin responsiveness in phenylketonuria. Pediatrics 2017;140:e20161591, https://doi.org/10.1542/peds.2016-1591.Search in Google Scholar PubMed

19. Sharman, R, Sullivan, KA, Young, RM, McGill, JJ. Tyrosine monitoring in children with early and continuously treated phenylketonuria: results of an international practice survey. J Inherit Metab Dis 2010;33:S417–20, https://doi.org/10.1007/s10545-010-9211-6.Search in Google Scholar PubMed

20. Zielke, HR, Zielke, CL, Baab, PJ, Collins, RM. Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implication for maple syrup urine disease and phenylketonuria. Neurochem Int 2002;40:347–54, https://doi.org/10.1016/s0197-0186(01)00077-8.Search in Google Scholar PubMed

21. Pilotto, A, Blau, N, Leks, E, Schulte, C, Deuschl, C, Zipser, C, et al.. Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria. J Inherit Metab Dis 2019;42:398–406, https://doi.org/10.1002/jimd.12049.Search in Google Scholar PubMed

22. Kalsner, LR, Rohr, FJ, Strauss, KA, Korson, MS, Levy, HL. Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids. J Pediatr 2001;139:421–7, https://doi.org/10.1067/mpd.2001.117576.Search in Google Scholar PubMed

23. Landvogt, C, Mengel, E, Bartenstein, P, Buchholz, HG, Schreckenberger, M, Siessmeier, T, et al.. Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria. J Cerebr Blood Flow Metabol 2008;28:824–31, https://doi.org/10.1038/sj.jcbfm.9600571.Search in Google Scholar PubMed

24. Lou, HC, Güttler, F, Lykkelund, C, Bruhn, P, Niederwieser, A. Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. Eur J Pediatr 1985;144:17–20, https://doi.org/10.1007/bf00491918.Search in Google Scholar

25. Burlina, AB, Bonafé, L, Ferrari, V, Suppiej, A, Zacchello, F, Burlina, AP. Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment. J Inherit Metab Dis 2000;23:313–6. https://doi.org/10.1023/a:1005694122277.10.1023/A:1005694122277Search in Google Scholar

26. Boot, E, Hollak, CEM, Huijbregts, SCJ, Jahja, R, van Vliet, D, Nederveen, AJ, et al.. Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria. Psychol Med 2017;47:2854–65, https://doi.org/10.1017/s0033291717001398.Search in Google Scholar PubMed

27. Waisbren, SE, Prabhu, SP, Greenstein, P, Petty, C, Schomer, D, Anastasoaie, V, et al.. Improved measurement of brain phenylalanine and tyrosine related to neuropsychological functioning in phenylketonuria. JIMD Rep 2017;34:77–86, https://doi.org/10.1007/8904_2016_11.Search in Google Scholar PubMed PubMed Central

28. McKean, CM. The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res 1972;47:469–76, https://doi.org/10.1016/0006-8993(72)90653-1.Search in Google Scholar PubMed

29. de Groot, MJ, Hoeksma, M, Reijngoud, DJ, de Valk, HW, Paans, AM, Sauer, PJ, et al.. Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis. Orphanet J Rare Dis 2013;8:133, https://doi.org/10.1186/1750-1172-8-133.Search in Google Scholar PubMed PubMed Central

30. Webster, D, Wildgoose, J. Tyrosine supplementation for phenylketonuria. Cochrane Database Syst Rev 2013;6:CD001507, https://doi.org/10.1002/14651858.CD001507.pub3.Search in Google Scholar PubMed PubMed Central

31. Spada, M, Dianzani, I, Bonetti, G, Biondi, A, Leone, L, Giannattasio, S, et al.. Phenylalanine and tyrosine metabolism in phenylketonuria heterozygotes: influence of different phenylalanine hydroxylase mutations. J Inherit Metab Dis 1998;21:236–9. https://doi.org/10.1023/a:1005355802928.10.1023/A:1005355802928Search in Google Scholar PubMed

32. Luciana, M, Sullivan, J, Nelson, CA. Associations between phenylalanine-to-tyrosine ratios and performance on tests of neuropsychological function in adolescents treated early and continuously for phenylketonuria. Child Dev 2001;72:1637–52, https://doi.org/10.1111/1467-8624.00370.Search in Google Scholar PubMed

33. Batshaw, ML, Valle, D, Bessman, SP. Unsuccessful treatment of phenylketonuria with tyrosine. J Pediatr 1981;99:159–60, https://doi.org/10.1016/s0022-3476(81)80985-7.Search in Google Scholar PubMed

34. Weglage, J, Ullrich, K, Pietsch, M, Fünders, B, Zass, R, Koch, HG. Untreated non-phenylketonuric-hyperphenylalaninaemia: intellectual and neurological outcome. Eur J Pediatr 1996;155:S26–8, https://doi.org/10.1007/pl00014244.Search in Google Scholar PubMed

Received: 2020-05-29

Accepted: 2020-09-19

Published Online: 2020-11-19

Published in Print: 2020-12-16

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2020-0319

Keywords for this article

amino acids supplementation; diet; phenylalanine; phenylketonuria; tyrosine