The Effect of Large Neutral Amino Acids on Blood Phenylalanine Levels in Patients with Classical Phenylketonuria

Year 2017, , 79 - 81, 01.09.2017

Pelin Teke Kısa Engin Köse Nusret Ören Nur Arslan

https://doi.org/10.5152/jbachs.2017.240

Abstract

Purpose: Phenylketonuria PKU is an inherited metabolic disease caused by low levels of the enzyme phenylalanine hydroxylase. Treatment includes dietary restriction of phenylalanine Phe and supplementation with tetrahydrobiopterin and large neutral amino acids LNAAs . The purpose of this study is to evaluate the effect of LNAA therapy on blood Phe levels in patients undergoing treatment for at least 6 months.Methods: Blood Phe levels in 34 patients with classical PKU receiving LNAA supplementation for longer than 6 months were compared before the treatment and during the first 3 years of treatment.Results: The mean age of patients was 20.7±6.6 years, and the mean age at the beginning of LNAA therapy was 16.0±6.1 years. The median duration of LNAA use was 32 months minimum-maximum: 8-171 months . The mean blood Phe level before the use of LNAA supplementation was 23.1±5.9 mg/dL, whereas the first blood Phe level 1 month after the start of LNAA therapy was 18.9±5.5 mg/dL p=0.000 . The mean blood Phe levels in the first n=34 , second n=33 , and third year n=28 after the beginning of LNAA supplementation were 21.1±5.0 mg/dL, 21.2±6.4 mg/dL, and 21.3±5.8 mg/dL, respectively. There was no significant variation between these and pre-treatment values p>0.05 .Conclusion: There were no significant decreases in the blood Phe levels of patients receiving LNAA supplementation observed in this study. This may be due to poor dietary compliance. Nevertheless, since LNAA supplementation reduces the passage of Phe through the blood-brain barrier, it is still recommended in all adolescent and adult patients with PKU not complying with diet therapy, even if blood values do not change

Keywords

Phenylalanine, classical phenylketonuria, LNAA supplementation

References

• Blau N, van Spronsen FJ, Lev HL. Phenyketonuria. Lancet 2010; 376:1417-27. [CrossRef]
• Özalp İ, Coşkun T, Tokatlı A, et al. Neonatal PKU screening in Turkey: 7 years experience in a developing country. Screening 1995; 4:139- 147. [CrossRef]
• Zurfluh MR., Zschocke J, Lindner M,et al. Molecular genetics of tet- rahydrobiopterin-responsive phenylalanine hydroxylase deficien- cy. Hum Mutat 2008; 29:167-175. [CrossRef]
• National Institutes of Health Consensus Development Panel. Nation- al Institutes of Health consensus development conference statement: Phenylketonuria: screening and management. Pediatr 2001; 108:972-82.
• Andersen AE, Avins L. Lowering brain phenylalanine levels by giving other large neutral amino acids. A new experimental therapeutic ap- proach to phenylketonuria. Arch Neurol 1976; 33:684-86. [CrossRef]
• van Vliet D, Bruinenberg VM, Mazzola PN,et al. Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model. Am J Clin Nutr 2016; 104:1292-1300. [CrossRef]
• van Spronsen FJ, de Groot MJ, Hoeksma M, Reijngoud DJ, van Rijn M. Large neutral amino acids in the treatment of PKU: from theory to practice. J Inherit Metab Dis 2010; 33:671-676. [CrossRef]
• Yano S, Moseley K, Azen C. Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: effects of tryptophan and tyrosine supplementation. J Pediatr 2014; 165:184-89. [CrossRef]
• Camp KM, Parisi MA, Acosta PB. Phenylketonuria Scientific Review Conference: State of the science and future research needs. Mol Genet Metab 2014; 112:87-122. [CrossRef]
• Schindeler S, Ghosh-Jerath S, Thompson S, et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuro- psychological study. Mol Genet Metab 2007; 91:48-54. [CrossRef]
• Matalon R, Michals-Matalon K, Bhatia G et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis 2007; 30:153-58. [CrossRef]
• Matalon R, Michals-Matalon K, Bhatia G et al. Large neutral amino acids in the treatment of phenylketonuria (PKU). J Inherit Metab Dis 2006; 29:732-38. [CrossRef]
• Concolino D, Mascaro I, Moricca MT, et al. Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids. Eur J Clin Nutr 2017; 71:51-55. [CrossRef]
• Walter JH, White FJ, Hall SK et al. How practicial are recommendations for dietary control in phenylketonuria? Lancet 2002; 360:55-7. [CrossRef]
• Gunduz M, Cakar S, Kuyum P, Makay B, Arslan N. Comparison of atherogenic risk factors among poorly-controlled and well-con- trolled adolescent phenylketonuria patients. Cardiol Young 2016; 26:901-908 [CrossRef]
• Demirdas S, van Spronsen FJ, Hollak CEM, et al. Micronutrients, es- sential fatty acids and bone health in phenylketonuria. Ann Nutr Metab 2017; 70:111-121. [CrossRef]
• Borghi L, Salvatici E, Riva E, Giovannini M, Vegni EA. Psychological and psychosocial implications for parenting a child with phenyl- ketonuria: a systematic review. Minerva Pediatr 2017 (in press) doi: 10.23736/S0026-4946.17.04950-7.
• Gunduz M, Arslan N, Unal O, Cakar S, Kuyum P, Bulbul S. Depression and anxiety among parents of phenylketonuria children. Neurosci- ences 2015; 20:350-356. [CrossRef]
• de Groot MJ, Hoeksma M, Blau N, Reijngoud DJ, van Spronsen FJ. Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Met 2010: 99;86-89. [CrossRef]
• Jahja R, Huijbregts SC, de Sonneville LM, van der Meere JJ, van Spron- sen FJ. Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J Pediatr 2014; 164:895-99. [CrossRef]
• 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. [CrossRef]
• Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK. Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria. J Pediatr 1995; 27:936-943. [CrossRef]
• Moats R, Moseley KD, Koch R, Nelson M Jr. Brain phenylalanine con- centrations in phenylketonuria: research and treatment of adults. Pediatr 2003; 112:1575-79.
• van Spronsen FJ, Hoeksma M, Reijngoud DJ. Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? J Inherit Metab Dis 2009; 32:46-51. [CrossRef]
• Kalkanoglu HS, Ahring KK, Sertkaya D et al. Behavioural effects of phenylalanine-free amino acid tablet supplementation in intellec- tually disabled adults with untreated phenylketonuria. Acta Paedi- atr 2005; 94:1218-22. [CrossRef]