Editing Phenylketonuria (section)

===Nutritional supplements===
Supplementary "protein substitute" formulas are typically prescribed for people with PKU (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. Tyrosine, which is normally derived from phenylalanine and which is necessary for normal brain function, is usually supplemented. Consumption of the protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein [[catabolism]] from releasing Phe stored in the muscles and other tissues into the blood. Many PKU patients have their highest Phe levels after a period of fasting (such as overnight) because fasting triggers catabolism.<ref>{{Cite journal |vauthors=MacDonald A, Rylance GW, Asplin D, Hall SK, Booth IW |year=1998 |title=Does a single plasma phenylalanine predict the quality of control in phenylketonuria? |journal=Archives of Disease in Childhood |volume=78 |issue=2 |pages=122–6 |doi=10.1136/adc.78.2.122 |pmc=1717471 |pmid=9579152}}</ref> A diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood Phe levels, since a nutritionally insufficient diet may also trigger catabolism. For all these reasons, the prescription formula is an important part of the treatment for patients with classic PKU.{{citation needed|date=September 2020}}

Evidence supports dietary supplementation with large neutral amino acids (LNAAs).<ref>{{Cite journal |vauthors=van Spronsen FJ, de Groot MJ, Hoeksma M, Reijngoud DJ, van Rijn M |date=December 2010 |title=Large neutral amino acids in the treatment of PKU: from theory to practice |journal=Journal of Inherited Metabolic Disease |volume=33 |issue=6 |pages=671–6 |doi=10.1007/s10545-010-9216-1 |pmc=2992655 |pmid=20976625}}</ref> The LNAAs (e.g. [[Leucine|leu]], [[Tyrosine|tyr]], [[Tryptophan|trp]], [[Methionine|met]], [[Histidine|his]], [[Isoleucine|ile]], [[Valine|val]], [[Threonine|thr]]) may compete with phe for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the [[blood–brain barrier]] into the brain. Its use is limited in the US due to the cost but is available in most countries as part of a low protein / PHE diet to replace missing nutrients.{{Citation needed|date=September 2024}}

Another treatment strategy is casein glycomacropeptide (CGMP), which is a milk peptide naturally free of Phe in its pure form<ref name="pmid15051860">{{Cite journal |last=Etzel MR |date=Apr 2004 |title=Manufacture and use of dairy protein fractions. |journal=The Journal of Nutrition |volume=134 |issue=4 |pages=996S–1002S |doi=10.1093/jn/134.4.996S |pmid=15051860 |doi-access=free}}</ref> CGMP can substitute for the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids. The fact that CGMP is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention<ref name="pmid19244369">{{Cite journal |vauthors=van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA, Ney DM |date=Apr 2009 |title=Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. |journal=The American Journal of Clinical Nutrition |volume=89 |issue=4 |pages=1068–77 |doi=10.3945/ajcn.2008.27280 |pmc=2667457 |pmid=19244369}}</ref> and increased satiety<ref name="pmid20466571">{{Cite journal |vauthors=MacLeod EL, Clayton MK, van Calcar SC, Ney DM |date=August 2010 |title=Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. |journal=Molecular Genetics and Metabolism |volume=100 |issue=4 |pages=303–8 |doi=10.1016/j.ymgme.2010.04.003 |pmc=2906609 |pmid=20466571}}</ref> compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved<ref name="pmid19244369" /> when CGMP substitutes part of the free amino acids and this may help ensure improved compliance to the PKU diet.{{Citation needed|date=September 2024}}

Furthermore, CGMP contains a high amount of the Phe-lowering LNAAs, which constitutes about 41 g per 100 g protein<ref name="pmid15051860" /> and will therefore help maintain plasma Phe levels in the target range.