Editing Phenylketonuria (section)

==Treatment==
PKU is not curable. However, if it is diagnosed early enough, an affected newborn can grow up with normal brain development by managing and controlling phenylalanine ("Phe") levels through diet, or a combination of diet and medication.<ref>{{Cite journal |last=Widaman |first=Keith F. |date=2009-02-01 |title=Phenylketonuria in Children and Mothers: Genes, Environments, Behavior |journal=Current Directions in Psychological Science |volume=18 |issue=1 |pages=48–52 |doi=10.1111/j.1467-8721.2009.01604.x |issn=0963-7214 |pmc=2705125 |pmid=20126294}}</ref> If dietary treatment is not initiated within 2 weeks after birth, the child is likely to develop permanent intellectual disability, even if dietary interventions begin shortly thereafter.<ref name=":1" />

===Diet===
People who follow the prescribed dietary treatment from birth may (but not always) have no symptoms. Their PKU would be detectable only by a blood test. People must adhere to a diet low in Phe for optimal brain development. Since Phe is necessary to synthesize many proteins, it is required for appropriate growth, but levels must be strictly controlled.<ref name=":1" />

<!-- For people who do not have phenylketonuria, the U.S. Institute of Medicine recommended at least 33&nbsp;mg/kg body weight/day phenylalanine plus tyrosine for adults 19 years and older.<ref name="DRItext">{{Cite book |last=Institute of Medicine |author-link=Institute of Medicine |title=Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids |publisher=The National Academies Press |year=2002 |isbn=978-0-309-08525-0 |location=Washington, DC |pages=589–768 |chapter=Protein and Amino Acids |doi=10.17226/10490 |chapter-url=https://www.nap.edu/read/10490/chapter/12}}</ref> For people with PKU, a recommendation for children up to age 10 years is 200 to 500&nbsp;mg/d; for older children and adults below 600 &nbsp;mg/day. Where in the range depends on body weight and age, and on monitoring blood concentration.<ref>{{Cite journal |vauthors=Macleod EL, Ney DM |year=2010 |title=Nutritional Management of Phenylketonuria |journal=Annales Nestlé (English Ed.) |volume=68 |issue=2 |pages=58–69 |doi=10.1159/000312813 |pmc=2901905 |pmid=22475869}}</ref> -->[[File:Phenylalanine warning for phenylketonurics.jpg|thumb|Warning for people with phenylketonuria on a label for an aspartame-containing drink]]
[[Optimal health ranges]] (or "target ranges") are between 120 and 360 [[molar concentration|μmol/L]] or equivalently 2 to 6&nbsp;mg/dL. This is optimally achieved during at least the first 10 years,<ref>[https://books.google.com/books?id=BkVtT9ZyyJsC&pg=PA255 Chapter 55, page 255] {{webarchive|url=https://web.archive.org/web/20160511032418/https://books.google.com/books?id=BkVtT9ZyyJsC&pg=PA255 |date=2016-05-11 }} in:{{Cite book |last1=Behrman, Richard E. |title=Nelson essentials of pediatrics |last2=Kliegman, Robert |last3=Nelson, Waldo E. |last4=Karen Marcdante |last5=Jenson, Hal B. |publisher=Elsevier/Saunders |year=2006 |isbn=978-1-4160-0159-1}}</ref> to allow the brain to develop normally.{{Citation needed|date=September 2024}}

The diet requires restricting or eliminating foods high in Phe, such as [[soybeans]], [[egg white]]s, [[shrimp]], [[chicken breast]], [[spirulina (dietary supplement)|spirulina]], [[watercress]], [[fish as food|fish]], [[nut (fruit)|nuts]], [[crayfish]], [[lobster]], [[tuna]], [[turkey as food|turkey]], [[legume]]s, and low-fat [[cottage cheese]].<ref>{{Cite web |title=Foods highest in Phenylalanine |url=http://nutritiondata.self.com/foods-000086000000000000000-1.html |url-status=live |archive-url=https://web.archive.org/web/20150505003259/http://nutritiondata.self.com/foods-000086000000000000000-1.html |archive-date=2015-05-05 |website=self.com}}</ref> Starchy foods, such as [[potato]]es and [[maize|corn]] are generally acceptable in controlled amounts, but the quantity of Phe consumed from these foods must be monitored. A corn-free diet may be prescribed in some cases. A food diary is usually kept to record the amount of Phe consumed with each meal, snack, or drink. An "exchange" system can be used to calculate the amount of Phe in a portion of food from the protein content identified on a nutritional information label. Lower-protein "medical food" substitutes are often used in place of normal [[bread]], [[pasta]], and other grain-based foods, which contain a significant amount of Phe. Many fruits and vegetables are lower in Phe and can be eaten in larger quantities. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required.  The sweetener [[aspartame]], present in many diet foods and soft drinks, must also be avoided, as aspartame contains phenylalanine.<ref name="cfr">{{Cite web |date=1 April 2018 |title=CFR – Code of Federal Regulations, Title 21, Part 172: Food additives permitted for direct addition to food for human consumption. Subpart I – Multipurpose Additives; Sec. 172.804 Aspartame |url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.804 |access-date=22 August 2019 |publisher=US Food and Drug Administration}}</ref>

The amino acid [[tyrosine]] becomes [[Essential amino acid|essential]] in people with phenylalanine hydroxylase deficiency. Thus, in addition to the careful ''reduction'' of Phe in the diet, Tyr must be ''supplemented'' to ensure that nutritional needs are met.<ref name=":1" />

Different people can tolerate different amounts of Phe in their diet. Regular blood tests are used to determine the effects of dietary Phe intake on blood Phe level.{{Citation needed|date=February 2024}}

===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.

===Enzyme substitutes===
In 2018, the FDA approved an enzyme substitute called [[pegvaliase]] which metabolizes phenylalanine.<ref name="FDA2018Sub">{{Cite web |title=Press Announcements - FDA approves a new treatment for PKU, a rare and serious genetic disease |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm608835.htm |access-date=9 December 2018 |website=www.fda.gov |language=en}}</ref> It is for adults who are poorly managed on other treatments.<ref name=FDA2018Sub/>

[[Tetrahydrobiopterin]] (BH4) (a cofactor for the [[oxidation]] of phenylalanine) when taken by mouth can reduce [[blood]] levels of this amino acid in some people.<ref>{{Cite journal |last1=Burton |first1=Barbara K. |last2=Kar |first2=Santwana |last3=Kirkpatrick |first3=Peter |year=2008 |title=Sapropterin |journal=Nature Reviews Drug Discovery |volume=7 |issue=3 |pages=199–200 |doi=10.1038/nrd2540 |s2cid=263991793}}</ref><ref name="pmid18230057">{{Cite journal |vauthors=Michals-Matalon K |date=February 2008 |title=Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria |journal=Expert Opinion on Investigational Drugs |volume=17 |issue=2 |pages=245–51 |doi=10.1517/13543784.17.2.245 |pmid=18230057 |s2cid=207475494}}</ref>

===Mothers===
For women with PKU, it is important for the health of their children to maintain low Phe levels before and during pregnancy.<ref>{{Cite journal |vauthors=Lee PJ, Ridout D, Walter JH, Cockburn F |year=2005 |title=Maternal phenylketonuria: report from the United Kingdom Registry 1978–97 |journal=Archives of Disease in Childhood |volume=90 |issue=2 |pages=143–146 |doi=10.1136/adc.2003.037762 |pmc=1720245 |pmid=15665165}}</ref> Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly, and intellectual disability as a result.<ref>{{Cite journal |vauthors=Rouse B, Azen C, Koch R, Matalon R, Hanley W, de la Cruz F, Trefz F, Friedman E, Shifrin H |year=1997 |title=Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae |journal=American Journal of Medical Genetics |volume=69 |issue=1 |pages=89–95 |doi=10.1002/(SICI)1096-8628(19970303)69:1<89::AID-AJMG17>3.0.CO;2-K |pmid=9066890}}</ref> PKU-affected women themselves are not at risk of additional complications during pregnancy.{{citation needed|date=September 2020}}

In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6&nbsp;mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general, monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6&nbsp;mg/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2&nbsp;mg/dL, anecdotal reports indicate that the mothers may experience adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.<ref name="web">[http://www.medschool.lsuhsc.edu/genetics_center/louisiana/article_pregnancy_PKU.htm lsuhsc.edu] {{webarchive|url=https://web.archive.org/web/20080408095930/http://www.medschool.lsuhsc.edu/genetics_center/louisiana/article_pregnancy_PKU.htm |date=2008-04-08 }} Genetics and Louisiana Families</ref>