Phenylketonuria#Screening and presentation

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Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.

Because the mother's body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth. The disease is not detectable by physical examination at that time, because no damage has yet been done. Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by a heel prick, typically performed 2–7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding.{{Cite web |title=Phenylketonuria (PKU) Test |url=https://www.healthlinkbc.ca/medical-tests/hw41965 |url-status=dead |archive-url=https://web.archive.org/web/20180517005840/https://www.healthlinkbc.ca/medical-tests/hw41965 |archive-date=May 17, 2018 |access-date=Aug 28, 2020 |website=HealthLink BC}}{{Cite journal |vauthors=Berry SA, Brown C, Grant M, Greene CL, Jurecki E, Koch J, Moseley K, Suter R, van Calcar SC, Wiles J, Cederbaum S |date=August 2013 |title=Newborn screening 50 years later: access issues faced by adults with PKU |journal=Genetics in Medicine |volume=15 |issue=8 |pages=591–9 |doi=10.1038/gim.2013.10 |pmc=3938172 |pmid=23470838}}

If a child is not diagnosed during the routine newborn screening test and a phenylalanine-restricted diet is not introduced, then phenylalanine levels in the blood will increase over time. Toxic levels of phenylalanine, along with insufficient levels of tyrosine, can interfere with infant development in ways that have permanent effects. The disease may present clinically with seizures, hypopigmentation (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenylacetone). In most cases, a repeat test should be done around two weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed.{{Cite web |date=14 October 2016 |title=Phenylketonuria (PKU) |url=https://madriella.org/encyclopedia/phenylketonuria-pku/ |access-date=11 April 2021 |website=Madriella Doula Network |publisher=Madriella Network}}

Untreated children often fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities, seizures, and severe learning disabilities are major clinical problems later in life. A characteristic "musty or mousy" odor on the skin, as well as a predisposition for eczema, persists throughout life in the absence of treatment.{{Cite web |title=Phenylketonuria |url=https://markerdb.ca/conditions/267 |access-date=11 April 2021 |website=MarkerDB |publisher=Wishart Research Group}}

The damage done to the brain if PKU is untreated during the first months of life is not reversible. Affected children who are detected at birth and treated are much less likely to develop neurological problems or have seizures and intellectual disability, though such clinical disorders are still possible including asthma, eczema, anemia, weight gain, renal insufficiency, osteoporosis, gastritis, esophagus, and kidney deficiencies, kidney stones, and hypertension. Additionally, mood disorders occur 230% higher than controls; dizziness and giddiness occur 180% higher; chronic ischemic heart disease, asthma, diabetes, and gastroenteritis occur 170% higher; and stress and adjustment disorder occur 160% higher.{{Cite journal |last=Burton BK, Jones KB, Cederbaum S, Rohr F, Waisbren S, Irwin DE |display-authors=etal |year=2018 |title=Prevalence of comorbid conditions among adult patients diagnosed with phenylketonuria. |journal=Mol Genet Metab |volume=125 |issue=3 |pages=228–234 |doi=10.1016/j.ymgme.2018.09.006 |pmid=30266197 |doi-access=free}}{{Cite journal |last=Trefz KF, Muntau AC, Kohlscheen KM, Altevers J, Jacob C, Braun S |display-authors=etal |year=2019 |title=Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities - a retrospective study of German health insurance claims data. |journal=Orphanet J Rare Dis |volume=14 |issue=1 |pages=181 |doi=10.1186/s13023-019-1153-y |pmc=6647060 |pmid=31331350 |doi-access=free}} In general, however, outcomes for people treated for PKU are good. Treated people may have no detectable physical, neurological, or developmental problems at all.{{Citation needed|date=September 2024}}

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PKU is an autosomal recessive metabolic genetic disorder. As such, two PKU alleles are required for an individual to experience symptoms of the disease. For a child to inherit PKU, both parents must have and pass on the defective gene.{{Cite web |title=Phenylketonuria (PKU) - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302 |access-date=2020-03-10 |website=Mayo Clinic |language=en}} If both parents are carriers for PKU, any child they have will have a 25% chance to be born with the disorder, a 50% chance the child will be a carrier, and a 25% chance the child will neither develop nor be a carrier for the disease.

PKU is characterized by homozygous or compound heterozygous mutations in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.{{Cite book |last1=James |first1=William D. |title=Andrews' Diseases of the Skin: clinical Dermatology |last2=Berger |first2=Timothy G. |publisher=Saunders Elsevier |year=2006 |isbn=978-0-7216-2921-6}}{{Rp|541}} This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, Phe accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.{{Cite journal |last1=Gonzalez |first1=Jason |last2=Willis |first2=Monte S. |date=Feb 2010 |title=Ivar Asbjörn Følling |journal=Laboratory Medicine |volume=41 |issue=2 |pages=118–119 |doi=10.1309/LM62LVV5OSLUJOQF |doi-access=free}}

Carriers of a single PKU allele do not exhibit symptoms of the disease, but appear to be protected to some extent against the fungal toxin ochratoxin A. Louis Woolf suggested that this accounted for the persistence of the allele in certain populations,{{Cite journal |author-link=Louis Isaac Woolf |vauthors=Woolf LI |date=May 1986 |title=The heterozygote advantage in phenylketonuria |journal=American Journal of Human Genetics |volume=38 |issue=5 |pages=773–5 |pmc=1684820 |pmid=3717163}} in that it confers a selective advantage—in other words, being a heterozygote is advantageous.{{Cite book |last=Lewis |first=Ricki |title=Human Genetics |date=1997 |publisher=Wm. C. Brown |isbn=978-0-697-24030-9 |location=Chicago, IL |pages=247–248}}

The gene for PAH is located on chromosome 12 in the bands 12q22-q24.2.{{Cite book |last1=Rosenberg |first1=Roger N. |url=https://books.google.com/books?id=p3i0BdSlpukC&pg=PA820 |title=The Molecular and Genetic Basis of Neurologic and Psychiatric Disease |last2=Barchi |first2=Robert L. |author-link2=Robert L. Barchi |last3=DiMauro |first3=Salvatore |author-link3=Salvatore DiMauro |last4=Prusiner |first4=Stanley B. |author-link4=Stanley B. Prusiner |last5=Nestler |first5=Eric J. |author-link5=Eric J. Nestler |date=2003 |publisher=Butterworth-Heinemann |isbn=9780750673600 |page=820 |language=en}} As of 2000, around 400 disease-causing mutations had been found in the PAH gene. This is an example of allelic genetic heterogeneity.

When Phe cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood, which is toxic to the brain. If left untreated (and often even in treatment), complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder, as well as physical symptoms such as a "musty" odor, eczema, and unusually light skin and hair coloration.{{Cite journal |last1=Ashe |first1=Killian |last2=Kelso |first2=Wendy |last3=Farrand |first3=Sarah |last4=Panetta |first4=Julie |last5=Fazio |first5=Tim |last6=De Jong |first6=Gerard |last7=Walterfang |first7=Mark |date=2019 |title=Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments |journal=Front. Psychiatry |volume=10 |issue=561 |page=561 |doi=10.3389/fpsyt.2019.00561 |pmc=6748028 |pmid=31551819 |doi-access=free}}

Classical PKU, and its less severe forms "mild PKU" and "mild hyperphenylalaninemia" are caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts Phe to other essential compounds in the body, in particular tyrosine, which is a conditionally essential amino acid for PKU patients, because without PAH, it cannot be produced in the body through the breakdown of Phe.{{Citation needed|date=September 2024}}

PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as "hyperPhe" or "mild HPA"),{{Cite book |last1=Regier |first1=Debra S. |url=http://www.ncbi.nlm.nih.gov/books/NBK1504/ |title=GeneReviews® |last2=Greene |first2=Carol L. |date=July 25, 1993 |publisher=University of Washington, Seattle |editor-last=Adam |editor-first=Margaret P. |chapter=Phenylalanine Hydroxylase Deficiency |pmid=20301677 |editor-last2=Mirzaa |editor-first2=Ghayda M. |editor-last3=Pagon |editor-first3=Roberta A. |editor-last4=Wallace |editor-first4=Stephanie E. |editor-last5=Bean |editor-first5=Lora JH |editor-last6=Gripp |editor-first6=Karen W. |editor-last7=Amemiya |editor-first7=Anne |via=PubMed}} a less severe accumulation of phenylalanine. Compared to classic PKU patients, patients with "hyperphe" have greater PAH enzyme activity and are able to tolerate larger amounts of phenylalanine in their diets. Without dietary intervention, mild HPA patients have blood Phe levels higher than those with normal PAH activity. Currently, no international consensus exists on the definition of mild HPA, but it is most frequently diagnosed at blood Phe levels between 2 and 6 mg/dL.{{Cite journal |vauthors=de la Parra A, García MI, Waisbren SE, Cornejo V, Raimann E |date=December 2015 |title=Cognitive functioning in mild hyperphenylalaninemia |journal=Molecular Genetics and Metabolism Reports |volume=5 |pages=72–75 |doi=10.1016/j.ymgmr.2015.10.009 |pmc=5471391 |pmid=28649547}}

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). If phenylalanine is in excess in the blood, it saturates the transporter. Excessive phenylalanine levels tend to decrease the levels of other LNAAs in the brain. As these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup triggers the development of the brain, causing intellectual disability.{{Cite journal |vauthors=Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D, Boesch C, Bremer HJ |year=1999 |title=Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria |journal=Journal of Clinical Investigation |volume=103 |issue=8 |pages=1169–1178 |doi=10.1172/JCI5017 |pmc=408272 |pmid=10207169}}

Recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, and bone pathology are slightly suboptimal even for patients who are treated and maintain their Phe levels in the target range if their diets are not supplemented with other amino acids.{{Cite journal |vauthors=Enns GM, Koch R, Brumm V, Blakely E, Suter R, Jurecki E |date=1 October 2010 |title=Suboptimal outcomes in patients with PKU treated early with diet alone: Revisiting the evidence |journal=Molecular Genetics and Metabolism |volume=101 |issue=2–3 |pages=99–109 |doi=10.1016/j.ymgme.2010.05.017 |pmid=20678948}}

Classic PKU affects myelination and white-matter tracts in untreated infants; this may be one major cause of neurological problems associated with phenylketonuria. Differences in white-matter development are observable with magnetic resonance imaging. Abnormalities in the gray matter can also be detected,{{Cite journal |vauthors=Terribilli D, Schaufelberger MS |date=10 May 2020 |title=Age-related gray matter volume changes in the brain during non-elderly adulthood |journal=Neurobiology of Aging |volume=32 |issue=2–6 |pages=354–368 |doi=10.1016/j.neurobiolaging.2009.02.008 |pmc=3004040 |pmid=19282066}} particularly in the motor and premotor cortex, thalamus, and the hippocampus.{{Cite journal |last1=Hawks |first1=Zoë |last2=Hood |first2=Anna M. |last3=Lerman-Sinkoff |first3=Dov B. |last4=Shimony |first4=Joshua S. |last5=Rutlin |first5=Jerrel |last6=Lagoni |first6=Daniel |last7=Grange |first7=Dorothy K. |last8=White |first8=Desirée A. |date=2019-01-01 |title=White and gray matter brain development in children and young adults with phenylketonuria |journal=NeuroImage: Clinical |volume=23 |pages=101916 |doi=10.1016/j.nicl.2019.101916 |issn=2213-1582 |pmc=6627563 |pmid=31491833}}

PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.{{Cite journal |vauthors=Adler-Abramovich L, Vaks L, Carny O, Trudler D, Magno A, Caflisch A, Frenkel D, Gazit E |date=August 2012 |title=Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria |journal=Nature Chemical Biology |volume=8 |issue=8 |pages=701–6 |doi=10.1038/nchembio.1002 |pmid=22706200}}

{{Main|Tetrahydrobiopterin deficiency}}

A rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency, which occurs when the PAH enzyme is normal, and a defect is found in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH₄).{{Cite journal |vauthors=Surtees R, Blau N |year=2000 |title=The neurochemistry of phenylketonuria |journal=European Journal of Pediatrics |volume=169 |pages=S109–S113 |doi=10.1007/PL00014370 |pmid=11043156 |s2cid=26196359}} BH₄ is necessary for proper activity of the enzyme PAH, and this coenzyme can be supplemented as treatment. Those with this form of hyperphenylalaninemia may have a deficiency of tyrosine (which is created from phenylalanine by PAH), in which case treatment is supplementation of tyrosine to account for this deficiency.{{citation needed|date=September 2020}}

Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to convert Phe to Tyr and is required to convert Tyr to L-DOPA via the enzyme tyrosine hydroxylase. L-DOPA, in turn, is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU (without dihydrobiopterin involvement), prolactin levels would be relatively normal.{{Cite journal |last1=Opladen |first1=Thomas |last2=López-Laso |first2=Eduardo |date=26 May 2020 |title=Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |page=126 |doi=10.1186/s13023-020-01379-8 |pmc=7251883 |pmid=32456656 |doi-access=free}}{{citation needed|date=September 2020}}

As of 2020, tetrahydrobiopterin deficiency was known to result from defects in five genes.{{Cite journal |vauthors=Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, García-Cazorla A, Honzík T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thöny B, Scholl-Bürgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhánek J, Kuseyri Hübschmann O |date=May 2020 |title=Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |pages=126 |doi=10.1186/s13023-020-01379-8 |pmc=7251883 |pmid=32456656 |doi-access=free}}

File:Inborn errors of metabolism of phenylalanine and tyrosine.svg (new variant subtype) utilized in the first step of the metabolic pathway.]]

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not occur, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine.{{Cite journal |vauthors=Michals K, Matalon R |year=1985 |title=Phenylalanine metabolites, attention span and hyperactivity |journal=American Journal of Clinical Nutrition |volume=42 |issue=2 |pages=361–5 |doi=10.1093/ajcn/42.2.361 |pmid=4025205}} Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however, most patients are diagnosed via newborn screening.{{citation needed|date=October 2021}}{{Cite web |title=Phenylketonuria (PKU) - Diagnosis |url=https://www.mayoclinic.org/diseases-conditions/phenylketonuria/diagnosis-treatment/drc-20376308 |access-date=18 July 2024 |website=Mayo Clinic}}

Image:Phenylketonuria testing.jpg

PKU is commonly included in the newborn screening panel of many countries, with varied detection techniques. Most babies born in Europe, North America, and Australia are screened for PKU soon after birth.{{Cite news |last=Mayo Clinic Staff |date=2007-12-20 |title=Phenylketonuria (PKU) |url=http://www.mayoclinic.com/health/phenylketonuria/DS00514/DSECTION=1 |url-status=live |archive-url=https://web.archive.org/web/20080317011112/http://www.mayoclinic.com/health/phenylketonuria/DS00514/DSECTION%3D1 |archive-date=2008-03-17 |access-date=2008-03-13 |publisher=Mayo Clinic}}{{Cite book |last=Longo |first=Nicola |title=Harrison's Principles of Internal Medicine |publisher=McGraw Hill |year=2022 |edition=21st |location=New York |chapter=Chapter 420: Inherited Disorders of Amino Acid Metabolism in Adults}} Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU.{{Cite book |title=Pediatric Endocrinology and Inborn Errors of Metabolism |publisher=McGraw Hill Medical |editor-last=Sarafoglou |editor-first=Kyriakie |location=New York |page=26 |editor-last2=Hoffmann |editor-first2=Georg F. |editor-last3=Roth |editor-first3=Karl S.}}

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.{{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}} 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.

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.

File:Phenylalanine warning for phenylketonurics.jpg

Optimal health ranges (or "target ranges") are between 120 and 360 μmol/L or equivalently 2 to 6 mg/dL. This is optimally achieved during at least the first 10 years,[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}} 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 whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, legumes, and low-fat cottage cheese.{{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}} Starchy foods, such as potatoes and 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.{{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}}

The amino acid tyrosine becomes 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.

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}}

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.{{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}} 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).{{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}} The LNAAs (e.g. leu, tyr, trp, met, his, ile, val, 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{{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}} 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{{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}} and increased satiety{{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}} compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved 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 and will therefore help maintain plasma Phe levels in the target range.

In 2018, the FDA approved an enzyme substitute called pegvaliase which metabolizes phenylalanine.{{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}} It is for adults who are poorly managed on other treatments.

Tetrahydrobiopterin (BH4) (a cofactor for the oxidation of phenylalanine) when taken by mouth can reduce blood levels of this amino acid in some people.{{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}}{{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}}

For women with PKU, it is important for the health of their children to maintain low Phe levels before and during pregnancy.{{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}} 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.{{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}} 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 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 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 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.[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

The average number of new cases of PKU varies in different human populations. United States Caucasians are affected at a rate of 1 in 10,000.{{Cite journal |last1=Bickel, H. |last2=Bachmann, C. |last3=Beckers, R. |last4=Brandt, N.J. |last5=Clayton, B.E. |last6=Corrado, G |display-authors=etal |year=1981 |title=Neonatal mass screening for metabolic disorders |url=https://link.springer.com/article/10.1007/BF00441305 |journal=European Journal of Pediatrics |volume=137 |pages=133–139 |doi=10.1007/BF00441305 |s2cid=44705699 |number=137}} Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births. A 1987 study from Slovakia reports a Roma population with an extremely high incidence of PKU (one case in 40 births) due to extensive inbreeding.{{Cite journal |vauthors=Ferák V, Siváková D, Sieglová Z |year=1987 |title=Slovenskí Cigáni (Rómovia) – populácia s najvyšším koeficientom inbrídingu v Európe. |journal=Bratislavské Lekárske Listy |volume=87 |pages=168–175 |number=2}} It is the most common amino acid metabolic problem in the United Kingdom.{{citation needed|date=May 2015}}

Before the causes of PKU were understood, PKU caused severe disability in most people who inherited the relevant mutations. Nobel and Pulitzer Prize-winning author Pearl S. Buck had a daughter named Carol who lived with PKU before treatment was available, and wrote an account of its effects in a book called The Child Who Never Grew.{{Cite journal |vauthors=Borg C, Mondot S, Mestre M, Cavero I |date=November 1991 |title=Nicorandil: differential contribution of K+ channel opening and guanylate cyclase stimulation to its vasorelaxant effects on various endothelin-1-contracted arterial preparations. Comparison to aprikalim (RP 52891) and nitroglycerin |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=259 |issue=2 |pages=526–34 |pmid=1682478}} Many untreated PKU patients born before widespread newborn screening are still alive, largely in dependent living homes/institutions.{{Cite web |title=NPKUA > Education > About PKU |url=http://www.npkua.org/Education/AboutPKU.aspx |url-status=live |archive-url=https://web.archive.org/web/20150101143758/http://www.npkua.org/Education/AboutPKU.aspx |archive-date=2015-01-01 |website=npkua.org}}

Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934{{Cite journal |last=Følling |first=Asbjørn |date=1 January 1934 |title=Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. |journal=Hoppe-Seyler's Zeitschrift für Physiologische Chemie |volume=227 |issue=1–4 |pages=169–181 |doi=10.1515/bchm2.1934.227.1-4.169}} when he noticed hyperphenylalaninemia (HPA) was associated with intellectual disability. In Norway, this disorder is known as Følling's disease, named after its discoverer.{{Cite journal |vauthors=Centerwall SA, Centerwall WR |year=2000 |title=The discovery of phenylketonuria: the story of a young couple, two affected children, and a scientist |journal=Pediatrics |volume=105 |issue=1 Pt 1 |pages=89–103 |doi=10.1542/peds.105.1.89 |pmid=10617710 |s2cid=35922780}} Følling was one of the first physicians to apply detailed chemical analysis to the study of disease.{{Citation needed|date=September 2024}}

In 1934 at Rikshospitalet, Følling saw a young woman named Borgny Egeland. She had two children, Liv and Dag, who had been normal at birth but subsequently developed intellectual disability. When Dag was about a year old, the mother noticed a strong smell in his urine. Følling obtained urine samples from the children and, after many tests, he found that the substance causing the odor in the urine was phenylpyruvic acid. The children, he concluded, had excess phenylpyruvic acid in the urine, the condition which came to be called phenylketonuria (PKU).

His analysis of the urine of the two affected siblings led him to request many physicians near Oslo to test the urine of other affected patients. This led to the discovery of the same substance he had found in eight other patients. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine.{{Cite journal |last1=Williams |first1=RA |last2=Mamotte |first2=CD |last3=Burnett |first3=JR |date=2008 |title=Phenylketonuria: an inborn error of phenylalanine metabolism |journal=The Clinical Biochemist Reviews |volume=29 |issue=1 |pages=31–41 |pmc=2423317 |pmid=18566668 |quote=Mild oxidation of the purified substance produced a compound which smelled of benzoic acid, leading Følling to postulate that the compound was phenylpyruvic acid.3 There was no change in the melting point upon mixing of the unknown compound with phenylpyruvic acid thus confirming the mystery compound was indeed phenylpyruvic acid.}}

In 1954, Horst Bickel, Evelyn Hickmans and John Gerrard published a paper that described how they created a diet that was low in phenylalanine and the patient recovered. Bickel, Gerrard, and Hickmans were awarded the John Scott Medal in 1962 for their discovery.{{Citation |last=Marelene Rayner-Canham, Geoff Rayner-Canham |title=Evelyn Hickmans |work=Chemistry was Their Life: Pioneer British Women Chemists, 1880–1949 |pages=198 |year=2008 |publisher=World Scientific |isbn=9781908978998}}

PKU was the first disorder to be routinely diagnosed through widespread newborn screening. Robert Guthrie introduced the newborn screening test for PKU in the early 1960s.{{Cite journal |vauthors=Mitchell JJ, Trakadis YJ, Scriver CR |year=2011 |title=Phenylalanine hydroxylase deficiency |journal=Genetics in Medicine |volume=13 |issue=8 |pages=697–707 |doi=10.1097/GIM.0b013e3182141b48 |pmid=21555948 |s2cid=25921607 |doi-access=free}} With the knowledge that PKU could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. Ireland was the first country to introduce a national screening programme in February 1966,{{Cite book |last=Koch |first=Jean |title=Robert Guthrie--the PKU story: crusade against mental retardation |date=1997 |publisher=Hope Pub. House |isbn=0932727913 |location=Pasadena, Calif. |pages=65–66 |oclc=36352725}} Austria also started screening in 1966{{Cite journal |vauthors=Kasper DC, Ratschmann R, Metz TF, Mechtler TP, Möslinger D, Konstantopoulou V, Item CB, Pollak A, Herkner KR |year=2010 |title=The National Austrian Newborn Screening Program – Eight years experience with mass spectrometry. Past, present, and future goals |journal=Wiener Klinische Wochenschrift |volume=122 |issue=21–22 |pages=607–613 |doi=10.1007/s00508-010-1457-3 |pmid=20938748 |s2cid=27643449}} and England in 1968.{{Cite journal |vauthors=Komrower GM, Sardharwalla IB, Fowler B, Bridge C |year=1979 |title=The Manchester regional screening programme: A 10-year exercise in patient and family care |journal=British Medical Journal |volume=2 |issue=6191 |pages=635–638 |doi=10.1136/bmj.2.6191.635 |pmc=1596331 |pmid=497752}}

In 2017, the European Guidelines were published.{{Cite journal |vauthors=van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ |date=October 2017 |title=The complete European guidelines on phenylketonuria: diagnosis and treatment |journal=Orphanet Journal of Rare Diseases |language=En |volume=12 |issue=1 |pages=162 |doi=10.1186/s13023-017-0685-2 |pmc=5639803 |pmid=29025426 |doi-access=free}} They were called for by the patient organizations such as the European Society for Phenylketonuria and Allied Disorders Treated as Phenylketonuria.{{Cite news |title=Consensus Paper - E.S.PKU |url=https://www.espku.org/projects/consensus-paper/ |access-date=2018-11-23 |work=E.S.PKU |language=en-GB}}{{Cite journal |vauthors=Hagedorn TS, van Berkel P, Hammerschmidt G, Lhotáková M, Saludes RP |date=December 2013 |title=Requirements for a minimum standard of care for phenylketonuria: the patients' perspective |journal=Orphanet Journal of Rare Diseases |language=En |volume=8 |issue=1 |pages=191 |doi=10.1186/1750-1172-8-191 |pmc=3878574 |pmid=24341788 |doi-access=free}} They have received some critical reception.{{Cite journal |vauthors=Burgard P, Ullrich K, Ballhausen D, Hennermann JB, Hollak CE, Langeveld M, Karall D, Konstantopoulou V, Maier EM, Lang F, Lachmann R, Murphy E, Garbade S, Hoffmann GF, Kölker S, Lindner M, Zschocke J |date=September 2017 |title=Issues with European guidelines for phenylketonuria |journal=The Lancet. Diabetes & Endocrinology |volume=5 |issue=9 |pages=681–683 |doi=10.1016/S2213-8587(17)30201-2 |pmid=28842158 |doi-access=free}}

The word phenylketonuria uses combining forms of phenyl + ketone + -uria; it is pronounced {{IPAc-en|ˌ|f|iː|n|aɪ|l|ˌ|k|iː|t|ə|ˈ|nj|ʊər|i|ə|,_|ˌ|f|ɛ|n|-|,_|-|n|ɪ|l|-|,_|-|n|əl|-|,_|-|t|oʊ|-}}{{refn|{{MerriamWebsterDictionary|Phenylketonuria}}}}{{refn|{{Cite encyclopedia |title=Phenylketonuria |encyclopedia=Lexico UK English Dictionary |publisher=Oxford University Press |url=http://www.lexico.com/definition/Phenylketonuria |archive-url=https://web.archive.org/web/20200805104920/https://www.lexico.com/definition/phenylketonuria |archive-date=2020-08-05 |url-status=dead}} }}.

Other therapies are under investigation, including gene therapy.

BioMarin is conducting clinical trials to investigate PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase or 'PAL'), which is an enzyme substitution therapy in which the missing PAH enzyme is replaced with an analogous enzyme that also breaks down Phe. PEG-PAL was in Phase 2 clinical development as of 2015,{{Cite web |title=BioMarin : Pipeline: Pipeline Overview: BMN 165 for PKU |url=https://www.bmrn.com/pipeline/peg-pal-for-pku.php |url-status=dead |archive-url=https://web.archive.org/web/20150101054444/https://www.bmrn.com/pipeline/peg-pal-for-pku.php |archive-date=2015-01-01 |website=bmrn.com}} but was put on clinical hold in September 2021. In February 2022, the FDA issued a statement requiring further data from non-clinical studies to assess oncogenic risk resulting from PEG-PAL treatments.{{Cite web |title=BioMarin Provides Updates on Progress in Gene Therapy Programs |url=https://investors.biomarin.com/2022-02-17-BioMarin-Provides-Updates-on-Progress-in-Gene-Therapy-Programs |access-date=2023-09-04 |website=BioMarin Investors |language=en-US}}

• Hyperphenylalanemia
• Lofenalac
• Tetrahydrobiopterin deficiency
• Flowers for Algernon, which features a character who has PKU.

{{Reflist}}

{{Medical resources

| oMIM_mult = {{OMIM2|261630}}

| orphanet_mult = {{Orphanet2|226}}

| DiseasesDB = 9987

| ICD11 = {{ICD11|5C50.0}}

| ICD10 = {{ICD10|E70.0}}, {{ICD10|E70.1}}

| ICD9 = {{ICD9|270.1}}

| OMIM = 261600

| MedlinePlus = 001166

| eMedicineSubj = ped

| eMedicineTopic = 1787

| eMedicine_mult = {{eMedicine2|derm|712}} {{eMedicine2|article|947781}}

| MeshID = D010661

| GeneReviewsName = Phenylalanine Hydroxylase Deficiency

| GeneReviewsNBK = NBK1504

| Orphanet = 716

}}

{{Amino acid metabolic pathology}}

Category:Intellectual disability

Category:Autosomal recessive disorders

Category:Amino acid metabolism disorders

Category:Skin conditions resulting from errors in metabolism

Category:Disorders causing seizures

Category:Biology of attention deficit hyperactivity disorder

Category:Rare diseases

Category:Wikipedia medicine articles ready to translate

Category:Newborn screening