Editing Phenylketonuria (section)

==Pathophysiology==
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.<ref>{{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}}</ref>

===Classical PKU===
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"),<ref>{{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}}</ref> 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&nbsp;mg/dL.<ref>{{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}}</ref>

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the [[blood–brain barrier]] (BBB) via the [[CD98|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 [[Human brain|brain]], causing intellectual disability.<ref name="Pietz">{{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}}</ref>

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.<ref name="pmid20678948">{{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}}</ref>

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,<ref>{{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}}</ref> particularly in the motor and premotor cortex, thalamus, and the hippocampus.<ref>{{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}}</ref>

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.<ref>{{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}}</ref>

===Tetrahydrobiopterin-deficient hyperphenylalaninemia===
{{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 (biochemistry)|cofactor]] [[tetrahydrobiopterin]] (BH<sub>4</sub>).<ref>{{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}}</ref> BH<sub>4</sub> 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.<ref>{{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}}</ref>{{citation needed|date=September 2020}}

As of 2020, tetrahydrobiopterin deficiency was known to result from defects in five genes.<ref name="pmid32456656">{{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}}</ref>

===Metabolic pathways===

[[File:Inborn errors of metabolism of phenylalanine and tyrosine.svg|800px|centre|thumb|Pathophysiology of phenylketonuria, which is due to the absence of functional phenylalanine hydroxylase (classical subtype) or functional enzymes for the recycling of [[tetrahydrobiopterin]] (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 [[glutamic acid|glutamate]]. Metabolites include [[phenylacetic acid|phenylacetate]], [[phenylpyruvate]] and [[phenethylamine]].<ref>{{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}}</ref> 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}}<ref>{{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}}</ref>