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| {{Phenylketonuria}}
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| '''For patient information click [[Phenylketonuria (patient information)|here]]'''
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| {{CMG}}; {{AE}}
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| ==Overview==
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| '''Phenylketonuria''' ('''PKU''') is an [[autosomal recessive]] [[genetic disorder]] characterized by a deficiency in the enzyme [[phenylalanine hydroxylase]] (PAH). This enzyme is necessary to metabolize the amino acid [[phenylalanine]] to the amino acid [[tyrosine]]. When PAH is deficient, phenylalanine accumulates and is converted into phenylketones, which are detected in the [[urine]].
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| Left untreated, this condition can cause problems with brain development, leading to progressive [[mental retardation]] and [[seizures]]. However, PKU is one of the few genetic diseases that can be controlled by diet. A diet low in phenylalanine and high in tyrosine can bring about a nearly total cure.
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| == History ==
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| Phenylketonuria was discovered by the [[Norwegians|Norwegian]] physician [[Asbjorn_Folling|Asbjørn Følling]] in 1934<ref name="Folling">{{cite journal | author=Folling, A. | year=1934 | title=Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet | journal=Ztschr. Physiol. Chem. | volume=227 | pages=169-176}}</ref> when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as '''Følling's disease''', named after its discoverer.<ref>{{cite journal | author=Centerwall, S. A. & Centerwall, W. R. | year=2000 | title=The discovery of phenylketonuria: the story of a young couple, two affected children, and a scientist. | url=http://pediatrics.aappublications.org/cgi/content/full/105/1/89 | journal=Pediatrics | volume=105 (1 Pt 1) | pages=89-103 | id=PMID 10617710}}</ref> Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of 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 that he had found in eight other patients. The substance found was subjected to much more basic and rudimentary chemical analysis. He conducted tests and found reactions that gave rise to [[benzaldehyde]] and [[benzoic acid]], which led him to conclude 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. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.
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| ==Screening and presentation==
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| [[Image:Phenylketonuria testing.jpg|left|thumb|Blood is taken from a two-week old infant to test for phenylketonuria]]
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| PKU is normally detected using the [[HPLC]] test, but some clinics still use the [[Guthrie test]], part of national biochemical screening programs.
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| If a child is not screened at birth (e.g. in home deliveries), the disease may present clinically with [[seizure]]s, [[albinism]] (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to [[phenylacetate]], one of the ketones produced).
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| Untreated children are normal at birth, but fail to attain early developmental milestones, develop [[microcephaly]], and demonstrate progressive impairment of cerebral function. [[Hyperactivity]], [[Electroencephalography|EEG]] abnormalities and seizures, and severe [[mental retardation]] are major clinical problems later in life. A "musty" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to [[hypopigmentation]] and [[eczema]] are also observed.
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| In contrast, affected children who are detected and treated at birth are less likely to develop neurological problems and have seizures and mental retardation, though such clinical disorders are still possible.
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| ==Pathophysiology==
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| Classical PKU is caused by a defective gene for the [[enzyme]] [[phenylalanine hydroxylase]] (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the [[Cofactor (biochemistry)|cofactor]] [[tetrahydrobiopterin|5,6,7,8-tetrahydrobiopterin]] (BH<sub>4</sub>) by the patient.<ref>{{cite journal | author=Surtees, R., Blau, N. | year=2000 | title=The neurochemistry of phenylketonuria | journal=European Journal of Pediatrics | volume=169 | pages=S109-13 | id=PMID 11043156}}</ref> This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU <ref>[http://www.lulu.com/content/642697 PKU 2007] Genetics of Phenylketonuria - A Comprehensive Review</ref>.
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| The PAH gene is located on [[chromosome 12]] in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene.<ref>[http://www.lulu.com/content/642697 PKU 2007] Genetics of Phenylketonuria - A Comprehensive Review</ref>. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).<ref>[http://www.genenames.org/data/hgnc_data.php?hgnc_id=8582 http://www.genenames.org] Phenylalanine hydroxylase (PAH) gene summary, retrieved [[September 8]], [[2006]]</ref>
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| PKU is an [[autosomal recessive]] genetic disorder, meaning that each parent must have at least one defective [[allele]] of the gene for PAH, and the child must inherit two defective alleles, one from each parent. As a result, it is possible for a parent with PKU [[phenotype]] to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two defective alleles, and therefore the disease.
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| Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU<ref>{{cite journal | author=Oh, H. J., Park, E. S., Kang, S., Jo, I., Jung, S. C. | year=2004 | url=http://www.pedresearch.org/cgi/content/full/56/2/278 | title=Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer | journal=Pediatric Research | volume=56 | pages=278-284 | id=PMID 15181195}}</ref>. The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence which in humans would be considered the PKU mutation.
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| ===Metabolic pathways===
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| [[Image:PKU.PNG|centre|500px|thumb|Simplified pathway for phenylalanine metabolism<ref name="Folling"/>]]
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| The enzyme [[phenylalanine hydroxylase]] normally converts the [[amino acid]] [[phenylalanine]] into the amino acid [[tyrosine]]. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones though the minor route, a [[transaminase]] pathway with [[glutamate]]. Metabolites include [[phenylacetate]], phenylpyruvate and [[phenylethylamine]]<ref>{{cite journal | author=Michals, K., Matalon, R. | title=Phenylalanine metabolites, attention span and hyperactivity | journal=American Journal of Clinical Nutrition | year=1985 | volume=42(2) | pages=361-365 | id=PMID 4025205}}</ref>. Detection of phenylketones in the urine is diagnostic.
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| 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). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts [[brain]] development in children, leading to [[mental retardation]].<ref name="Pietz">{{cite journal | author=Pietz, J., Kreis, R., Rupp, A., Mayatepek, E., Rating, D., Boesch, C., Bremer, H. J. | year=1999 | url=http://www.jci.org/cgi/content/full/103/8/1169 | title=Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria | journal=Journal of Clinical Investigation | volume=103 | pages=1169–1178 | id=PMID 10207169}}</ref>
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| == Treatment ==
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| If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by eating a special diet low in [[phenylalanine]] for the rest of his or her life. This requires severely restricting or eliminating foods high in phenylalanine, such as [[breast milk]], meat, chicken, fish, nuts, cheese and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid. Some drugs such as [[lacosamide]] oral solution may contain aspartame as an ingredient.
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| Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a protein free diet. These can continue in other forms as the child grows up. (Since phenylalanine is necessary for the synthesis of many proteins, it is required but levels must be strictly controlled. In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented.)
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| In those patients with a deficit in BH<sub>4</sub> production, or with a PAH PAH mutation resulting in a low affinity of PAH for BH<sub>4</sub>, treatment consists of giving BH<sub>4</sub> as a supplement; this is referred to as BH<sub>4</sub> responsive PKU.
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| There are a number of other therapies currently under investigation, including [[gene therapy]], and an injectable form of PAH. In 2007, a new treatment, a drug named Kuvan, was approved by the FDA. The generic name is sapropterin dihydrochloride,and is a form of BH<sub>4</sub>. However, the expected cost of $57,000/year for children and up to $200,000/year for adults means that this treatment will likely be out for those who are uninsured. <ref>http://www.nytimes.com/2007/12/14/health/14genetic.html?ref=us</ref>
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| Treatment of PKU includes the elimination of phenylalanine from the diet, and supplementation of the diet with tyrosine and other amino acids, vitamins and minerals that are otherwise missing from the diet. Phenylalanine is commonly found in protein-containing foods such as meat, dairy products, fish, grains and legumes. Babies who are diagnosed with PKU must immediately be put on a special milk/formula substitute. Later in life, the diet continues to exclude phenylalanine-containing foods.
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| Previously, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. However, physicians now recommend that this special diet should be followed throughout life.
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| ===Maternal phenylketonuria===
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| [[Image:autorecessive.svg|thumb|left|250px|Phenylketonuria is inherited in an [[Recessive gene|autosomal recessive]] fashion]]
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| For women affected with PKU, it is essential for the health of their child to maintain low phenylalanine levels before and during pregnancy.<ref>{{cite journal | author=Lee, P.J., Ridout, D., Walker, J.H., Cockburn, F., | title=Maternal phenylketonuria: report from the United Kingdom Registry 1978–97 | journal=Archives of Disease in Childhood | volume=90 | pages=143-146 | year=2005 | id=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 result is that the child may develop congenital heart disease, growth retardation, microcephaly and mental retardation.<ref>{{cite journal | author=Rouse, B., Azen, B., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., Shifrin, H. | title=Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae. | journal=American Journal of Medical Genetics | year=1997 | volume=69 | issue=1 | pages= 89–95 | id=PMID 9066890}}</ref> PKU-affected women themselves are not at risk from additional complications during pregnancy.
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| In most countries, women with PKU who wish to have children are advised to lower their blood phenylalanine levels before they become pregnant and carefully control their phenylalanine levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, generally monitored on a day-to-day basis by a specialist metabolic dietitian. 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] Genetics and Louisiana Families</ref>
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| Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated that an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep their phenylalanine levels low. More research is needed.
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| ==Incidence==
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| The [[incidence (epidemiology)|incidence]] of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the population of Ireland<ref>{{cite journal | author=DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., Woo, S. L. C. | year=1986 | title=Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene | journal=Biochemistry | volume=25 | pages=743-749 | id=PMID 3008810}}</ref> to fewer than one in 100,000 births among the population of Finland.<ref>{{cite journal | author=Guldberg, P., Henriksen, K. F., Sipila, I., Guttler, F., de la Chapelle, A. | year=1995 | title=Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland | journal=J. Med. Genet | volume=32 | pages=976-978 | id=PMID 8825928}}</ref>
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| ==See also==
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| * [[Tetrahydrobiopterin deficiency]]
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| ==References==
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| {{Reflist}}
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| *Frank L. Lyman. (1963) ''Phenylketonuria'' Springfield: Thomas. 318 p.
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| *Bickel, H.; F. P. Hudson & L. I. Woolf. (1971) ''Phenylketonuria and some other inborn errors of amino acid metabolism: biochemistry, genetics, diagnosis, therapy'' Stuttgart, G. Thieme Verlag. 336 p. ISBN 3134669013.
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| {{metabolic pathology}}
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| [[Category:Metabolic disorders]]
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| [[Category:Genetic disorders]]
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| [[Category:Congenital disorders]]
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| [[Category:Pediatrics]]
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| [[Category:Neurology]]
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| [[Category:Metabolism]]
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| [[Category:Inborn errors of metabolism]]
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