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Phenylketonuria
Classification and external resources
Phenylalanine
ICD-10 E70.0
ICD-9 270.1
OMIM 261600
DiseasesDB 9987
MedlinePlus 001166
eMedicine ped/1787  derm/712
MeSH D010661
"PKU" redirects here. Phe redirects here For the BitTorrent feature see PHE. For the constellation see Phoenix (constellation. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books For other uses, see PKU (disambiguation).

Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the enzyme phenylalanine hydroxylase (PAH). A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Phenylalanine hydroxylase ( is an Enzyme which catalyses the reaction causing the addition of an Hydroxyl group to the end of the 6-carbon aromatic ring of This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. Phe redirects here For the BitTorrent feature see PHE. For the constellation see Phoenix (constellation. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine. Urine is a liquid waste product of the body secreted by the Kidneys by a process of filtration from Blood and Excreted through the Urethra. PKU is found on chromosome number 12.

Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures. Mental retardation is a generalized triarchic disorder characterized by subaverage cognitive functioning and deficits in two or more adaptive behaviors with onset before the age An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting 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 be a very effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.

Contents

History

Phenylketonuria was discovered by the Norwegian physician Asbjørn Følling in 1934[1] when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. Norwegians See also History of Norway and Demography of Norway. Asbjorn Folling (1888-1973 NoAsbjørn Følling) was a Norwegian Physician and Biochemist who first described the disease named after him -- Year 1934 ( MCMXXXIV) was a Common year starting on Monday (link will display full 1934 calendar of the Gregorian calendar. In Norway, this disorder is known as Følling's disease, named after its discoverer. [2] 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 (taste). 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. Benzaldehyde (C6H5CHO is a chemical compound consisting of a Benzene ring with an Aldehyde substituent Benzoic acid, C7H6O2 (or C6H5COOH is a colorless crystalline solid and the simplest Aromatic Carboxylic acid Benzene, or benzol, is an organic Chemical compound and a known Carcinogen with the molecular formula C 6 H 6 Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. The melting point of a solid is the temperature range at which it changes state from solid to Liquid. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.

Screening and presentation

Blood is taken from a two-week old infant to test for phenylketonuria
Blood is taken from a two-week old infant to test for phenylketonuria

PKU is normally detected using the HPLC test, but some clinics still use the Guthrie test, part of national biochemical screening programs. High-performance liquid chromatography (or High pressure liquid chromatography, HPLC) is a form of Column chromatography used frequently in Biochemistry The Guthrie test, also known as the Guthrie bacterial inhibition assay, is a medical test performed on newborn infants to detect Phenylketonuria, an Most babies in developed countries are screened for PKU soon after birth. [3]

If a child is not screened during the routine Newborn Screening test (typically performed at least 12 hours and generally 24-28 hours after birth), the disease may present clinically with seizures, 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). An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Albinism (from Latin albus, "white" see extended etymology) is a form of hypopigmentary Congenital disorder, Phenylacetic acid (abr PAA and Synonyms are α-toluic acid benzeneacetic acid alpha tolylic acid 2-phenylacetic acid is an Organic compound containing a In most cases a repeat test should be done at approximately 2 weeks of age to verify the initial test and uncover any Phenylketonuria that was initially missed.

Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Microcephaly is a Neurodevelopmental disorder in which the circumference of the head Hyperactivity, EEG abnormalities and seizures, and severe mental retardation are major clinical problems later in life. Hyperactivity can be described as a physical state in which a person is abnormally and easily excitable or exuberant Mental retardation is a generalized triarchic disorder characterized by subaverage cognitive functioning and deficits in two or more adaptive behaviors with onset before the age A "musty" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed. Hypopigmentation is the loss of skin color It is caused by Melanocyte depletion &mdash a decrease in the amino acid Tyrosine, which is used by melanocytes to make Eczema (from Greek έκζεμα) is a form of Dermatitis, or Inflammation of the Epidermis.

In contrast, affected children who are detected and treated are less likely to develop neurological problems and have seizures and mental retardation, though such clinical disorders are still possible.

Pathophysiology

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. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Phenylalanine hydroxylase ( is an Enzyme which catalyses the reaction causing the addition of an Hydroxyl group to the end of the 6-carbon aromatic ring of A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient. A cofactor is a non-protein Chemical compound that is bound (either tightly or loosely to an Enzyme and is required for Catalysis. Tetrahydrobiopterin, sapropterin, or BH4 is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylases [4] This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU.

The PAH gene is located on chromosome 12 in the bands 12q22-q24. Chromosome 12 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome 1. More than four hundred disease-causing mutations have been found in the PAH gene. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine). [5]

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. An allele (ˈæliːl (UK /əˈliːl/ (US (from the Greek αλληλος allelos, meaning each other) is one member of a pair or series of different forms 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. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties

Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU[6]. 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. The macaques (məˈkæk constitute a genus ( Macaca, /məˈkækə/ of Old World monkeys of the subfamily Cercopithecinae. [7]

Metabolic pathways

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. Phenylalanine hydroxylase ( is an Enzyme which catalyses the reaction causing the addition of an Hydroxyl group to the end of the 6-carbon aromatic ring of In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Phe redirects here For the BitTorrent feature see PHE. For the constellation see Phoenix (constellation. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. In Biochemistry, a transaminase or an aminotransferase is an Enzyme that Catalyzes a type of reaction between an Amino acid and an Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its Metabolites include phenylacetate, phenylpyruvate and phenylethylamine[8]. Phenylacetic acid (abr PAA and Synonyms are α-toluic acid benzeneacetic acid alpha tolylic acid 2-phenylacetic acid is an Organic compound containing a Phenethylamine, or β -phenylethylamine or 2-phenylethylamine is an Alkaloid and Monoamine. Detection of phenylketones in the urine is diagnostic.

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). The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic CD98 is a Glycoprotein that comprises the light subunit of the Large neutral Amino acid Transporter ( LAT1) 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. The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Mental retardation is a generalized triarchic disorder characterized by subaverage cognitive functioning and deficits in two or more adaptive behaviors with onset before the age [9]

Treatment

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. Phe redirects here For the BitTorrent feature see PHE. For the constellation see Phoenix (constellation. This requires severely restricting or eliminating foods high in phenylalanine, such as breast milk, meat, chicken, fish, nuts, cheese, legumes and other dairy products. Breast milk refers to the Milk produced by a mother to feed her baby In modern English usage meat most often refers to Animal tissue used as food mostly Skeletal muscle and associated Fat, but it may also refer Chicken is the Meat derived from the Chicken. It is the most common type of Poultry in the world and is frequently prepared as Food Nut is a general term for the large dry oily Seeds or Fruit of some Plants. Cheese is a Food made from Milk, usually the milk of cows, Buffalo, Goats or sheep, by coagulation. A legume is a Plant in the family Fabaceae (or Leguminosae or a Fruit of these specific plants Starchy foods such as potatoes, bread, pasta, and corn must be monitored. The potato is a Starchy Tuberous crop Vegetable from the perennial Solanum tuberosum of the Solanaceae Bread is a Staple food prepared by Baking a Dough of Flour and Water. Pasta ( Italian for "dough" is a generic term for Italian variants of Noodles. Maize (ˈmeɪz ( Zea mays L. ssp mays) known as corn in some countries is a cereal grain domesticated in Mesoamerica 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. Aspartame (or APM) (ˈæspɚteɪm or /əˈspɑrteɪm/ is the name for an artificial non- Saccharide Sweetener, aspartyl-phenylalanine-1-methyl

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. )

The oral administration of tetrahydrobiopterin (a cofactor in the oxidation of phenylalanine) can reduce blood levels of the amino acid in certain patients. Tetrahydrobiopterin, sapropterin, or BH4 is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylases Redox (shorthand for reduction-oxidation reaction describes all Chemical reactions in which atoms have their Oxidation number ( Oxidation state Blood is a specialized Bodily fluid that delivers necessary substances to the body's cells such as nutrients and oxygen—and transports Waste products [10][11] The company BioMarin Pharmaceutical has produced a tablet preparation of the compound (Kuvan), the first drug that can actually treat PKU, though concern has been expressed over its safety, cost, and the potential for PKU sufferers to override the benefits of the drug by increasing their intake of phenylalanine to dangerous levels. BioMarin Pharmaceutical ( is a biotechnology firm based in Novato, California. [12]

There are a number of other therapies currently under investigation, including gene therapy, and an injectable form of PAL. Gene therapy is the insertion of Genes into an individual's cells and tissues to treat a Disease, and Hereditary diseases in which a 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.

Maternal phenylketonuria

Phenylketonuria is inherited in an autosomal recessive fashion
Phenylketonuria is inherited in an autosomal recessive fashion

For women affected with PKU, it is essential for the health of their child to maintain low phenylalanine levels before and during pregnancy. [13] 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. [14] PKU-affected women themselves are not at risk from additional complications during pregnancy.

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. [15] 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.

Incidence

The 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[16] to fewer than one in 100,000 births among the population of Finland. Incidence is a measure of the risk of developing some new condition within a specified period of time Ireland (pronounced /ˈaɾlənd/ Éire) is the third largest island in Europe, and the twentieth-largest island in the world Finland, officially the Republic of Finland ( is a Nordic country situated in the Fennoscandian region of northern Europe. [17]

See also

Footnotes

  1. ^ Folling, A. Tetrahydrobiopterin deficiency (also known as BH4 deficiency) is a rare disorder that increases the blood levels of Phenylalanine. (1934). "Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet". Ztschr. Physiol. Chem. 227: 169-176.  
  2. ^ Centerwall, S. A. & Centerwall, W. R. (2000). "The discovery of phenylketonuria: the story of a young couple, two affected children, and a scientist.". Pediatrics 105 (1 Pt 1): 89-103. PMID 10617710.  
  3. ^ Mayo Clinic Staff. "Phenylketonuria (PKU)", Mayo Clinic, 2007-12-20. Mayo Clinic is a Non-profit medical practice Its headquarters the Mayo Medical School and its research facilities are in Rochester Minnesota in Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 69 - Vespasian, formerly a general under Nero, enters Rome to claim the title of Emperor. Retrieved on 2008-03-13. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 1138 - Cardinal Gregorio Conti is elected Antipope as Victor IV, succeeding Anacletus II.  
  4. ^ Surtees, R. , Blau, N. (2000). "The neurochemistry of phenylketonuria". European Journal of Pediatrics 169: S109-13. PMID 11043156.  
  5. ^ http://www.genenames.org Phenylalanine hydroxylase (PAH) gene summary, retrieved September 8, 2006
  6. ^ Oh, H. Events 70 - Roman forces under Titus sack Jerusalem. 1264 - The Statute of Kalisz Year 2006 ( MMVI) was a Common year starting on Sunday of the Gregorian calendar. J. , Park, E. S. , Kang, S. , Jo, I. , Jung, S. C. (2004). "Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer". Pediatric Research 56: 278-284. doi:10.1203/01.PDR.0000132837.29067.0E. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15181195.  
  7. ^ Gibbs, Richard A. ; Jeffrey Rogers, Michael G. Katze, Roger Bumgarner, George M. Weinstock, Elaine R. Mardis, Karin A. Remington, et al. (April 2007). "Evolutionary and Biomedical Insights from the Rhesus Macaque Genome". Science 316 (5822): 222-234. doi:10.1126. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  8. ^ Michals, K. , Matalon, R. (1985). "Phenylalanine metabolites, attention span and hyperactivity". American JouRnal of Clinical Nutrition 42(2): 361-365. PMID 4025205.  
  9. ^ Pietz, J. , Kreis, R. , Rupp, A. , Mayatepek, E. , Rating, D. , Boesch, C. , Bremer, H. J. (1999). "Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria". Journal of Clinical Investigation 103: 1169–1178. doi:10.1172/JCI5017. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10207169.  
  10. ^ Burton, BK; Kar S, Kirkpatrick P (2008). "Fresh from the Pipeline: Sapropterin". Nature Reviews Drug Discovery 7: 199-200. doi:10.1038/nrd2540. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  11. ^ Michals-Matalon K (2008). "Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria". Expert Opin Investig Drugs 17 (2): 245-51. doi:10.1517/13543784.17.2.245. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 18230057.  
  12. ^ Pollack, A. "Agency Approves Drug to Treat Genetic Disorder That Can Lead to Retardation", The New York Times, 2007-12-14. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 1287 - St Lucia's flood: The Zuider Zee sea wall in the Netherlands collapses killing over 50000 people Retrieved on 2008-04-03. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 1043 - Edward the Confessor is crowned King of England.  
  13. ^ Lee, P. J. , Ridout, D. , Walker, J. H. , Cockburn, F. , (2005). "Maternal phenylketonuria: report from the United Kingdom Registry 1978–97". Archives of Disease in Childhood 90: 143-146. doi:10.1136/adc.2003.037762. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15665165.  .
  14. ^ Rouse, B. , Azen, B. , Koch, R. , Matalon, R. , Hanley, W. , de la Cruz, F. , Trefz, F. , Friedman, E. , Shifrin, H. (1997). "Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies, malformations, and early neurological sequelae. ". American Journal of Medical Genetics 69 (1): 89–95. doi:10.1002/(SICI)1096-8628(19970303)69:1<89::AID-AJMG17>3.0.CO;2-K. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 9066890.  
  15. ^ lsuhsc.edu Genetics and Louisiana Families
  16. ^ DiLella, A. G. , Kwok, S. C. M. , Ledley, F. D. , Marvit, J. , Woo, S. L. C. (1986). "Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene". Biochemistry 25: 743-749. doi:10.1021/bi00352a001. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 3008810.  
  17. ^ Guldberg, P. , Henriksen, K. F. , Sipila, I. , Guttler, F. , de la Chapelle, A. (1995). "Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland". J. Med. Genet 32: 976-978. PMID 8825928.  

References

External links

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Dictionary

phenylketonuria

-noun

  1. (medicine) a metabolic disorder in which individuals lack the liver enzyme phenylalanine hydroxylase (PAH) which is needed to metabolize the amino acid phenylalanine
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