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Phenylketonuria

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"PKU" redirects here. For other uses, see PKU (disambiguation).

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Phenylketonuria
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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 phenylpyruvate (also known as phenylketone), which is detected in the urine.[citation needed]

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 be a very effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.

History

Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934[1] 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.[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. 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.

Screening and presentation

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. 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, using samples drawn by Neonatal heel prick), 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). 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. Hyperactivity, EEG abnormalities and seizures, and severe learning disabilities 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.

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 mutated 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 tetrahydrobiopterin (BH4) by the patient.[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-q24.1. 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 mutated allele of the gene for PAH, and the child must inherit two mutated 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 mutated alleles, and therefore the disease.

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.[7]

Metabolic pathways

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 through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine[8]. Elevated blood phenylalanine and 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). 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, leading to mental retardation.[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. This requires severely restricting or eliminating foods high in phenylalanine, such as meat, chicken, fish, nuts, cheese, legumes and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Infants may still be breastfed to provide all of the benefits of breastmilk, though the quantity must be monitored and supplementation will be required. 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.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low phenylalanine diet. These can continue in other forms as the child grows up such as pills, formulas, and specially formulated foods. (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.[10][11] The company BioMarin Pharmaceutical has produced a tablet preparation of the compound sapropterin (Kuvan),which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as 1/4 to 1/2 of the PKU population) keep their phenylalanine levels low[12] PKU patients who respond to Kuvan (20-56% of those who try it) may also be able to increase the amount of protein they can safely eat.[13] After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial in increasing quality of life for their patients.[14][15] Some concerns have been expressed over Kuvan's safety, cost, and the potential for PKU sufferers to override the benefits of the drug. [16]

There are a number of other therapies currently under investigation, including gene therapy, and an injectable form of PAH. Previously, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. However, most physicians now agree that this special diet should be followed throughout life.

Maternal phenylketonuria

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.[17] 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.[18] 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.[19] 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[20] to fewer than one in 100,000 births among the population of Finland.[21]

In relationships

It was discovered in 2007 that those with this disorder will discharge a concentrated amount of phenylalanine in breast milk and semen.[citation needed] If these bodily fluids are transferred between two individual phenylketonurics, there is a significant health risk to the receiving partner. The risk, however, has been determined to be statistically insignificant (for each exchange of bodily fluid, the risk is 1 in 15,000 squared, or, 1 in 225,000,000.) Since there have been no reported cases, the risk is theoretical. It was noted, however, that since the rise of the internet, people coping with this disorder have sought each other out, so the increased social interaction may become a cause for concern.[citation needed]

See also

Notes and references

  1. ^ Folling, A. (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. doi:10.1542/peds.105.1.89. PMID 10617710.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Mayo Clinic Staff (2007-12-20). "Phenylketonuria (PKU)". Mayo Clinic. Retrieved 2008-03-13. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  4. ^ Surtees, R., Blau, N. (2000). "The neurochemistry of phenylketonuria". European Journal of Pediatrics. 169: S109–13. doi:10.1007/PL00014370. PMID 11043156.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ http://www.genenames.org Phenylalanine hydroxylase (PAH) gene summary, retrieved September 8, 2006
  6. ^ Oh, H. 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. PMID 15181195.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Gibbs, Richard A. (2007). "Evolutionary and Biomedical Insights from the Rhesus Macaque Genome". Science. 316 (5822): 222–234. doi:10.1126/science.1139247. PMID 17431167. Retrieved 2008-02-26. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  8. ^ Michals, K., Matalon, R. (1985). "Phenylalanine metabolites, attention span and hyperactivity". American JouRnal of Clinical Nutrition. 42(2): 361–365. PMID 4025205.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. PMID 10207169.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Burton, BK (2008). "Fresh from the Pipeline: Sapropterin". Nature Reviews Drug Discovery. 7: 199–200. doi:10.1038/nrd2540. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  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. PMID 18230057.
  12. ^ Burton BK, Grange DK, Milanowski A, Vockley G, Feillet F, Crombez EA; et al. (2007). "The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study". Journal of Inherited Metabolic Disorders. 30: 700–707. doi:10.1007/s10545-007-0605-z. PMID 17846916. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Levy H, Burton B, Cederbaum S; et al. (2007). "Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment". Mol Genet Metab. 92 (4): 287–291. doi:10.1016/j.ymgme.2007.09.017. PMID 18036498. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK; et al. (2007). "Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study". Lancet. 370: 504–510. PMID 17693179. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  15. ^ Lee P, Treacy E, Crombez E; et al. (2008). "Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria". Am J Med Genet. 146A (22): 2851–2859. PMID 18932221. {{cite journal}}: Explicit use of et al. in: |author= (help); Text "doi:10.1002/ajmg.a.32562" ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Pollack, A (2007-12-14). "Agency Approves Drug to Treat Genetic Disorder That Can Lead to Retardation". The New York Times. Retrieved 2008-04-03.
  17. ^ 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. PMID 15665165.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link).
  18. ^ 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. PMID 9066890.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ lsuhsc.edu Genetics and Louisiana Families
  20. ^ 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. PMID 3008810.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

a dick sucking disease

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