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Phenylketonuria

Phenylketonuria introduction:
Phenylketonuria (PKU) is a genetic disorder that is characterized by an inability of the body to utilize the essential amino acid, phenylalanine. Amino acids are the building blocks for body proteins. 'Essential' amino acids can only be obtained from the food we eat as our body does not normally produce them. In 'classic PKU', the enzyme that breaks down phenylalanine phenylalaninehydroxylase is completely or nearly completely deficient. This enzyme normally converts phenylalanine to another amino acid, tyrosine. Without this enzyme, phenylalanine and its' breakdown chemicals from other enzyme routes, accumulate in the blood and body tissues, and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.
Although the term 'hyperphenylalaninemia' strictly means elevated blood phenylalanine, it is usually used to describe a group of disorders other than classic PKU. These other disorders may be caused by a partial deficiency of the phenylalanine breakdown enzyme or the lack of another enzyme important to the processing of this amino acid. A normal blood phenylalanine level is about 1 mg/dl. In classic PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. Levels are somewhat less in the other disorders of hyperphenylalaninemia. Chronically high levels of phenylalanine and some of its breakdown products can cause significant brain problems. Classic PKU is the most common cause of high levels of phenylalanine in the blood and will be the primary focus of this topic sheet.

History:

Phenylketonuria was discovered by the Norwegianphysician Ivar Asbjorn Follingin 1934when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Falling's disease, named after its discoverer. Dr. Folling 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 benzaldehydeand benzoic acid, which led him to conclude the compound contained a benzenering. Further testing showed the melting pointto 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.
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 or mousy" 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 or have seizures and mental retardation, though such clinical disorders are still possible.

Pathophysiology:

Classical PKU is caused by a mutated gene for the enzymephenylalaninehydroxylase(PAH), which converts the amino acid phenylalanine to other essential compounds in the body.
Classical PKU

The PAH gene is located on chromosome 12in 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)
PKU is an autosomal recessivegenetic disorder, meaning that each parent must have at least one mutated alleleof 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 phenotypeto 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. The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalaninehydroxylase has the same sequence which in humans would be considered the PKU mutation.

Tetrahydrobiopterin-deficient hyperphenylalaninemia

A rarer form of hyperphenilalaninemia occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactortetrahydrobiopterin(BH4) by the patient. This cofactor is necessary for proper activity of the enzyme.
Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterinis required to convert phenylalanine to tyrosine, but it is also required to convert tyrosine to DOPA(via the enzyme tyrosinehydroxylase), which in turn is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four different genes. These types are known as HPABH4A, HPABH4B, HPABH4C, and HPABH4D.

bolic pathways:
The enzyme phenylalaninehydroxylasenormally converts the amino acid phenylalanineinto the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be bolized into phenylketones through the minor route, a transaminasepathway with glutamate.
bolites include phenylacetate, phenylpyruvateand phenethylamine. Elevated blood just because 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 braindevelopment, leading to mental retardation.

Symptoms:
Infants with PKU appear normal at birth. Many have blue eyes and fairer hair and skin than other family members. Currently, most symptoms of untreated PKU are avoided by newborn screening, early identification, and management. The following describes untreated PKU symptoms-currently a rarity: About 50% of untreated infants have early symptoms, such as vomiting, irritability, an eczema-like rash, and a mousy odor to the urine. Some may also have subtle signs of nervous system function problems, such as increased muscle tone, and more active muscle tendon reflexes. Later, severe brain problems occur, such as mental retardation and seizures. Other commonly noted features in untreated children include: microcephaly (small head), prominent cheek and upper jaw bones with widely spaced teeth, poor development of tooth enamel, and decreased body growth.

Maternal phenylketonuria:
Phenylketonuria is inherited in anautosomal recessivefashion.
For women affected with PKU, it is essential for the health of their child to maintain low phenylalanine levels before and during pregnancy. 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. 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 (typically to between 2 and 6 micromol/deciliter) 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 bolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood phenylalanine levels will drop, requiring an increased phenylalanine intake to remain within the safe range of 2-6 micromol/dL. The mother's daily phenylalanine intake may double or even triple by the end of the pregnancy as a result. When maternal blood phenylalanine levels fall below 2 micromol/dL, anecdotal reports indicate that the mothers may suffer 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. Babies with PKU may drink breast milk, while also taking their special bolic 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 incidenceof 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 Irelandto 1 in 13,000 births in Norwayto fewer than one in 100,000 births among the population of Finland. Turkey, at 1 in 2600, has the highest incidence rate in the world. The illness is also more common in Italy and China, as well as in Yemeni populations.

Treatment:

If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling phenylalanine(Phe) levels through diet, or a combination of diet and medication. When phenylalanine can't be bolized by the body, abnormally high levels accumulate in the blood and are toxic to the brain. When left untreated, complications of PKU include severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning and abnormal behavior such as ADHD.
All PKU patients must adhere to a special diet low in phenylalanine for at least the first 16 years of their lives. This requires severely restricting or eliminating foods high in phenylalanine, such as meat, chicken, fish, nuts, cheese, legumesand other dairy products. Starchy foods such as potatoes, bread, pasta, and cornmust be monitored. Infants may still be breastfed to provide all of the benefits of breast milk, but the quantity must also be monitored and supplementation for missing nutrients will be required. Many diet foods and diet soft drinks that contain the sweetener aspartamemust 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 be replaced 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 for appropriate growth but levels must be strictly controlled in PKU patients). In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented.)
The oral administration of tetrahydrobiopterin(or BH4) (a cofactor for the oxidationof phenylalanine) can reduce blood levels of this amino acid in certain patients. The company BioMarin Pharmaceuticalhas produced a tablet preparation of the compound sapropterin dihydrochloride (Kuvan),which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges. Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat. 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 to patients with PKU.
There are a number of other therapies currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). Previously, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. Today most physicians recommend that PKU patients need to manage their Phe levels throughout life.

1. James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
2. Folling, A. (1934). "Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet". Ztschr. Physiol. Chem. 227: 169–176.
3. 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. http://pediatrics.aappublications.org/cgi/content/full/105/1/89.
4. Mayo Clinic Staff (2007-12-20). "Phenylketonuria (PKU)". Mayo Clinic. http://www.mayoclinic.com/health/phenylketonuria/DS00514/DSECTION=1. Retrieved 2008-03-13.
5. http://www.genenames.org/data/hgnc_data.php?hgnc_id=8582 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. http://www.pedresearch.org/cgi/content/full/56/2/278.
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/science.1139247. PMID 17431167. http://www.sciencemag.org/cgi/content/full/316/5822/222. Retrieved 2008-02-26.
8. Surtees, R., Blau, N. (2000). "The neurochemistry of phenylketonuria". European Journal of Pediatrics 169: S109–13. doi:10.1007/PL00014370. PMID 11043156.
9. ^ Online 'Mendelian Inheritance in Man' (OMIM) 261640
10. ^ Michals, K., Matalon, R. (1985). "Phenylalanine bolites, attention span and hyperactivity". American Journal of Clinical Nutrition 42(2): 361–365. PMID 4025205.
11. 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. http://www.jci.org/cgi/content/full/103/8/1169.
12. Burton, BK; Kar S, Kirkpatrick P (2008). "Fresh from the Pipeline: Sapropterin". Nature Reviews Drug Discovery 7: 199–200. doi:10.1038/nrd2540. http://www.nature.com/nrd/journal/v7/n3/full/nrd2540.html.
13. 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.
14. 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 bolic Disorders 30: 700–707. doi:10.1007/s10545-007-0605-z. PMID 17846916. http://www.nature.com/nrd/journal/v7/n3/full/nrd2540.html.
15. 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 b 92 (4): 287–291. doi:10.1016/j.ymgme.2007.09.017. PMID 18036498.
16. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FKet 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. doi:10.1016/S0140-6736(07)61234-3. PMID 17693179.
17. 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. doi:10.1002/ajmg.a.32562. PMID 18932221.
18. 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. .
19. 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.
20. lsuhsc.edu Genetics and Louisiana Families
21. 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.
22. www.rikshospitalet.no
23. 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. doi:10.1136/jmg.32.12.976. PMID 8825928.

24 http://emedicine.medscape.com/article/947781-overview