Professeur docteur oussama chaalane

PKU

Phenylketonuria

Dr Usama Fouad Shaalan MD- PhD MiniEncyclopedia الموسوعه المصغره للدكتور  أسامه فؤاد شعلان

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phenylketonuria (PKU)

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Phenylketonuria is a rare metabolic disorder that affects the way the body breaks down protein. If not treated shortly after birth, PKU can be destructive to the nervous system, causing mental retardation.

Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH).[1]:541 This enzyme is necessary to metabolize the amino acid phenylalanine (‘Phe’) 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.

Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. Historically, PKU has been treated with a low-phenylalanine diet. Research now has proved that diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Phe levels to a safe range and monitoring diet and cognitive development. Lowering of phenylalanine levels to a safe range may be achieved by combining a low phenylalanine-diet with medication. There is currently no cure for this disease. PKU is generally detected through newborn screening and diagnosed by a geneticist. PKU clinics around the world provide integrative care for PKU patients to optimize phe levels, dietary intake and cognitive outcomes.

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Mode of inheritance

PKU is an autosomal recessive disorder, meaning that you need to inherit mutations in both copies of the gene to develop the symptoms of the disorder. A carrier does not have symptoms of the disease, but can pass on the defective gene to his or her children. If both parents carry one copy of the faulty gene, each of their children have a 25 percent chance of being born with the disease.

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Screening and presentation

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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.[4]

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.

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symptoms of PKU

Babies born with PKU usually have no symptoms at first. But if the disease is left untreated, babies experience severe brain damage. This damage can cause epilepsy, behavioral problems, and stunt the growth of the baby. Other symptoms include: eczema (skin rash), a musty body odor (from too much phenylalanine), a small head (microcephaly), and fair skin (because phenylalanine is necessary for skin pigmentation).

Diagnosis

Because PKU must be treated early, babies in every U.S. state are routinely tested for the disease. A small blood sample is taken from the baby’s heel or arm and checked in a laboratory for high levels of phenylalanine.

Maternal phenylketonuria

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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.[18] 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.[19] 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 metabolic 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.[20] 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[21] to fewer than one in 100,000 births among the population of Finland.[22] 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[23].

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

Treatment of PKU

People who have PKU must eat a protein-free diet, because nearly all proteins contain phenylalanine. Infants are given a special formula without phenylalanine. Older children and adults have to avoid protein-rich foods such as meat, eggs, cheese, and nuts. They must also avoid artificial sweeteners with aspertame, which contains phenylalanine.

Interesting facts about PKU

Norwegian doctor Asbjørn Følling discovered PKU in 1934.

About 1 out of every 15,000 babies in the United States is born with PKU.

What is the Diet for PKU?

What is Included in a Low Phenylalanine Food Pattern?

The diet for PKU consists of a phenylalanine-free medical formula and carefully measured amounts of fruits, vegetables, bread, pasta, and cereals. Many people who follow a low phenylalanine (phe) food pattern eat special low protein breads and pastas. They are nearly free of phe, allow greater freedom in food choices, and provide energy and variety in the food pattern.

What is Not Included in a Low Phenylalanine Food Pattern?

Foods that contain large amounts of phe must be eliminated from a low phe diet. These foods are high protein foods, such as milk, dairy products, meat, fish, chicken, eggs, beans, and nuts. These foods cause high blood phe levels for people with PKU.

Aim for healthy food choices

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This target is an easy way to visualize the foods allowed on the diet for PKU. The phenylalanine-free formula, such as Phenyl-Free*, is the center of the target diet. As the foods get further away from the bull’s-eye, they are higher in phenylalanine. The foods outside the target are not included in the low-phenylalanine meal plan.

How Can This Food Pattern be Enough?

It is not unusual for someone who follows a low phe diet to have 2 kinds of vegetables and a baked potato for dinner. However, if these foods were the only foods a person consumed, his or her diet would be lacking protein, vitamins, and minerals. That is where the special formula comes in.

A special phenylalanine-free formula, such as Phenyl-Free*, contains protein, vitamins, minerals and energy (calories) with no phenylalanine. With formula, a person with PKU gets plenty of protein, without the side effects of the high phe content of most foods. The phenylalanine-free formula is the most important part of the diet for PKU.

How Long Must a Person With PKU Follow This Special Diet?

Research has shown that this diet should be followed for life. Keeping blood phe levels in the safe range helps to prevent problems with thinking and problem solving.

In the past, people with PKU were advised to stop their low phe diet when they were children. Most young people with PKU who were taken “off diet” did not monitor their blood phe levels and were not given any reason to be concerned about them. These people began to experience problems with paying attention, concentrating, and remembering. Recently, many of these same people have decided to go back “on diet” hoping to feel better. In order to go “on diet” a person must drink a special phenylalanine-free formula and choose low phe foods so that blood phe levels are in the safe range.

It is never too late to go back “on diet.” A low phe diet helps most young adults with PKU to feel better and improves attention span, concentration, and memory. In general, young adults who have made these changes report that they think and feel better. The effort that it takes to bring down blood phe levels is well worth it for everyone, no matter how long they have been “off diet.”

* Phenyl-Free is a registered trademark of Mead Johnson Co. A number of other formulas are available.

Kuvan® (sapropterin dihydrochloride): FDA-Approved for Phenylketonuria (PKU)

Filed in archive FDA Approvals , Genetics , Treatment by Gloria Gamat on December 19, 2007

Phenylketonuria (PKU) is a rare genetic disorderclip_image004 that causes mental retardation, smaller brain size, delayed speech and other neurological problems.
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If diabetes is characterized by the body not being able to metabolize sugar thereby resulting in high levels of glucose in the blood, PKU is characterized as the body not being able to metabolize phenylalanine (Phe), thereby resulting to high levels of Phe in the blood.

PKU is a genetic disorder in which the enzyme phenylalanine hydroxylase (PAH), which helps our bodies break down phenylalanine (Phe), an amino acid found in foods, does not function properly.
The result is high levels of phenylalanine in the blood. High levels of Phe are toxic to the brain and can lead to mental retardation, behavioral abnormalities, seizures, an inability to focus and organize information, and other neurologic complications.

Now, the US FDA has approved the first drug of its kind that has been found to slow the effects of PKU.
The said drug is Kuvan® (sapropterin dihydrochloride) that was developed by BioMarin Pharmaceutical Inc. (Novato, California, USA) in partnership with Merck Serono – a division of Merck KGaA (Darmstadt, Germany).
Kuvan was first granted orphan drug designation by the FDA in January 2004.
In January, 2006 Kuvan was granted a fast track designation by FDA based on its potential to offer a significant advantage to patients over current treatment options. The Kuvan new drug application (NDA) also received a priority review by FDA.
Kuvan works by increasing PAH enzyme activity in PKU patients with some residual PAH enzyme function. This then leads to an increased breakdown (metabolism) of phenylalanine (Phe), resulting in lower levels of Phe in the blood.
Kuvan must be used in combination with a phenylalanine-restricted diet. A patient can override the effects of Kuvan by not following a Phe-restricted diet.

Find more details from the FDA News and the Biomarin PR.

References

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  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.
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  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. 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.
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  10. ^ Michals, K., Matalon, R. (1985). “Phenylalanine metabolites, 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 Metabolic Disorders 30: 700–707. doi:10.1007/s10545-007-0605-z. PMID 17846916. http://www.nature.com/nrd/journal/v7/n3/full/nrd2540.html.
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  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. ^ 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.
  23. ^ http://emedicine.medscape.com/article/947781-overview

External links

Online PKU-Diet calculator

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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