Difference between revisions of "Phenylketonuria 2012"

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Treatments in development are enzyme substitution therapy and gene therapy. The enzyme phenylalanine ammonia lyase (PAL) catalyses Phe to ammonia and non-toxic trans-cinnamic acid. In mice it lowered the Phe level safely and persistently and is in clinical trials for humans since 2009. Gene therapy so far has managed to temporarily restore PAH activity for up to a year. Since a viral vector containing a functional PAH-gene could be injected in the liver but was not integrated in the genome, effects vanished when the liver regenerated. Reinjection lead to an immune response to the viral vector.
 
Treatments in development are enzyme substitution therapy and gene therapy. The enzyme phenylalanine ammonia lyase (PAL) catalyses Phe to ammonia and non-toxic trans-cinnamic acid. In mice it lowered the Phe level safely and persistently and is in clinical trials for humans since 2009. Gene therapy so far has managed to temporarily restore PAH activity for up to a year. Since a viral vector containing a functional PAH-gene could be injected in the liver but was not integrated in the genome, effects vanished when the liver regenerated. Reinjection lead to an immune response to the viral vector.
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[[File:PAL_PAH.png|200px|thumb|right| phenylalanine hydroxylase and phenylalanine ammonia lyase. PAH requires the presence of its cofactor, BH4, as well as a Fe+ molecule and oxygen. PAL
 
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does not need a cofactor. Taken from Bélanger-Quintana et al. (2011)]]
   
 
==References==
 
==References==

Revision as of 11:25, 20 April 2012

Phenylketonuria (PKU) is an autosomal recessive inherited disorder. It is monogenetic and the connected gene (PAH) is located at the chromosome 12, which encodes for the hepatic enzyme phenylalanine hydroxylase(PAH). People who suffer from this disorder have a strongly decreased activity of this enzyme and therefore suffer from the toxic effects of the accumulated phenylalanine(Phe) which leads mostly to mental retardation but also to certain other symptoms. Due to the ongoing development for treatment and adhering to dietary restrictions the patients can avoid most effects of the disease.

Summary

Phenylketonuria is a widely distributed an known disease, with rarely severe effects (with the right treatment). It affects the digestion of phenylalanine(Phe) mostly through decreasing the efficiency of the Enzyme phenylalanine hydroxilase (PAH). The main danger with this disease is the accumulation of Phe in the blood, which is toxic in high doses. Those will lead to mental retardation and other symptoms

Symptoms

Diagnosis

If the disease is recognised and treated within the first days of a newborn, before toxic amounts of phenylalanine can build, patients can avoid the symptoms of PKU. Newborn screenings generally carried out between day 2 and day 5 include a test for PKU. The most simple test is a bacterial inhibition assay (Guthrie test) that uses Bacillus subtilis, a bacteria that needs phenylalanine to grow. More reliable tests employ mass spectrometry, checking not only the level of Phe but also the tyrosine/phenylalanine ratio.

To differentiate patients with high Phe levels due to PKU from patients with BH4 deficiency, a cofactor of PAH, a 'BH4 loading test' can be performed. This also detects the subgroup of PKU patients that can be treated with BH4, since the cofactor also has some chaperone activity.

Treatment

The most effective way to treat the symptoms of PKU is to avoid food rich in phenylalanine. This requires a strict diet excluding all animal protein, dairy products and many vegetable food and including medical food, especially milk powder for newborns low in Phe.

10-60 % of the patients respond to treatment with tetrahydrobiopterin (BH4), the cofactor of PAH, or a synthetic alternative. This cofactor possesses chaperone activity and apparently can restore PAH function for certain mutations.

Treatments in development are enzyme substitution therapy and gene therapy. The enzyme phenylalanine ammonia lyase (PAL) catalyses Phe to ammonia and non-toxic trans-cinnamic acid. In mice it lowered the Phe level safely and persistently and is in clinical trials for humans since 2009. Gene therapy so far has managed to temporarily restore PAH activity for up to a year. Since a viral vector containing a functional PAH-gene could be injected in the liver but was not integrated in the genome, effects vanished when the liver regenerated. Reinjection lead to an immune response to the viral vector.

File:PAL PAH.png
phenylalanine hydroxylase and phenylalanine ammonia lyase. PAH requires the presence of its cofactor, BH4, as well as a Fe+ molecule and oxygen. PAL does not need a cofactor. Taken from Bélanger-Quintana et al. (2011)

References

N. Blau, J. Hennermann, U. Langenbeck, U. Lichter-Konecki, Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies; Molecular Genetics and Metabolism 104 (2011) S2-S9

A. Bélanger-Quintana, A. Burlina, C. Harding, A. Muntau, Up to date knowledge on different treatment strategies for phenylketonuria; Molecular Genetics and Metabolism 104 (2011) S19-S25