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Genetic Abnormalities Involved in PKU: A Guide to Phenylketonuria

written by: J.Sace•edited by: Paul Arnold•updated: 5/24/2009

Phenylketonuria is an inherited metabolic disorder caused by the mutation of the phenylalanine hydroxylase (PAH) gene of human chromosome 12. Continue reading to find out more about this disorder.

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    PKU Definition

    Phenylketonuria (PKU) is an inherited disease characterized by the inability of a person to metabolize the amino acid phenylalanine. Phenylalanine is normally converted to tyrosine (another amino acid) by the hepatic enzyme phenylalanine hydroxylase and the chemical cofactor tetrahydrobiopterin (or BH4). Tyrosine serves as the precursor amino acid for the production of the pigment melanin that gives our skin and hair their characteristic colors. It also serves as the precursor amino acid for the formation of essential body hormones (e.g. thyroxine) and neurotransmitters (e.g. dopamine and epinephrine).

    The absence of the hepatic enzyme phenylalanine hydroxylase to convert phenylalanine to tyrosine results in the elevation of phenylalanine level in the blood plasma. Blood phenylalanine compounds are converted to phenylketone which is highly toxic to body cells and tissues. Phenylketone also crosses the blood-brain barrier and can cause irreversible damage to the brain. Phenylketone is excreted in the urine and can be detected by biochemical tests.

    The symptoms of phenylketonuria are usually observed in new born babies a few days/weeks after their birth. The babies may have fairer skin and hair colors (different from the parents) due to the inadequate amount of melanin produced. Their urine and sweats have musty or mouse-like odor because of the high amount of phenylalanine contained in their bodies.

    Children with untreated phenylketonuria have intellectual disabilities, behavioral problems, heart defects, skin disorders, and other related diseases.

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    Phenylketonuria (PKU) Genetics: Mutation of the PAH Gene

    Phenylketonuria is caused by a mutation of the phenylalanine hydroxylase (PAH) gene which is found in the q arm of chromosome 12. The PAH gene gives specific instructions for the production of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. A single mutation to this gene results in the formation of non-functional or partially-functional phenylalanine hydroxylase.

    The PAH gene has been highly susceptible to mutations by nucleotide substitution. In fact, scientists have identified more than 500 mutations in the PAH gene. One of the most common PAH gene mutations identified in populations is the substitution of the amino acid arginine with tryptophan at position 408. This mutation is technically written as Arg408Try or R408W by geneticists.

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    Inheritance of Phenylketonuria

    A person develops phenylketonuria by inheriting the mutated form of PAH gene on chromosome 12 from both of his parents. If normal parents carry a mutated form of the gene (heterozygous for the PAH gene), the Punnett square shows that there is 25% chance that they would produce a child with phenylketonuria.

    A couple planning to produce a child have the option to undergo genetic testing to see if they carry a mutated PAH gene.

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    Is there a gene therapy for phenylketonuria?

    Strict phenylalanine-free and high tyrosine diet is still the current treatment for phenylketonuria. Foods that contain phenylalanine like meat, egg, fish, and the like are not given to affected children so as to avoid the potential damage caused by elevated phenylalanine levels in the blood. Foods that contain high amounts of tyrosine are given because the amino acid is the precursor for many physiologically important hormones and neurotransmitters. Furthermore, foods that contain low amounts of phenylalanine are specially processed to remove the amino acid for consumption by phenylketonurics.

    In 2005, Drs. Woo and Eisensmith of the USA reported a successful phenylketonuria gene therapy in laboratory mice. “Gene therapy is the delivery of genetic material to specific cell types of an organism to alter its physiology or function." (Woo and Eisensmith 2005) The two biomedical scientists inserted the phenylalanine hydroxylase gene into the chromosomes of mouse hepatic cells via a bacteriophage integrase system. They found a significant drop of blood phenylalanine level in the blood plasma of phenylketonuric mice after the insertion of the PAH gene in their hepatic cell chromosomes. The two researchers said that the “current method is toxic to humans" and it will take more time and study for the development of a gene therapy for phenylketonuria.

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    References for the Genetics of Phenylketonuria

    Phenylketonuria. 2009. National Library of Medicine. Retrieved May 22, 2009 from

    PAH Gene. 2005. Retrieved on May 22, 2009 from the National Institute of Health Website:

    Rauscher, Megan. 2005. Gene therapy corrects phenylketonuria in mice. Oncolink: Abraham Cancer Center of the University of Virginia. Retrieved May 22, 2009 from

    Eisensmith R. C. and Woo S. L. C. 2005. Somatic Gene Therapy for phenylketonuria and other hepatic deficiencies. Journal of Inherited Metabolic Diseases. Abstract retrieved from on May 22, 2009.