PHENYLKETONURIA - Biochemical Defects and their Effects

The mutation that causes PKU is in the enzyme phenylalanine hydroxylase (PAH). When this enzyme is defective a block is produced in a biochemical pathway. As PAH normally converts phenylalanine to tyrosine, the block occurs between phenylalanine and tyrosine. As phenylalanine cannot be converted to tyrosine it builds up in the blood, when it reaches high levels it is termed hyperphenylalaninemia. This is not the only result of this disrupted pathway as is shown below.

Diagram showing the metabolic block in PKU

As we can see, tyrosine is ordinarily used to produce thyroxine, dopa and subsequently melanin, in PKU the defective enzyme causes deficiency of all these products as well as tyrosine.

The raised phenylalanine in the blood results in increased phenylpyruvic acid which is excreted in the urine in PKU, this is useful in diagnosis.

The phenylpyruvic acid has also been shown to inhibit the enzyme pyruvate decarboxylase in brain (Bowden and McArthur,1972). This would lead to a decrease in energy for the developing brain and decreased myelin formation, which is found in PKU. Together, these could explain the mental retardation found in PKU.

Many substances are harmful to the developing foetus and phenylalanine appears to be one of these, hyperphenylalaninemia resulting in congenital heart defects and microcephaly (An abnormally small head and brain).

The lack of melanin leads to decreased pigmentation of the person with PKU. Such patients therefore have blond hair and blue eyes and certain normally pigmented parts of the brain (such as the substantia nigra) may also lack pigment.

Thyroxine deficiency can lead to hypothyroidism, which can be treated with hormone replacement.

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