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Phenylketonuria - a brief outline

by Kathryn Milward - (July 2001)

Described as an inborn error of amino acid metabolism, phenylketonuria (PKU) was the first genetic disorder found to be due to a specific enzyme deficiency, resulting in a patient's inability to metabolise a specific amino acid appropriately. Classical PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). Over 70 different mutations on the PAH gene found on Chromosome 12 have been found to cause the almost complete absence of PAH as seen in PKU patients. PKU patients deficient in PAH are unable to metabolise the amino acid phenylalanine leading to an accumulation of phenylalanine and it's metabolites within the body. PKU is an example of an autosomal recessive disorder.


The incidence of PKU is highly variable in different populations. Many PAH gene mutations are thought to be Celtic in origin, this is supported by high frequencies of PKU in the Irish and in the Scottish, and for example an incidence of 1/4500 is seen in the Irish. In other northern European populations there is a mean incidence of 1/10000 and in US Caucasians there is an incidence of approximately 1/8000. Phenylketonuria is rare in Mediterranean and non-European populations.


The main clinical manifestation in an untreated PKU patient is severe mental retardation. Many patients are described as having an unusual musty type odour thought to be due to the accumulation of the metabolite phenylacetic acid. Many patients are fair-haired, fair skinned and blue eyed due to the disruption in melanin synthesis. Microcephaly - a small head in relation to body size is common. One in four patients have seizures and many have eczema. Behavioural problems are also common including agitated, aggressive behaviour and hyperactivity.


All newborns in the majority of developed countries are now screened for PKU. In a PKU foetus there will be a normal concentration of phenylalanine due to rapid placental exchange, however after feeding begins the phenylalanine concentration will rapidly rise.

Screening is achieved via the Guthrie test where a heel prick at the age of seven days obtains a small amount of blood from the newborn from which the phenylalanine concentration is found. If the Guthrie test gives a positive result the test is repeated and further investigations are carried out.

High concentrations of phenylalanine in the newborn can be due to reasons other than PKU. Benign hyperphenylalaninaemia is a condition where there is an immaturity of the liver cells causing a temporary inability of the infant to metabolise phenylalanine appropriately. Screening for PKU is very important, as PKU is a brilliant example of a disorder where by altering the environment of the patient you can almost completely treat the disorder. By screening we are able to diagnose PKU newborns and begin immediate treatment. If you are able to begin treatment early by the introduction of a low phenylalanine diet you remove excess phenylalanine from the patient's environment therefore the risk of mental retardation decreases dramatically. It has been shown that if a patient begins a low phenylalanine diet in the first few weeks of life they are much more likely to develop normal intelligence.


As previously stated early treatment through a low phenylalanine diet can significantly reduce the risk of severe mental retardation. Dietary therapy has proved to be a very effective treatment of PKU and most patients tolerate the diet well. Phenylalanine is an essential amino acid and therefore cannot be completely excluded from the diet. The blood concentration of phenylalanine must be monitored so that it remains within an acceptable range.


With treatment PKU patients have near normal development, intelligence and lifespan.

Molecular Basis

Phenylalanine is an essential amino acid, therefore it must be provided for in the diet, as it is vital for protein synthesis and normal growth and development. The first step in the metabolism of phenylalanine is the conversion of phenylalanine to tyrosine, a reaction catalysed by phenylalanine hydroxylase (PAH) that predominantly occurs within the liver. Tyrosine is then converted to the thyroid hormone thyroxine, the neurotransmitter dopamine, the adrenal hormones adrenaline and nor-adrenaline and the pigment melanin.

Classical PKU patients lack phenylalanine hydroxylase and are therefore unable to metabolise phenylalanine to tyrosine, therefore phenylalanine accumulates within the body. Accumulated phenylalanine is converted by other pathways to various metabolites including phenylpyruvic acid and phenylacetic acid. These pathways and metabolites are found within healthy individuals, however in the PKU patient the absence of PAH results in these pathways occurring more frequently leading to abnormally high levels of the metabolites they generate. Increased concentrations of phenylalanine and it's metabolites causes the disruption and inhibition of various biochemical processes, which is thought to lead to the clinical manifestations as seen in PKU.

For example: -

1) Accumulated phenylalanine is metabolised to phenylpyruvic acid. Phenylpyruvic acid is thought to inhibit the enzyme pyruvate decarboxylase in the brain leading to defect's in the synthesis of myelin. Myelin is described as an insulating material and is vital in nervous system function. It covers axons - telephone line like structures that are responsible for communication between the different parts of the body. Without myelin the nervous system and the brain is unable to function normally. Autopsy and examination of the nervous system of PKU patients has shown a lack of myelin in the nervous system of PKU patients. It is therefore thought that the increased concentrations of phenylpyruvic acid at the critical time of brain development causes the defects seen in myelin synthesis leading to the mental retardation seen in untreated PKU patients.

2) Tyrosinase is also inhibited by the increased concentrations of phenylalanine and it's metabolites, tyrosinase is a vital enzyme in the conversion of tyrosine to melanin, therefore the pigment melanin is not produced normally explaining for the decreased pigmentation seen in PKU patients. Many of the clinical manifestations of PKU are not thought to be due to decreased tyrosine, as tyrosine is normally provided for in adequate amounts in the diet.


The PAH gene is found on the long arm of chromosome 12 (12q22-12q24.1.) It is 90Kb long, contains 13 exons and forms mRNA 2.4Kb long.
Over 70 different mutations have been found within the PAH gene to cause PKU.
Certain mutations are more common in certain populations than in others.
Two common mutations are a mis-sense mutation and a splice site mutation.

The Missense Mutation - One base in the DNA sequence is substituted for another, therefore when the gene is translated to form phenylalanine hydroxylase an incorrect amino acid is incorporated into the protein chain, this one incorrect amino acid completely renders the protein inactive.

The Splice-Site Mutation - This mutation causes a large area of the DNA sequence within the PAH gene to be removed. The two resulting fragments join together but form a stop sequence at the point where they join. Therefore when the DNA sequence is used to form a protein, the process stops at the newly formed stop sequence thus the protein does not form.

Other Information

There is thought to be a heterozygous advantage to the PKU mutation. This means that by being heterozygous for the PKU mutation (you have one copy of the PKU mutation) you are at an evolutionary advantage.

It is thought that those heterozygous to the PKU mutation have increased protection from ochratoxin A. Ochratoxin A is a toxin produced by various species of fungus that grow on stored grains and foods. In Ireland and Scotland the mild wet climate encourages the growth of these species of fungus, famines in Ireland and Scotland meant mouldy foods were consumed and ochratoxin A was introduced into the body. Ochratoxin A is thought to cause spontaneous abortion; therefore women heterozygous to the PKU mutation suffered fewer spontaneous abortions caused by Ochratoxin A.



    Roland Ellis, Croom Helm, 1980.
    William L. Nyhan, Appleton-Century Crofts, 1984.
    John Holton, 2nd Edition, Churchill Livingstone, 1994.
    R.F.Mueller, I.D.Young, 10th Edition, Churchill Livingstone, 1998.
    Victor A. Mckusick (et al), 12th Edition, Baltimore John Hopkins University Press, 1998.


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