A Tour around Phenylketonuria
Date of publication 19 July 2004

When the Vikings popped back home after a quick bout of burning and pillaging some 1000 years ago, in addition to battle trophies it appears they brought something else: Celtic slaves carrying the metabolic disorder phenylketonuria. Today, the high incidence of the condition in Ireland and Scotland is matched by that in Iceland, but decreases as one moves to Denmark and then on to Norway and Sweden, as the proportion of inhabitants of Celtic extraction declines. Moreover, Norwegians who bear the mutated gene responsible are significantly different from the general population serologically, indicating descent from a completely assimilated Celtic sub-population.

In normal individuals, the aromatic amino acid phenylalanine (for the 2D chemical structure click here or for a stunning view of crystallites illuminated by polarised light try this site) is converted to tyrosine by the enzyme phenylalanine hydroxylase. Sufferers from phenylketonuria (PKU) are unable to effect this conversion, leading to a rise in plasma phenylalanine levels above 20 mg/dL, and the conversion of some phenylalanine to phenylketones. Both the unconverted amino acid and the phenylketones are neurotoxic; untreated PKU is characterised by impaired intellectual development, and other common features include light pigmentation, a 'mousy' odour and peculiarities of gait, stance and sitting posture, as well as eczema and epilepsy. The condition is inherited as an autosomal recessive characteristic, so individuals must receive a mutant gene from both parents in order to be affected. Heterozygous carriers may have substantially higher levels of phenylalanine than people with two normal genes, but remain perfectly healthy.

A simplified diagram of phenylalanine metabolism can be found here, but at this site there is a comprehensive explanation of the role played by phenylalanine hydroxylase in the synthesis of the neurotransmitters dopamine, adrenaline and noradrenaline. This process requires the presence of tetrahydrobiopterin as a co-factor; absence or deficiency of this compound can result in a condition very similar to classical PKU. The three-dimensional structure of phenylalanine hydroxylase - which was determined by this laboratory - is described in some detail. Each molecule incorporates a regulatory, catalytic and tetramerisation domain. To date, more than 400 variants have been identified which cause PKU or milder hyperphenylalaninaemia (HPA); most are in the catalytic domain, with a few in the regulatory domain. If you find the pathogenesis of PKU particularly interesting, abstracts of just about every research paper published on the topic can be found here.

At this point we should take a brief look at maternal PKU, a consequence of poorly controlled phenylalanine levels in female PKU sufferers who become pregnant. As phenylalanine is preferentially retained in the foetus, elevated plasma levels in the mother are even higher in the developing child and can have a devastating effect. In up to 90% of such cases, babies exhibit mental impairment and/or microcephaly. Many also have cardiac defects, low birthweight and characteristic facial features. Fortunately, if these women control their plasma levels by following the special PKU diet (described below) for three months before and then throughout their pregnancy, their babies are unaffected and quite healthy.

The clinical overview of PKU found here cites the enormous variation in prevalence; whites and Asians are commonly affected, but blacks are not, and while the incidence in Turkey is 1 per 2,600 births, in Finland it is less than 1 in 100,000. In the developed world, babies are screened within the first few days of life by measuring the phenylalanine concentration in a small blood specimen, and this has largely eliminated mental impairment caused by the condition. The screening procedure in the USA, and various issues surrounding it, are described at length on the American Academy of Family Physicians' site. Either the Guthrie inhibition assay or the McCamon-Robins fluorometric test is used, and although the result is positive in 1% of newborn infants, only 10% of these will be found to have PKU on subsequent testing. If phenylalanine levels are consistently below 10 mg/dL then treatment is not usually considered necessary.

Babies identified as having PKU are given a special low phenylalanine feed until blood levels fall to within the treatment range, when a small amount of breast milk or formula milk is introduced. Following weaning, treatment consists of a low phenylalanine diet with tyrosine supplementation, to enable normal psychomotor development to occur. It is now generally believed that the diet should be continued for life in all these patients. Five per cent of natural protein consists of phenylalanine, so high protein foods such as meat, fish, eggs, cheese, soya and nuts are not allowed, and neither are ordinary bread, biscuits, cakes and pasta. The diet followed in the UK has three components:

• a protein substitute which contains all the amino acids except phenylalanine
• a small measured quantity of phenylalanine
• foods which can be eaten at will - most fruit, vegetables, butter and sugar, as well as special products such as low protein flour, bread and pasta.

In addition, the artificial sweetener aspartame - marketed under various names such as 'Nutrasweet' and 'Canderel' - must be avoided. As can be seen from this site, 50% of the product consists of phenylalanine, while extended storage and the action of heat increase the availability of the compound to the body. Unfortunately, aspartame is widely used in a whole host of prepared foods and soft drinks, and is also an ingredient in numerous over-the-counter and prescription medicines - just take a look at this list of brand name products!

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