Phenylketonuria (PKU) is a congenital metabolic disorder which, untreated, results in severe intellectual disability. It is caused by deficient activity of the enzyme phenylalanine hydroxylase (PAH) which is expressed only in liver, and which catalyses the conversion of phenylalanine to tyrosine. Phenylalanine accumulates and competes with tyrosine and another amino acid, tryptophan, for entry into the brain.
Tyrosine and tryptophan are hydroxylated to form DOPA and 5-hydroxtryptophan respectively which are precursors of important neurotransmitters. It is supposed that reduced transport of tyrosine and tryptophan into and within the brain and reduced synthesis of neurotransmitters are factors in the causation of the intellectual disability.
Babies with PKU are born with virtually normal levels of phenylalanine, and without brain damage or other abnormalities, because the mother metabolises phenylalanine while the baby is in utero. Without intervention, phenylalanine levels rise quickly to 10 to 40 times normal, and progressive impairment of neuronal development ensues.
Over 95% of untreated PKU patients have significant intellectual disability with a mean IQ of 45. Intellectual disability is by far the most prominent feature of untreated PKU.
Other clinical features include eczema, spasticity, tremors, abnormal gait, seizures, and autisic features. Treatment (see below) avoids these problems and results in growth and development within the normal range.
PKU occurs in most populations in the world, with a varying birth prevalence. For example it is very common in Turkey (1: 2,500) and very rare in Finland and Japan (1: 100,000-200,000). In New South Wales the birth prevalence is 1:10,000 births. About 20 to 25 babies with PKU are born each year in Australia. Inheritance is autosomal recessive. The gene is located on chromosome 12, and over 550 mutations have been identified, with some 6 "common" mutations in European populations, and another 6 or so "common" in Asian populations. Phenylalanine hydroxylase activity is modified to different extents by many different mutations in the PAH gene. Activity of <1% of normal results in very high levels of phenylalanine, so called "classical PKU".
Less severe deficiencies result in milder disease, with some patients having plasma phenylalanine levels permanently elevated, but not high enough to cause any intellectual impairment ("persistent hyperphenylalaninaemia"). There is a continuum of effects, with no clear biological distinction.
Because early treatment is needed and PKU cannot be diagnosed clinically in the newborn, babies in developed countries are all screened for PKU (and some other disorders) soon after birth. This testing, introduced by the late Dr Robert Guthrie, became widespread in the late 1960s. See below under Newborn Screening.
Babies with plasma phenylalanine levels of 400 ยต mol/L or greater are nowadays felt to need treatment. This is achieved with a low-phenylalanine diet, and phenylalanine-free amino acid supplements. If treatment is started within the first 2-3 weeks and continued, normal growth and development can be expected.
Optimally treatment should start before one month of age, and should continue throughout childhood and adolescence, and probably for life.However, many adolescents and adults do not keep rigorously to the diet. The long-term outlook for neurological function in PKU patients off treatment is largely unknown, although a few certainly develop significant neurological symptoms, only some of which are secondary to dietary vitamin B12 deficiency.
Recently it has been found that treatment with the co-factor for phenylalanine hydroxylase, tetrahydrobiopterin (BH4), is effective in some PKU patients, mainly those with a milder biochemical phenotype and some residual enzyme activity. Some of these patients may be able to maintain satisfactory blood phenylalanine levels without diet. However, this medication is extremely expensive, and is currently not available in Australia for most patients.
If a woman with untreated or poorly controlled PKU becomes pregnant, the fetus is exposed to high levels of phenylalanine in utero, and suffers irreversible damage, with poor growth, microcephaly, intellectual delay, an abnormal facial appearance, and sometimes congenital heart disease. This is known as the maternal phenylketonuria syndrome. Such an outcome can be avoided if PKU women have well-controlled plasma phenylalanine levels before conception, and throughout pregnancy. All mothers of microcephalic babies should be tested for PKU.
Approximately one person in 50 in NSW is a PKU carrier. Carriers of PKU cannot be detected reliably by biochemical testing. Prenatal diagnosis is possible by DNA analysis for most couples who have already had an affected child. This is not usually so for the extended family, as there are over 550 different mutations already described in the phenylalanine hydroxylase gene, so that sequencing of the whole gene might be needed for the unrelated partner. Direct measurement of phenylalanine hydroxylase activity would require fetal liver biopsy, which is possible in some centres but would not usually be considered justified. In practice, prenatal diagnosis is seldom requested.
In Australia (and all developed countries) newborns are tested for a number of metabolic disorders which are treatable if diagnosed early, before symptoms have become apparent. Currently about 30 disorders are tested for in Australia, many extremely rare, overall affecting about one baby in every 1,000. Parents should be given complete and easily understood information regarding the risks and benefits of newborn screening, including information regarding false positives and false negatives, and treatment. The archetypal disorder illustrating newborn screening is phenylketonuria (PKU).
The following issues are important in newborn screening for PKU.
In Australia the newborn screening test used was previously the "Guthrie" bacterial inhibition assay but this has been replaced by tandem mass spectrometry (MS/MS). This is easily administered, a few drops of blood being taken by heel prick onto a filter-paper card which is analysed in a central laboratory.
The test is not reliable during the first 48 hours of life. False negative results after this time are extremely rare, and usually result from clerical errors. There has been no false negative test in New South Wales for over 30 years. The ratio of false positive to true positive results is variable, depending on various laboratory factors. In NSW this has been approximately 1:1, the false positives being identified as marginal elevations of phenylalanine rather than probable cases of PKU. This form of testing is highly acceptable to the community.
Prior to mass screening and treatment, about 47% of patients with PKU had an IQ < 35, 47% 35 - 68, and 6% > 68. Since dietary phenylalanine restriction, > 95% of patients have normal IQs. A longitudinal study reported a mean IQ of 100 in a group of 12 year olds. Dietary restriction is an effective and acceptable form of treatment, but becomes more of an issue for women with PKU who want to, or do become pregnant.
The NSW Newborn Screening Service is located at The Children's Hospital at Westmead. Their highly informative website is recommended for further reading on this subject www.chw.edu.au/prof/services/newborn/
Medical Research Council Working Party on Phenylketonuria. Phenylketonuria due to phenylalanine hydroxylase deficiency: An unfolding story. Br Med J 1993; 306(6870): 115-119
Fernandes J, Saudubray JM, Van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. (3nd Ed.) Berlin: Springer-Verlag 2000.
4th edition available in Badham library.
opac.library.usyd.edu.au/record=b3251487~S4
Cederbaum, Stephen. Phenylketonuria: an update. Current opinion in pediatrics, 2002 14(6): 702-706.