PHENYLKETONURIA

Phenylketonuria, often abbreviated to PKU, is an inherited disorder of metabolism affecting approximately one in every 8,000 to 10,000 newborns in Australia. If untreated, PKU can cause progressively more severe mental retardation (resulting in IQ < 30), brain damage, and seizures. Today, all newborns in developed countries are screened for PKU in the first few days of life, because diagnosis at birth allows treatment to begin immediately; it is possible to avoid the affects of PKU altogether if it is treated and monitored correctly. There is currently no cure for PKU.

Cause and Effect

Phenylalanine is one of the 20 amino acids our body uses to form proteins (which are essential in virtually all cellular processes, and make up roughly 15% of our total mass). Phenylalanine is also considered an essential amino acid, because it must be supplied in our diet, and cannot be synthesised in our bodies from other molecules. About 50% of our dietary phenylalanine is used for the production of proteins, Amino Acid Phenylalanine and the remainder is converted to another amino Source: Wikimedia Commons acid called tyrosine by the enzyme phenylalanine hydroxylase for other uses. PKU-affected individuals display elevated levels of phenylalanine due to a defective phenylalanine hydroxylase, which is unable (or less able) to convert phenylalanine into tyrosine. Although normal at birth, affected infants exhibit rising phenylalanine levels in the blood plasma as a result of this excess. The capillaries which supply nutrients to the brain are less permeable than in other areas of the body. This gives the brain extra protection from infection, since pathogens such as bacteria are less able to leave the blood stream and infect the brain. As a result, bacterial brain infections are very rare. However, because the brain also needs to produce protein for correct development, amino acids such as phenylalanine must penetrate the walls of the brains capillaries so that they can be used for protein production. Since the capillaries act like a sieve, keeping larger objects such as bacteria out of the brain, but allowing smaller molecules such as amino acids through, it is possible for the brain to collect the amino acids it needs from the bloodstream. In PKU-affected individuals, phenylalanine is in excess in the blood, and will also saturate the capillaries of the brain, resulting in reduced levels of other amino acids being transported from the bloodstream to the brain. However, since these other amino acids are just as important for protein synthesis, phenylalanine buildup hinders the development of the brain, causing the mental retardation displayed in untreated PKU individuals. Additionally, because phenylalanine is not being effectively converted into tyrosine, there is a reduced amount of tyrosine in the tissues of the body. Since tyrosine is important in the production of melanin (our dark colour pigment), PKU-affected children commonly have fair skin, light blond hair and blue eyes.

Last Updated: 25 June 2010

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Incidence
It is speculated that the reduced-melanin appearance of PKU-affected individuals may be a contributing factor to the pattern of its incidence around the world. In northern European populations such as Ireland, Scotland, and Scandinavia, the incidence of PKU is highest; one in just 4,500 newborns are diagnosed with PKU in Ireland. Asian and African populations are among those with the lowest incidence rates, with only one in about one in 50,000 AfricanAmericans diagnosed with the disease.

Genetics and Inheritance

PKU is a genetically inherited disease which follows a standard autosomal recessive pattern. All of our cells have two copies of our genes (one inherited from our mother, the other from our father). To have PKU, an individual must have inherited a copy of a mutated (defective) phenylalanine hydroxylase gene from both parents. As such, two unaffected parents may have a PKU-affected child if they are both carriers of the mutation. This also means that a PKU-affected parent has no chance of conceiving an affected child if the other parent is not a carrier for the mutation. It should also be noted that there are also other, far less common mutations, which can also cause PKU.

P p P P P p

P p P p p p

Autosomal recessive genetic inheritance pattern

Source: Wikimedia Commons

Diagnosis
A few days after birth, a blood sample taken from a neonatal heel prick is analysed for elevated levels of phenylalanine (approximate normal range for week-old newborn: 50-200 mol/L). This is normally detected using high performance liquid chromatography (HPLC) techniques, but some clinics may still use the Guthrie Test, which was the only technique available when PKU screening programs first began Blood of an infant collected for PKU screening in 1965 (Victoria). Both are equally reliable Source: USAF Archives (2007) and accurate (theoretically to 100%), but HPLC is a less specific technique, which means that it can also test for other disorders of metabolism and the blood in general. Additionally, a repeat test is conducted when the newborn is approximately 2 weeks of age in order to confirm the previous assessment and uncover any possibility of PKU that was originally undetected. If positive results for either of these two tests are obtained, treatment should begin immediately.

Last Updated: 25 June 2010

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PHENYLKETONURIA
Treatment
Since there is currently no cure for PKU, the treatment for this disease involves the regulation of dietary phenylalanine intake. Since proteins consist of amino acids like phenylalanine, protein is avoided where possible, meaning that meat, chicken, fish, nuts, cheese, legumes (e.g. beans, peas and lentils) and most other dairy products are either heavily restricted or eliminated from the diet. Starchy foods such as potatoes, bread, pasta and corn must also be regulated, since they also contain protein, although at lower levels. Breastfeeding PKU-affected children has been traditionally discouraged (due to its high protein content), but more recent research into the benefits of breast feeding suggests that if the case permits, a regulated amount of breast milk is not only permissible, but encouraged in the interests of good overall nutrition. Adhering to this diet is crucial, especially in infancy and childhood, when the developing brain is most fragile. The consensus among doctors used to be that this diet was only truly necessary in childhood, and that a normal diet could be gradually introduced during adolescence. Since then, research has suggested that the brain continues to develop for a greater period of time, and that cognitive maturity occurs much later; recent studies have estimated that the brain is not mature until approximately 25 years of age. It therefore follows that the correct development of the brain could be unfavorably affected if a low-protein diet is abandoned prematurely, and studies over time have proved this. Most physicians and dieticians recommend that a low-protein diet is maintained over the entirety of a PKU-affected individuals life, for optimal protection against the possibility of brain damage. The maintenance of a low-protein diet is also important in pregnancy, because the mother is the source of nutrients for the developing fetus. If the mother has elevated levels of phenylalanine in her blood plasma, she will supply her fetus with excess phenylalanine, risking brain damage in the womb. Today, dieting alone is usually enough to avoid the effects of PKU. In some cases, affected individuals may have to take tyrosine supplements, or supplements of cofactors involved in phenylalanine metabolism. However, other treatments are being investigated, including gene therapy (which attempts to restore a mutated phenylalanine hydroxylase gene to its unmutated form), and enzymatic substitution therapy (where a patient is administered the enzyme phenylalanine ammonia lyase, which can mimic the function of phenylalanine hydroxylase). The goal for medical science is to find a form of treatment which allows PKU-affected individuals to eat the same wide range of foods as an unaffected individual, so that in the future, PKU sufferers may lead a complete and nutritionally balanced life.

Internet Resources
www.pahdb.mcgill.ca Phenylalanine Hydroxylase Locus Knowledgebase (Canada)

Last Updated: 25 June 2010

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