Phenylketonuria (PKU), is a metabolic genetic disorder inherited in an autosomal recessive manner (1). The disorder is based around problems with metabolism of the essential amino acid Phenylalanine (Phe). If Phenylalanine is allowed to reach high levels, it will impact on the brain and central nervous system leading to the clinical presentation and diagnosis of Phenylketonuria (2). There are different types of Phenylketonuria based on plasma concentration of Phenylalanine. In Classic PKU, Phenylalanine levels are greater than 1200 ?mol/L, in Mild/Variant PKU, Phenylalanine levels are between 600 and 1200 ?mol/L and in a very mild form of PKU known as Hyperphenylalaninemia (HPA) Phenylalanine levels are raised above the upper reference limit, but are less than 600 ?mol/L (3). This essay will discuss the inheritance, biology, diagnosis and treatment of Phenylketonuria as a genetic disorder with a defined inheritance pattern. As shown in Figure 1, Phenylketonuria is inherited in an autosomal recessive manner. This means the condition is not sex-linked and the effects will only be manifest when both copies of the faulty gene are inherited (the genotype ‘rr’). In autosomal recessive disorders, carriers (‘Rr’) have one copy of the faulty allele and one copy of the normal allele. They will be unaffected by the disease but there is a 50% chance that they will pass on the faulty allele to their offspring. If two carriers of the same faulty allele reproduce, there is a 25% chance they will have a child affected by the condition – i.e. Phenylketonuria (5). As summarised by Figure 2, Phenylalanine is an amino acid that is converted to another amino acid, Tyrosine which is crucial for the production of key proteins and important chemicals– for example noradrenaline, adrenaline and dopamine (7). The PAH gene codes for the production of the hepatic enzyme Phenylalanine Hydroxylase which is pivotal in Phenylalanine metabolism by catalysing its conversion to Tyrosine (8). However, in patients with Phenylketonuria there is often a deficiency of the enzyme, caused by mutations in the PAH gene (3). The human PAH gene is located on chromosome 12q23.2 and it is made up of 13 exons which code for a polypeptide of 452 amino acids. Mutations can take place in any of the 13 exons and can take many different forms including missense mutations, deletions, insertions and splicing defects – in fact there are over 500 recorded associated. Such mutations inhibit the conversion of Phenylalanine to Tyrosine, often leading to Phenylalanine accumulation. The severity of Phenylketonuria depends on the effect that specific mutations have on the structure and function of Phenylalanine Hydroxylase (3). The effects associated with Phenylketonuria are related to neurotoxicity – particularly cognitive function and brain development. Although in the past it was believed that plasma Tyrosine deficiency may have contributed these effects (3), more recent studies would suggest that it is raised Phenylalanine plasma concentrations alone that contribute to the disorder (9). From investigations using Magnetic Resonance Spectroscopy, new studies would also suggest that the pathophysiological effects observed in patients with Phenylketonuria are somewhat caused by transport of Large Neutral Amino Acids (LNAA) across the blood-brain barrier. The Amino Acid transporter LAT1 allows Phenylalanine to enter the brain. When plasma concentrations of Phenylalanine are increased, the affinity of LAT1 for Phenylalanine also increases at the expense of other amino acids (3). This results in cerebral concentrations of Phenylalanine increasing and consequently cerebral concentrations of other LNAAs decreasing. Increased cerebral concentration of Phenylalanine means hindered brain development whereas reduced cerebral concentrations of LNAAs like Tryptophan and Tyrosine can lead to deficiencies in important chemicals like serotonin and dopamine (3).The results of the factors listed above are the typical neurotoxic effects of Phenylketonuria (3). Further scientific research is necessary to establish the exact mechanism of how elevated Phenylalanine concentrations impact on intellectual impairment. Decarboxylation of Phenylalanine results in the formation of metabolites including Phenylpyruvate, Phenylacctate and Phenylacetate, shown in Figure 2, which are not usually produced in Phenylalanine metabolism and may be responsible for the associated pathophysiological effects (3,6).In Northern Ireland, the occurrence of Phenylketonuria is approximately 1:4,500 (10). In the UK, a screening programme means all babies are offered a heel prick test at around 5 days old. This involves blood spot screening and analysis for a number of conditions – including raised Phenylalanine levels which is indicative of Phenylketonuria. If raised Phenylalanine levels are left untreated, the typical signs and symptoms of Phenylketonuria will begin to appear. These include fair skin and blue eyes due to the inability of the body to convert Phenylalanine into Melanin, a musty odour in the breath or urine, seizures and shaking, developmental and growth delays, mental retardation, vomiting and skin rashes. However, with early detection and appropriate treatment, the impact of Phenylketonuria will be minimal (2, 11).Whilst there are currently many trials being undertaken to establish alternative treatments for patients with Phenylketonuria (including LNAA therapy, enzyme replacement therapy and gene therapy) (12), present treatments centre around very strict dietary restriction from birth that continue throughout life. In babies, the small amount of Phenylalanine found in breast or formula milk is deemed to be sufficient. In older children and adults, it is important to limit Phenylalanine intake by restricting natural protein; this means avoiding foods like eggs, dairy products, fish and meat (2, 11, 13). Aspartame, found in sugar-free foods and drinks, is an artificial sweetener which contains high amounts of Phenylalanine and so these items should also be avoided (3). Those affected by Phenylketonuria will often have to take amino acid supplements (particularly Tyrosine) and sachets of Phenylalanine-free protein to ensure normal growth and functioning. Patients with Phenylketonuria often have decreased bone mineral density meaning DEXA scans will be required to monitor for osteoporosis. Extremely strict diet control is required for pregnant women with PKU as high phenylalanine levels could be fatal for their foetus (13, 14).To conclude, it is clear that Phenylketonuria is a complex and interesting autosomal recessive genetic metabolic disorder. Whilst what may appear to be simple problems associated with Phenylalanine metabolism and a deficiency of the Phenylalanine Hydroxylase enzyme, Phenylketonuria can have devastating impacts. However, medical advancements like the UK screening programme allows the disorder to be identified early and appropriate treatment can begin immediately. Although patients will have to follow a very strict diet, if they do so, they should be able to live an ordinary life without the disorder having any major impact. There is still room for further research to be carried out in relation to Phenylketonuria and this should allow for increased knowledge on the exact mechanisms and alternative treatments for the disorder.