Phenylketonuria Essay

The Biology of Phenylketonuria
Abstract

Introduction
Phenylketonuria (PKU) is a rare congenital autosomal recessive condition that is caused by an error in amino acid metabolism. Due to a mutation in the phenylalanine hydroxylase (PAH) gene, the body is unable to hydrolyse excessive quantities of phenylalanine (Phe) leading to toxic concentrations in the brain. Under the action of PAH together with co-factor tetrahydrobiopterin (BH4), iron and oxygen, phenylalanine is converted to tyrosine (Tyr). Sufferers of PKU often face developmental problems, intellectual deficiency and abnormal behaviour (1). On an epidemiological note, occurrence of PKU is highest amongst Caucasians with incidence of 1 in 10,000 births (2). The highest rate of occurrence …show more content…
Metabolic alterations include: lipid metabolism, neurotransmitter metabolism and protein synthesis.
Several studies have shown that lipid metabolism is deficient in phenylketonuric patients. Such a study carried out by Nagasaka and colleagues (4) showed that PKU causes the down-regulation of an enzyme (3-hydroxy-3-methylglutaryl coenzyme A reductase) responsible for cholesterogenesis. As a result, the total serum lipoprotein level is significantly lowered. This is associated with hypomyelination where myelin sheath synthesis is disrupted causing neural damage - symptomatically characterised by slow speech and communication exhibited by patients.
High levels of Phe can severely disrupt neurotransmitter synthesis. This is because there is a high affinity between Phe and Large Neutral Amino Acid (LNAA) transporter, thus competing with other LNAAs such as Tyr and Tryptophan (Trp) from crossing the Blood-Brain Barrier (BBB). Furthermore, Phe is a competitive inhibitor of enzymes Tyr hydroxylase and Trp hydroxylase. These enzymes together with Tyr and Trp are required for neurotransmitter synthesis especially serotonin and dopamine (5). Neurobehavioural symptoms such as hyperactivity, lethargy, moodiness and depression are hallmarks of deficient neurotransmitter metabolism due to lack of serotonin and dopamine …show more content…
Indeed, some untreated patients with PAH mutation have normal cognitive function. Patients with same genotype may have different plasma Phe concentrations. One theory postulates that this is because a few missense mutations have an impact on protein folding, varying the oligomerisation of the emerging PAH protein during translation (8). Nevertheless, the PAH genotype is thought to be the main factor affecting metabolic phenotype. In missense paired alleles, the less severe of the two mutations governs the severity of the disorder. In similar severity of mutations, the phenotype is said to be milder

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