Classic PKU is caused by mutations in the gene located on chromosome 12 that encodes the enzyme

phenylalanine hydroxylase (PAH). This enzyme normally catalyzes the hydroxylation of phenylalanine to
tyrosine, the rate-limiting step in the major pathway by which phenylalanine is catabolized.

Phe competes with other large neutral amino acids (LNAA) for a carrier protein responsible for their
uptake into the CNS Thus, HPA simultaneously increases the brain Phe level and reduces levels in the
brain of other amino acids essential for protein synthesis and neurotransmitter production. Accordingly,
a reduced level of LNAA other than Phe should be considered in its own right as a contributor to the
pathophysiology of neurological impairment in PKU Various additional mechanisms that may be
involved in the brain damage: altered myelin metabolism (high concentrations of Phe and/or reduced
availability of other LNAA may inhibit the development of myelin, leading to lack of myelin formation in
untreated patients, and to edema within myelin in early-treated patients with PKU), impaired dopamine
and serotonin synthesis (high brain Phe concentration inhibit the rate-limiting enzymes in the
biosynthesis of biogenic amines; tyrosine and tryptophan hydroxylases), impairment of glutamatergic
synaptic transmission and the activity of key enzymes, such as pyruvate kinase, tyrosine and tryptophan
hydroxylase and HMG-CoA reductase (all due to high brain Phe concentrations)
Phenylalanine is hydroxylated to form tyrosine by a mixed function oxidase, phenylalanine hydroxylase
(PAH), which requires molecular oxygen and tetrahy-drobiopterin. Tetrahydrobiopterin is not
synthesized from a vitamin; it can be synthesized in the body from GTP. However, as is the case with
other cofactors, the body contains limited amounts. Therefore, dihydrobiopterin must be reconverted to
tetrahydrobiopterin for the reaction to continue to produce tyrosine.

Amino acids are the basic building blocks that make up proteins. Phenylalanine is an essential amino
acid which is necessary for life but cannot be produced or made by human body. It is then acquired
through consumption of food containing proteins. Once phenylalanine enters the body most of it is
converted to tyrosine by phenylalanine hydroxylase and tetrahydrobiopterin as a cofactor. Tyrosine is
then converted to neurotransmitters which is important for normal brain development and function.
Deficiency of Phenylalanine hydroxylase is the main cause of PKU. Inability to convert phenylalanine to
tyrosine can cause buildup of phenylalanine and it metabolites. As phenylalanine rises, it outcompetes
large neutral amino acids (mainly tyrosine and tryptophan) for binding sites on L-amino acid Transporter
1 to get across the blood brain barrier. It then lowers the transport of other large neutral amino acids
causing decrease in cerebral protein synthesis and neurotransmitters. Which then decreases the levels
of dopamine, norepinephrine, and serotonin causing white matter lesions, oxidative damage,
hypomyelination, and demyelination. Thus, leading to Intellectual disability and abnormal brain
development.