Phenylketonuria (PKU) is an inherited disorder in which the body is unable to break down phenylalanine, an essential amino acid found in foods that contain protein such as cheese, meats and milk. There are not many different causes of phenylketonuria, as an inherited disorder means the condition runs in the family. In this sense, it can be said that one of the causes of phenylketonuria is that both parents of the affected person carry and pass the defective phenylalanine hydroxylase (PAH) gene onto their child. Generally, though, mutations in the PAH gene are what make up the causes of phenylketonuria, with different mutations determining the severity of the condition.
As an autosomal recessive disorder, phenylketonuria occurs when a child inherits a defective PAH gene from both parents. The parents of the affected person do not necessarily have the disorder because they only carry one defective copy of the gene, not two, as their child does. A person who carries the gene but does not have the disorder is referred to as a carrier. In most cases, carriers pass on the gene unknowingly. This is because carriers usually do not exhibit any symptoms of the disorder and, thus, do not realize they carry the defective gene.
Although mutations in the PAH gene are causes of phenylketonuria, different levels of these mutations are responsible for different forms of phenylketonuria. To understand this, it is best to first have some background information on the disorder itself. Essentially, the PAH gene carries instructions that enable the body to make the phenylalanine hydroxylase enzyme, which is responsible for breaking down phenylalanine and converting it into other compounds. Mutations in the PAH gene can reduce or stop altogether the production of this enzyme, which then enables phenylalanine to accumulate to excessive amounts in the body. The buildup of this amino acid is dangerous because it can harm the central nervous system and result in brain damage.
Mild forms of the disorder, such as variant phenylketonuria, occur when the gene mutation still allows some enzyme activity to persist within the body, effectively helping to break down phenylalanine. The more severe form, classic phenylketonuria, occurs when the enzyme activity is absent or so reduced to the point where buildup of the amino acid is allowed to happen. While varied mutations in the PAH gene determine the severity of an affected person’s condition, it is thought that other genes might also play a role in severity of phenylketonuria, although not much is known about this.