Phenylketonuria





Phenylketonuria
Evidence supports the theory that an unknown disease causing mental retardation surfaced among wives and slaves of Vikings in Ireland and Scotland long ago. Despite this Celtic origin, it was not until 1934 that a biochemist named A. Folling from Norway discovered phenylketonuria through urine testing. He correctly identified the disease as one in which the body cannot handle phenylalanine, an essential amino acid found in protein. Then in 1947, George Jervis, an American scientist presented that the exact cause of PKU was an enzyme found in the liver called phenylalanine hydroxylase (PAH). Discovery of a mutant PAH enzyme made it possible to start searching for treatments for the condition. It is now commonly accepted that Phenylketonuria, often called PKU for short, is an inborn error of protein metabolism. In other words, the body is unable to produce proteins or enzymes needed to convert certain toxic chemicals into nontoxic products. The inability of the body to complete this process can lead to neurological damage. Phenylketonuria involves one particular part of a protein, the amino acid called phenylalanine, or PHE for short. When an individual eats food-containing protein, various enzymes break down the protein into amino acids used for the body’s growth and repair of its tissues. Everyone needs a certain amount of PHE to perform these functions. Most of the time the unused PHE is then converted to another amino acid. In the case of PKU, the disorder is inherited when a baby inherits two mutant genes for the enzyme phenylalanine hydroxylase. A mutant gene for PKU occurs as a result of a mutation at the PAH locus, 12q24 which is considered to be a large gene being 90 kb long with 13 exons and encoding a polypeptide of 452 amino acids. There are over 365 identified possible mutant alleles that play a role in PKU and 105 of the mutations are found on the gene encoding for PAH. Most PAH variants are single-base substitutions such as missense, nonsense, and splicing mutations. This mutation causes a near or complete deficiency of the enzyme phenylalanine hydroxylase, which converts phenylalanine into another amino acid, tyrosine. As a result, PHE accumulates in the blood and in other parts of the body, which prevents the brain from developing normally. A normal blood phenylalanine level is about 1 mg/dl. With PKU, levels range from 6 to 80 mg/dl but are usually greater than 30 mg/dl.
Phenylketonuria is a single gene disorder, meaning that, a mutant or abnormal gene causes the disorder. PKU is inherited in an autosomal recessive fashion. This means that the affected individual must have two defective genes in order to have the disorder. People with only one copy of the defective gene are called carriers and show no symptoms of having the disease. In order for a child to inherit PKU, both parents must be carriers. When this occurs, there is a twenty-five percent chance of their producing an affected child and a twenty-five percent chance that both of the normal genes will be passed on. There is also a fifty-percent chance that a baby will inherit the PKU gene from one parent and the normal gene from the other, making the baby a carrier like his or her parents. These chances remain the same for each pregnancy and males and females are equally likely to inherit this disease. Other characteristics of an autosomal recessive genetic disorder that apply to PKU include clustering of the disease phenotype among siblings and consanguineous mating accounts for five percent of the cases of PKU. The prevalence of Phenylketonuria in the United States is approximately 1 in 10,000 to 15,000 births, which is most commonly present in Caucasians. Approximately 1 person in 50 has inherited a PKU allele. This means that some 5 million people in the United States are carriers. Internationally, the disease frequency varies by population. Turkey has the highest incidence in the world with approximately 1 in 2600 births. However, the disease is also common among people of north European descent and less common among Jewish, Asian, and African-American families.
Tests available for the detection of phenylketonuria include a enzyme assay to detect the carrier state in parents, chorionic villus sampling to detect fetal PKU, and PKU screening which is mandatory in most states in the United