Phenylketonuria

Phenylketonuria [PKU] is a human genetic disorder (though it is possible to exist in mice), in which the body lacks phenylalanine hydroxylase, the enzyme necessary to metabolize phenylalanine to tyrosine. Left untreated, the disorder can cause brain damage and progressive mental retardation as a result of the accumulation of phenylalanine and its breakdown products. The incidence of occurrence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the Irish to fewer than one in 100,000 births among the population of Finland.

History
Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934 when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Følling's disease, named after its discoverer. Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of two retarded siblings led him to request many physicians near Oslo to test the urine of other retarded patients. This led to the discovery of the same substance that he had found in eight other patients. The substance found was subjected to much more basic and rudimentary chemical analysis than is available today. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.

Defects
Classical PKU is caused by a defective gene for the enzyme phenylalanine hydroxylase (PAH). It is inherited as an autosomal recessive trait. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient.2

This enzyme normally converts the amino acid phenylalanine to tyrosine. If, due to a faulty or missing enzyme, this reaction does not take place, levels of phenylalanine in the body can be far higher than normal, and levels of tyrosine lower than normal.



Large neutral amino acid transporter
Large neutral amino acids (LNAAs), including phenylalanine, compete for transport across the blood brain barrier (BBB).3 Excessive phenylalanine in the blood saturates the large neutral amino acid transporter (LNAAT), which carries LNAAs across the BBB.3 Thus phenylalanine significantly decreases the levels of LNAAs in the brain. These amino acids are required for protein and neurotransmitter synthesis.3 Reduced protein and neurotransmitter synthesis disrupts brain development in children, leading to mental retardation.





Low levels of tyrosine also leads to lowered production of the pigment melanin, so children with this condition tend have fairer hair and greener eyes than other members of their family. The excess phenylalanine is converted instead into phenylketones, which are excreted in the urine - hence the name for this condition. The sweat and urine of an affected child has a musty odour due to these ketones.

Diagnosis
The problem is readily detectable within days of birth from a small blood sample -- the Guthrie heel prick test, so screening for phenylketonuria is done routinely in most industrialised countries, usually combined with testing thyroid function and other genetic disorders of metabolism.

In some areas, a repeat test is required at the age of two weeks, but, if a child has been tested shortly after birth (once feeding has commenced), there is no evidence that this second test is really necessary.

Therapy
If the condition is diagnosed early enough, an affected child can grow up with normal brain development, by eating a special diet low in phenylalanine. This requires severely restricting or eliminating foods high in protein, such as meat, nuts, cheese and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must also be avoided. Supplementary formulas are used in these patients to provide the protein and other necessary nutrients that would otherwise be lacking in a diet free of protein. In those patients with a deficit in BH4 production or PAH has a low affinity for BH4, treatment consists of giving this cofactor as a supplement; this is referred to as BH4 responsive PKU. There are a number of potential other therapies currently under investigation, including gene therapy, and an injectable form of PAH. However, it is likely that it will be many years before these are available for use in affected individuals.

Reference

 * 1) Folling A. Uber ausscheidung von phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in verbingdung mit imbezillitat. Hoppe-Seylers Z Physiol Chem 1934;227:169–76.
 * 2) Surtees, R., Blau, N., The neurochemistry of phenylketonuria. European Journal of Pediatrics. 159:S109-13, (2000).
 * 3) Pietz, J., Kreis, R., Rupp, A., et al., Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. Journal of Clinical Investigation. 103:1169–1178, (1999).