Phenylketonuria (PKU) is a human genetic disorder that occurs in 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.
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 8 other patients. The substance found had to be subjected to much more basic and rudimentary chemical analysis than is available today. He tested and found that reactions 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 that was the substance in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.
PKU usually 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 its cofactor tetrahydrobiopterin (BH4) is not synthesized by the patient.
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. Excess phenylalanine in the blood harms brain development in the child, leading to mental retardation; low levels of tyrosine leads to lowered production of the pigment melanin, so children with this condition tend to be fair haired and blue eyed. 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.
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.
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. Suplementary 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, treatment consists of giving this cofactor as a supplement.