Phenylketonuria

Phenylketonuria (PKU) is a human genetic disorder, 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. more...

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 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 there was the substance 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.

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