Phenylketonuria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Pathophysiology
Genetics
Classical PKU is caused by a defective gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor 5,6,7,8-tetrahydrobiopterin (BH4) by the patient.[1] This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU [2].
The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene.[3]. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).[4]
PKU is an autosomal recessive genetic disorder, meaning that each parent must have at least one defective allele of the gene for PAH, and the child must inherit two defective alleles, one from each parent. As a result, it is possible for a parent with PKU phenotype to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two defective alleles, and therefore the disease.
Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU[5]. The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence which in humans would be considered the PKU mutation.
File:Autorecessive.svg
Metabolic pathways
The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones though the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenylethylamine[6]. Detection of phenylketones in the urine is diagnostic.
Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development in children, leading to mental retardation.[7]
References
- ↑ Surtees, R., Blau, N. (2000). "The neurochemistry of phenylketonuria". European Journal of Pediatrics. 169: S109–13. PMID 11043156.
- ↑ PKU 2007 Genetics of Phenylketonuria - A Comprehensive Review
- ↑ PKU 2007 Genetics of Phenylketonuria - A Comprehensive Review
- ↑ http://www.genenames.org Phenylalanine hydroxylase (PAH) gene summary, retrieved September 8, 2006
- ↑ Oh, H. J., Park, E. S., Kang, S., Jo, I., Jung, S. C. (2004). "Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer". Pediatric Research. 56: 278–284. PMID 15181195.
- ↑ Michals, K., Matalon, R. (1985). "Phenylalanine metabolites, attention span and hyperactivity". American Journal of Clinical Nutrition. 42(2): 361–365. PMID 4025205.
- ↑ Pietz, J., Kreis, R., Rupp, A., Mayatepek, E., Rating, D., Boesch, C., Bremer, H. J. (1999). "Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria". Journal of Clinical Investigation. 103: 1169–1178. PMID 10207169.