Phenylketonuria

Genome research is emerging as a new and important tool in biology used to obtain information on gene sequences, genomic interaction, and how genes work in concert to produce the final syndrome or phenotype. Defect in phenylalanine hydroxylase (PAH) gene result in Phenylketonuria (PKU). Molecular studies using the brain of the mouse model for PKU (PAHenu2) showed altered expression of several genes including upregulation of orexin A and a low activity of branched chain aminotransferase. These studies suggest that a single gene (PAH) defect is associated with altered expression, transcription and translation of other genes. It is the combination of the primary gene defect, the altered expression of other genes, and the new metabolic environment that is created, which lead to the phenotype

Methylmalonic Acidemia: Can Treatment be Improved?

Methylmalonic acidemia (MMA) is a severe metabolic disorder, particularly with complete deficiency of methylmalonyl-CoA mutase. Dietary restriction has led to overt signs of deficiencies including skin rashes, hair loss, and poor growth. More liberal intake of the restricted amino acids has resulted in better growth and less frequent episodes of illness

Frequency of 12 mutations in 114 children with phenylketonuria in the Midwest region of the USA

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42497/1/10545_2004_Article_BF00711829.pd

Phenylketonuria in Portugal: Genotype-Phenotype Correlations Using Molecular, Biochemical, and Haplotypic Analyses

The impairment of the hepatic enzyme phenylalanine hydroxylase (PAH) causes elevation of phenylalanine levels in blood and other body fluids resulting in the most common inborn error of amino acid metabolism (phenylketonuria). Persistently high levels of phenylalanine lead to irreversible damage to the nervous system. Therefore, early diagnosis of the affected individuals is important, as it can prevent clinical manifestations of the disease.info:eu-repo/semantics/publishedVersio

Molecular Genetics and Metabolism 86 (2005) S17-S21 Minireview Response of patients with phenylketonuria in the US to tetrahydrobiopterin

Abstract Tetrahydrobiopterin (BH 4 ) responsive forms of phenylketonuria (PKU) have been recognized since 1999. Subsequent studies have shown that patients with PKU, especially those with mild mutations, respond with lower blood phenylalanine (Phe) concentrations following oral administration of 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ). To determine the incidence of BH 4 responding PKU patients in the United States and characterize their phenylalanine hydroxylase (PAH) mutations, a study was undertaken at UTMB in Galveston and the Children's Hospital of Los Angeles on 38 patients with PKU. Patients were screened by a single oral dose of BH 4 , 10 mg/kg and blood Phe and tyrosine were determined at 0, 4, 8, and 24 h. Twenty-two individuals (58%) responded with marked decrease in blood Phe (>30%) at 24 h. Some of the patients that responded favourably were clinically described as having Classical PKU. Blood tyrosine concentrations did not change signiWcantly. Twenty subjects with PKU, responsive and nonresponsive to BH 4 , were enrolled in a second study to evaluate blood Phe response to ascending single doses of BH 4 with 10, 20, and 40 mg/kg and to evaluate multiple daily doses, for 7 days each, with 10 and 20 mg/kg BH 4 . The 7-day trial showed a sustained decrease in blood Phe in 14 of 20 patients taking 20 mg/kg BH 4 (70%). Of these 14 patients, 10 (71%) responded with a signiWcant decrease in blood Phe following 10 mg/kg BH 4 daily. To understand the mechanism of response to BH 4 , the kinetics and stability of mutant PAH were studied. We found that mutant PAH responds with increase in the residual enzyme activity following BH 4 administration. The increase in activity is multi-factorial caused by increased stability, chaperone eVect, and correction of the mutant Km. These studies indicate that BH 4 can be of help to patients with PKU, including some considered to have Classical PKU. The PKU population in US is heterogeneous and mutations can be varied so mutations need to be characterized and response to BH 4 tested. It is more likely that mutations with residual activity should respond to BH 4 , therefore the clinical deWnition of "Classical PKU" should be reconciled with the residual activity of PAH mutations