title: The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness.
abstract: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c.163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified. A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH4), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH4.
authors.affiliation: Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.
authors.forename: Gladys
authors.initials: G
authors.lastname: Ho
authors.forename: Ian
authors.initials: I
authors.lastname: Alexander
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: Barbara
authors.initials: B
authors.lastname: Dennison
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ellaway
authors.forename: Sue
authors.initials: S
authors.lastname: Thompson
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou