Objective: The main feature of phenylketonuria(PKU) is mental retardation. Although classical PKU is defined as that the hepatic phenylalanine hydroxylase (PAH) activity ranges 0-1% of normal enzyme, the untreated PKU patients show a wide range of intellectual phenotype. This study sought to find the molecular basis of such variation of intellectual phenotype among PKU.
Methods: 45 classical PKU patients included in the research were screened for detecting six mutant alleles which were rather common among Chinese PKU patients, i.e. R243Q, R413P, Y204C, Y356X, W326X and R111X. PCR-ASO and PCR-SSCP techniques were used. The expression of those mutant PAH genes was analysed by methods of site-directed mutagencies. 27 PKU patients whose two mutant alleles were both defined were involved in this study. The IQ of these patients were tested by DDST system.
Results: Among 27 patients, 4/27 (15%) were mild retardation, 10/27(37%) were moderate, the severe mental retardation accounted for 12/27(44%). The relationship between genotype and intellectual phenotype in this group was examined. It was found that the intellectual phenotype of 8 patients were compatible with genotype but not well matched in 19 cases. The enzyme activity of Y204C expressed in vitro was 100%, but all 3 patients with Y204C/Y204C were severely mental retarded. Enzyme activities of R413P and Y356X were <3% and 0 respectively in expression analysis, but the patients in this group had mild or moderate mental retardation.
Conclusion: Intellectual phenotype was not well matched with the genotype in classical PKU patients, so that genotype can not be used to predicte the intellectual phenotype in PKU patients.