Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.
OBJECTIVE  To examine the relationship of phenylalanine hydroxylase ( PAH ) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria ( PKU ) . METHODOLOGY  PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study ( MPKUCS ) . A total of 84 different mutations were detected , and complete genotype was obtained in 199 individuals . Based on previous knowledge about mutation-phenotype associations , 78 of the mutations could be assigned to one of four classes of severity ( severe PKU , moderate PKU , mild PKU , and mild hyperphenylalaninemia [ MHP ] ) . Then , 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications . The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity . These patients are considered functionally hemizygous . RESULTS  The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level . Cognitive performance ( IQ ) was also significantly related to genotype . The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96 , respectively , whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84 , respectively . Of the patients with PKU , 92 % had been treated during childhood . Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations . Females with moderate or mild PKU who were treated early and treated for > 6 years showed IQ scores 10 points above average for their group . CONCLUSIONS  The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances . Both factors depend on the intellectual resources of the mother with PKU . The significant relationship among genotype , biochemical phenotype , and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy . .
