Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome

Pediatrics. 2003 Dec;112(6 Pt 2):1530-3.


Objective: The aim of the present study was to examine to what extent maternal and offspring phenylalanine hydroxylase (PAH) genotypes in conjunction with maternal IQ and dietary control during pregnancy are related to cognitive development in offspring of women with phenylketonuria (PKU).

Methods: PAH gene mutations were determined in 196 maternal PKU subjects and their offspring. The women were grouped according to PAH genotype, which predicts the metabolic phenotype (severe PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). IQ was determined in both the mothers (Wechsler Adult Intelligence Scale-Revised at >18 years) and their children (Wechsler Intelligence Scale for Children-Revised at > or = 6-7 years of age).

Results: According to PAH genotypes, 62% of the women exhibited severe PKU, 19% exhibited mild PKU, and 19% exhibited MHP. Maternal IQ increased, and the assigned phenylalanine (Phe) levels decreased with decreasing severity of PAH genotype. In offspring of mild maternal PKU, multiple regression analysis showed offspring IQ to be significantly related to maternal IQ but not to Phe exposure during pregnancy, which was <750 micromol/L in all cases of mild PKU. In offspring of mothers with severe PKU and average Phe exposure during pregnancy of 360 to 750 micromol/L, multiple regression analysis revealed both maternal IQ and Phe exposure to be significant predictors of offspring IQ. When average Phe exposure was <360 micromol/L, cognitive development was normal (mean IQ: 105), whereas an average Phe exposure of >750 micromol/L severely depressed offspring IQ (mean IQ: 56) in this group regardless of maternal IQ. It could not be documented that the offspring PAH genotype affects cognitive development.

Conclusion: Female individuals with severe PKU should be offered a diet for a lifetime. If good metabolic control is established, then women with PKU will have children with IQ scores that are not influenced by their disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Child
  • Cognition
  • Female
  • Genotype
  • Humans
  • Intelligence* / genetics
  • Mutation
  • Phenylalanine / blood
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonuria, Maternal / classification
  • Phenylketonuria, Maternal / diet therapy
  • Phenylketonuria, Maternal / genetics*
  • Phenylketonurias / genetics*
  • Pregnancy
  • Regression Analysis


  • Phenylalanine
  • Phenylalanine Hydroxylase