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PEDIATRICS Vol. 112 No. 6 December 2003, pp. 1530-1533

SUPPLEMENT ARTICLE

Impact of the Phenylalanine Hydroxylase Gene on Maternal Phenylketonuria Outcome

Flemming Güttler, MD, PhD^*, Colleen Azen, MS, Per Guldberg, PhD^*, Anne Romstad, PhD^*, William B. Hanley, MD, Harvey L. Levy, MD^||, Reuben Matalon, MD, PhD^¶, Bobbye M. Rouse, MD^¶, Friedrich Trefz, MD^#, Felix de la Cruz, MD^** and Richard Koch, MD

^* The John F. Kennedy Institute, Glostrup, Denmark
Children’s Hospital, Division of Medical Genetics, and the University of Southern California, Los Angeles, California
Hospital for Sick Children, Toronto, Ontario, Canada
^|| Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
^¶ University of Texas Medical Branch, Children’s Hospital, Galveston, Texas
^# University of Tübingen, Reutlingen, Germany
^** National Institute of Child Health and Human Development, Bethesda, Maryland

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 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 µmol/L in all cases of mild PKU. In offspring of mothers with severe PKU and average Phe exposure during pregnancy of 360 to 750 µmol/L, multiple regression analysis revealed both maternal IQ and Phe exposure to be significant predictors of offspring IQ. When average Phe exposure was <360 µmol/L, cognitive development was normal (mean IQ: 105), whereas an average Phe exposure of >750 µmol/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.

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Abbreviations: PAH, phenylalanine hydroxylase • PKU, phenylketonuria • MHP, mild hyperphenylalaninemia • MPKUCS, Maternal PKU Collaborative Study • Phe, phenylalanine • WISC-R, Wechsler Intelligence Scale for Children–Revised • MPKU, maternal phenylketonuria • APL, assigned blood Phe level

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