Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency

Report from the maternal phenylketonuria collaborative study

Flemming Güttler, Colleen Azen, Per Guldberg, Anne Romstad, William B. Hanley, Harvey L. Levy, Reuben Matalon, Bobbye M. Rouse, Friedrich Trefz, Felix De La Cruz, Richard Koch

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)258-262
Number of pages5
JournalPediatrics
Volume104
Issue number2 I
DOIs
StatePublished - Aug 1999

Fingerprint

Maternal Phenylketonuria
Phenylketonurias
Genotype
Phenotype
Mutation
Phenylalanine Hydroxylase
Mothers

Keywords

  • Genotype-phenotype correlation
  • Hyperphenylalaninemia
  • Maternal phenylketonuria
  • Phenylalanine hyroxylase
  • Phenylketonuria

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency : Report from the maternal phenylketonuria collaborative study. / Güttler, Flemming; Azen, Colleen; Guldberg, Per; Romstad, Anne; Hanley, William B.; Levy, Harvey L.; Matalon, Reuben; Rouse, Bobbye M.; Trefz, Friedrich; De La Cruz, Felix; Koch, Richard.

In: Pediatrics, Vol. 104, No. 2 I, 08.1999, p. 258-262.

Research output: Contribution to journalArticle

Güttler, Flemming ; Azen, Colleen ; Guldberg, Per ; Romstad, Anne ; Hanley, William B. ; Levy, Harvey L. ; Matalon, Reuben ; Rouse, Bobbye M. ; Trefz, Friedrich ; De La Cruz, Felix ; Koch, Richard. / Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency : Report from the maternal phenylketonuria collaborative study. In: Pediatrics. 1999 ; Vol. 104, No. 2 I. pp. 258-262.
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abstract = "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.",
keywords = "Genotype-phenotype correlation, Hyperphenylalaninemia, Maternal phenylketonuria, Phenylalanine hyroxylase, Phenylketonuria",
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T1 - Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency

T2 - Report from the maternal phenylketonuria collaborative study

AU - Güttler, Flemming

AU - Azen, Colleen

AU - Guldberg, Per

AU - Romstad, Anne

AU - Hanley, William B.

AU - Levy, Harvey L.

AU - Matalon, Reuben

AU - Rouse, Bobbye M.

AU - Trefz, Friedrich

AU - De La Cruz, Felix

AU - Koch, Richard

PY - 1999/8

Y1 - 1999/8

N2 - 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.

AB - 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.

KW - Genotype-phenotype correlation

KW - Hyperphenylalaninemia

KW - Maternal phenylketonuria

KW - Phenylalanine hyroxylase

KW - Phenylketonuria

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