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GENATLAS PHENOTYPE
last update : 19-01-2011
Symbol PKU
Location 12q23.1
Name phenylketonuria
Other name(s)
  • hyperphenylalaninemia, variant PKU
  • phenylalanine hydroxylase deficiency
    • Corresponding gene PAH
    Other symbol(s) PKU, non-PKU, HPA
    Main clinical features
  • intolerance to the dietary intake of phenylalanine
  • dietary restriction may avoid profound and irreversible mental retardation
  • three group of phenotypes
  • Group 1 (mean±SD in vitro residual activity 53.0%) corresponds to the very mild phenotype
  • Group 2 (mean±SD in vitro residual activity, 41.5%) corresponds to the mild PKU phenotype
  • Group 3 (mean in vitro residual activity 6.9%) corresponds to severe PKU and includes the only moderate mutant (A309V), in addition to a large group of mutations unambiguously reported as "severe"
  • associated to bone impairment characterized by circulating osteoclast precursors and activated T cell increase (PMID: 21152388))
    • Genetic determination autosomal recessive
    Related entries hyperphenylalaninemia
    Function/system disorder metabolism/aminoacids
    Type disease
    Gene product
    Name phenylalanine hydroxylase (PAH)
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
          over 400 different disease-causing mutations have been identified in the PAH gene ; Most patients are compound heterozygotes.
    missense   abnormal protein/loss of function result in misfolding of PAH, increased protein turnover, and a loss of enzymatic function
    missense   abnormal protein/loss of function (R158Q, I174T and R408W) result in the classical phenylketonuria (PMID: 19036622)
    Remark(s)
  • commonly diagnosed upon routine screening of newborns (Guthrie card bloodspot). PAH genotype is the main determinant of metabolic phenotype in most cases. In compound heterozygote the less severe of the two PAH mutations determine disease severity
  • decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome
  • protein-misfolding disease in which global conformational changes hinder molecular motions essential for physiological enzyme function (PMID: 18538294))
    • Genotype/Phenotype correlations Classic PKU is associated with a high risk of mental impairment in the absence of treatment, non-PKU HPA with a much lower risk and variant PKU are intermediate. Pregnancies in women with PAH deficiency are at risk of congenital abnormalities and should be monitored from before conception