Molecular basis of phenylketonuria and a correlation between genotype and phenotype in a heterogeneous southeastern US population

Pediatrics. 1996 Apr;97(4):512-6.


Objective: To determine the molecular basis of phenylketonuria (PKU) and related hyperphenylalaninemia (HPA) and to establish correlations between phenylalanine hydroxylase (PAH) genotypes and biochemical and clinical phenotypes in an ethnically diverse US population, PAH genotypes were determined in 35 patients with PKU or HPA and 1 carrier from the Medical Genetics Clinic of the Emory University School of Medicine.

Methodology: Patients were identified through Georgia's population-based newborn screening program. PAH genotypes in these individuals were determined from dried blood spots or whole-blood samples using a combination of polymerase chain reaction-mediated amplification, denaturing gradient gel electrophoresis, and direct-sequence analysis. The phenotypic severity of patients with PKU and HPA was based on pretreatment serum phenylalanine (PHE) levels during the neonatal period and on dietary tolerance of PHE later in life.

Results: Sixty-eight (96%) of 71 mutant alleles were identified. Major mutations in this population included R408W (11 of 71), I65T (11 of 71), Y414C (6 of 71), L348V (4 of 71), and IVS10 (4 of 71). Five new nucleotide substitutions, E76A (1 of 71), R241L (1 of 71), Q304R (2 of 71), C334S (1 of 71), and R400R (2 of 71) were also detected. Thirty-two of the thirty-five nonrelated patients examined in this study were completely genotyped. Strong correlations were observed between the level of PAH activity predicted from the genotype, when known from previous in vitro expression studies of the mutant proteins, and pretreatment serum PHE levels (r = .841) or clinical severity (Kendall rank-order correlation coefficient, .936).

Conclusions: These results demonstrate strong correlations between PAH genotype and biochemical and clinical phenotypes in this heterogeneous American sample population, extending our previous findings from relatively homogeneous European populations. These correlations further demonstrate the clinical utility of genotype analysis in the treatment of patients with PKU and HPA.

Publication types

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

MeSH terms

  • Alleles
  • Base Sequence
  • Ethnicity / genetics
  • Europe
  • Forecasting
  • Gene Expression Regulation
  • Genetics, Population
  • Genotype
  • Georgia
  • Heterozygote
  • Humans
  • Infant, Newborn
  • Molecular Biology
  • Mutation / genetics
  • Neonatal Screening
  • Phenotype
  • Phenylalanine / blood
  • Phenylalanine / genetics
  • Phenylalanine Hydroxylase / genetics
  • Phenylketonurias / drug therapy
  • Phenylketonurias / genetics*
  • Polymerase Chain Reaction
  • Sequence Analysis


  • Phenylalanine
  • Phenylalanine Hydroxylase