Molecular basis of phenotypic heterogeneity in phenylketonuria

N Engl J Med. 1991 May 2;324(18):1232-8. doi: 10.1056/NEJM199105023241802.


Background: Phenylketonuria is a metabolic disorder that results from a deficiency of the hepatic enzyme phenylalanine hydroxylase. Its clinical phenotype varies widely, and to date more than 10 mutations in the phenylalanine hydroxylase gene have been identified in persons with the disorder. We attempted to relate the clinical phenotype of patients to their genotype.

Methods: We studied 258 patients with phenylketonuria from Denmark and Germany for the presence of eight mutations previously found in patients from these countries. The in vitro activity of the enzymes associated with these mutations was determined by expression analysis in heterologous mammalian cells. The level of activity was then used to predict the in vivo level of phenylalanine hydroxylase activity in patients with various combinations of mutant phenylalanine hydroxylase alleles.

Results: The eight mutations involved 64 percent of all mutant phenylalanine hydroxylase alleles in the patients. Expression analysis showed that these mutant enzymes produced from 0 to 50 percent of normal enzyme activity. The predicted level of phenylalanine hydroxylase activity correlated strongly with the pretreatment serum level of phenylalanine (r = 0.91, P less than 0.001 in the Danish patients and r = 0.74, P less than 0.001 in the German patients), phenylalanine tolerance in the Danish patients (r = 0.84, P less than 0.001), and the serum phenylalanine level measured after standardized oral protein loading in the German patients (r = 0.84, P less than 0.001).

Conclusions: Our results strongly support the hypothesis that there is a molecular basis for phenotypic heterogeneity in phenylketonuria. The establishment of genotype will therefore aid in the prediction of biochemical and clinical phenotypes in patients with this disease.

Publication types

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

MeSH terms

  • Alleles
  • Denmark / epidemiology
  • Gene Expression Regulation, Enzymologic
  • Germany / epidemiology
  • Humans
  • Mutation
  • Nucleic Acid Hybridization
  • Phenotype
  • Phenylalanine / blood
  • Phenylalanine Hydroxylase / genetics*
  • Phenylalanine Hydroxylase / metabolism
  • Phenylketonurias / enzymology*
  • Phenylketonurias / genetics


  • Phenylalanine
  • Phenylalanine Hydroxylase