Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1990 Sep;27(9):564–568. doi: 10.1136/jmg.27.9.564

Genetic analysis of treated and untreated phenylketonuria in one family.

L A Tyfield 1, A L Meredith 1, M J Osborn 1, R Primavesi 1, T L Chambers 1, J B Holton 1, P S Harper 1
PMCID: PMC1017218  PMID: 1977916

Abstract

We describe a family in which four subjects in two generations have a disorder of phenylalanine metabolism. Two first cousins had different biochemical presentations in the neonatal period. The older child was thought to have a more severe form of phenylketonuria (PKU), and the younger child a milder form. While carrying out family studies we discovered that their mutual grandfather and his older unmarried brother, both of normal intelligence, had a marked and previously undiagnosed hyperphenylalaninaemia. DNA analysis using RFLP haplotypes has shown that there are four independent mutant PKU alleles in this family which are found on three haplotype patterns. None of the affected family members carries a previously defined mutation at the phenylalanine hydroxylase (PAH) locus and so DNA analysis was not able to explain the apparently different biochemical phenotypes in the affected members of this family.

Full text

PDF
564

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aulehla-Scholz C., Vorgerd M., Sautter E., Leupold D., Mahlmann R., Ullrich K., Olek K., Horst J. Phenylketonuria: distribution of DNA diagnostic patterns in German families. Hum Genet. 1988 Apr;78(4):353–355. doi: 10.1007/BF00291734. [DOI] [PubMed] [Google Scholar]
  2. Berry H. K., Hsieh M. H., Bofinger M. K., Schubert W. K. Diagnosis of phenylalanine hydroxylase deficiency (phenylketonuria). Am J Dis Child. 1982 Feb;136(2):111–114. doi: 10.1001/archpedi.1982.03970380023006. [DOI] [PubMed] [Google Scholar]
  3. Blitzer M. G., Bailey-Wilson J. E., Shapira E. Discrimination of phenylketonurics from persistent hyperphenylalaninemia patients using a simple phenylalanine loading test. Clin Chim Acta. 1985 Dec 13;153(2):137–142. doi: 10.1016/0009-8981(85)90164-0. [DOI] [PubMed] [Google Scholar]
  4. Chakraborty R., Lidsky A. S., Daiger S. P., Güttler F., Sullivan S., Dilella A. G., Woo S. L. Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria. Hum Genet. 1987 May;76(1):40–46. doi: 10.1007/BF00283048. [DOI] [PubMed] [Google Scholar]
  5. DiLella A. G., Huang W. M., Woo S. L. Screening for phenylketonuria mutations by DNA amplification with the polymerase chain reaction. Lancet. 1988 Mar 5;1(8584):497–499. doi: 10.1016/s0140-6736(88)91295-0. [DOI] [PubMed] [Google Scholar]
  6. DiLella A. G., Kwok S. C., Ledley F. D., Marvit J., Woo S. L. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry. 1986 Feb 25;25(4):743–749. doi: 10.1021/bi00352a001. [DOI] [PubMed] [Google Scholar]
  7. DiLella A. G., Marvit J., Brayton K., Woo S. L. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. 1987 May 28-Jun 3Nature. 327(6120):333–336. doi: 10.1038/327333a0. [DOI] [PubMed] [Google Scholar]
  8. DiLella A. G., Marvit J., Lidsky A. S., Güttler F., Woo S. L. Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria. 1986 Aug 28-Sep 3Nature. 322(6082):799–803. doi: 10.1038/322799a0. [DOI] [PubMed] [Google Scholar]
  9. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  10. Güttler F., Ledley F. D., Lidsky A. S., DiLella A. G., Sullivan S. E., Woo S. L. Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria. J Pediatr. 1987 Jan;110(1):68–71. doi: 10.1016/s0022-3476(87)80290-1. [DOI] [PubMed] [Google Scholar]
  11. Hertzberg M., Jahromi K., Ferguson V., Dahl H. H., Mercer J., Mickleson K. N., Trent R. J. Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria. Am J Hum Genet. 1989 Mar;44(3):382–387. [PMC free article] [PubMed] [Google Scholar]
  12. Kwok S. C., Ledley F. D., DiLella A. G., Robson K. J., Woo S. L. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry. 1985 Jan 29;24(3):556–561. doi: 10.1021/bi00324a002. [DOI] [PubMed] [Google Scholar]
  13. Lehmann W. D. Progress in the identification of the heterozygote in phenylketonuria. J Pediatr. 1989 Jun;114(6):915–924. doi: 10.1016/s0022-3476(89)80431-7. [DOI] [PubMed] [Google Scholar]
  14. Lichter-Konecki U., Konecki D. S., DiLella A. G., Brayton K., Marvit J., Hahn T. M., Trefz F. K., Woo S. L. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene. Biochemistry. 1988 Apr 19;27(8):2881–2885. doi: 10.1021/bi00408a032. [DOI] [PubMed] [Google Scholar]
  15. Lichter-Konecki U., Schlotter M., Konecki D. S., Labeit S., Woo S. L., Trefz F. K. Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population. Hum Genet. 1988 Apr;78(4):347–352. doi: 10.1007/BF00291733. [DOI] [PubMed] [Google Scholar]
  16. Okano Y., Wang T., Eisensmith R. C., Steinmann B., Gitzelmann R., Woo S. L. Missense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene. Am J Hum Genet. 1990 Jan;46(1):18–25. [PMC free article] [PubMed] [Google Scholar]
  17. Rey F., Berthelon M., Caillaud C., Lyonnet S., Abadie V., Blandin-Savoja F., Feingold J., Saudubray J. M., Frézal J., Munnich A. Clinical and molecular heterogeneity of phenylalanine hydroxylase deficiencies in France. Am J Hum Genet. 1988 Dec;43(6):914–921. [PMC free article] [PubMed] [Google Scholar]
  18. Riess O., Michel A., Speer A., Meiske W., Cobet G., Coutelle C. Linkage disequilibrium between RFLP haplotype 2 and the affected PAH allele in PKU families from the Berlin area of the German Democratic Republic. Hum Genet. 1988 Apr;78(4):343–346. doi: 10.1007/BF00291732. [DOI] [PubMed] [Google Scholar]
  19. Scriver C. R., Gregory D. M., Sovetts D., Tissenbaum G. Normal plasma free amino acid values in adults: the influence of some common physiological variables. Metabolism. 1985 Sep;34(9):868–873. doi: 10.1016/0026-0495(85)90112-x. [DOI] [PubMed] [Google Scholar]
  20. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  21. Sullivan S. E., Moore S. D., Connor J. M., King M., Cockburn F., Steinmann B., Gitzelmann R., Daiger S. P., Woo S. L. Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland. Am J Hum Genet. 1989 May;44(5):652–659. [PMC free article] [PubMed] [Google Scholar]
  22. Trefz F. K., Bartholomé K., Bickel H., Lutz P., Schmidt H., Seyberth H. W. In vivo residual activities of the phenylalanine hydroxylating system in phenylketonuria and variants. J Inherit Metab Dis. 1981;4(2):101–102. doi: 10.1007/BF02263611. [DOI] [PubMed] [Google Scholar]
  23. Tyfield L. A., Meredith A. L., Osborn M. J., Harper P. S. Identification of the haplotype pattern associated with the mutant PKU allele in the Gypsy population of Wales. J Med Genet. 1989 Aug;26(8):499–503. doi: 10.1136/jmg.26.8.499. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES