Summary
Neonatal hyperphenylalaninaemia caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) represents a wide spectrum of metabolic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compounds. We have investigated four unusual families in which both PKU and MHP were present. In each family three different mutations in the PAH gene were identified, including two associated with PKU and one associated with MHP. The unexpected outcome of discordant phenotypes within the families described is explained by previously unrecognized parental MHP. By mutation analysis we have also predicted the phenotypical outcome in a hyperphenylalaninaemic infant born to a mother who before pregnancy had been diagnosed as having MHP. Our results demonstrate the utility of nucleic acid analysis in follow-up in PKU screening programmes.
Similar content being viewed by others
References
Avigad S, Kleiman S, Weinstein M et al (1991) Compound heterozygosity in nonphenylketonuria hyperphenylalanemia: the contribution of mutations for classical phenylketonuria.Am J Hum Genet 49: 393–399.
Berman JL, Cunningham GC, Day RW, Ford R, Hsia DY-Y (1969) Causes for high phenylalanine with normal tyrosine in newborn screening programs.Am J Dis Child 117: 54–65.
Childs B, Der Kaloustian V (1968) Genetic heterogeneity.N Engl J Med 279: 1205–1212.
Cohen BE, Szeinberg A, Berman W et al (1969) Mental retardation in a family with phenylketonuria and mild hyperphenylalaninemia.Pediatrics 44: 655–660.
Economou-Petersen E, Henriksen KF, Guldberg P, Güttler F (1992) Molecular basis for nonphenylketonuria hyperphenylalaninemia.Genomics 14: 1–5.
Guldberg P, Henriksen KF, Güttler F (1993a) Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis.Genomics 17:141–146.
Guldberg P, Romano V, Ceratto N et al (1993b) Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in Southern Europe.Hum Mol Genet 2: 1703–1707.
Guthrie R, Susi A (1963) A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants.Pediatrics 32: 338–343.
Güttler F (1980) Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood.Acta Paediatr Scand (Supplement)280: 1–80.
Güttler F, Lou H (1990) Phenylketonuria and hyperphenylalaninemia. In Fernandes J, Saudubray J-M, Tada K, eds.Inborn Metabolic Disease: Diagnosis and Treatment. Berlin, Heidelberg: Springer-Verlag, 161–174.
Güttler F, Kaufman S, Milstein S (1977) Phenylalanine has no effect on dehydropteridine reductase activity in phenylketonuria fibroblasts.Lancet 2: 1139–1140.
Hsia DY-Y (1970) Phenylketonuria and its variants. In Steinberg AG, Bearn AG, eds.Progress in Medical Genetics, vol. VII. New York: London: Grune and Stratton, 29–68.
Hsia DY-Y, O'Flynn ME, Berman JL (1968) Atypical phenylketonuria with borderline or normal intelligence.Am J Dis Child 116: 143–157.
Kang ES, Kaufman S, Gerald PS (1970) Clinical and biochemical observations of patients with atypical phenylketonuria.Pediatrics 45: 83–92.
Kaufman S, Max EE, Kang ES (1975) Phenylalanine hydroxylase activity in liver biopsies from hyperphenylalaninemia heterozygotes: deviation from proportionality with gene dosage.Pediatr Res 9: 632–634.
Ledley FD, Levy HL, Woo SLC (1986) Molecular analysis of the inheritance of phenylketonuria and mild hyperphenylalaninemia in families with both disorders.N Engl J Med 314: 1276–1280.
Levy HL, Shih VE, Karolkewicz V et al (1971) Persistent mild hyperphenylalaninemia in the untreated state. A prospective study.N Engl J Med 285: 424–429.
Lou HC, Toft PB, Andresen J et al (1992) An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninemia.J Inher Metab Dis 15: 687–695.
McCaman MW, Robins E (1962) Fluorimetric method for determination of phenylalanine in serum.J Lab Clin Med 59: 885–890.
Okano Y, Eisensmith RC, Güttler F et al (1991) Molecular basis of phenotypic heterogeneity in phenylketonuria.N Engl J Med 324: 1232–1238.
PAH Gene Mutation Analysis Consortium (1993) December Release (#7). Scriver C, Hoang L, Byck S, Prevost L, eds.
Scriver CR, Kaufman S, Woo SLC (1989) The hyperphenylalaninemias. In Scriver CR, Beaudet AL, Sly W, Valle D, eds.The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill, 495–546.
Scriver CR, John SMW, Rozen R, Eisensmith R, Woo SLC (1993) Associations between populations, phenylketonuria mutations and RFLP haplotypes at the phenylalanine hydroxylase locus: an overview.Dev Brain Dysfunct 6: 11–25.
Svensson E, Eisensmith RC, Dworniczak B et al (1992) Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12.Hum Mutat 1: 129–137.
Svensson E, von Döbeln U, Eisensmith RC, Hagenfeldt L, Woo SLC (1993) Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients.Eur J Pediatr 152: 132–139.
Tyfield LA, Meredith AL, Osborn MJ et al (1990) Genetic analysis of treated and untreated phenylketonuria in one family.J Med Genet 27: 564–568.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Guldberg, P., Levy, H.L., Koch, R. et al. Mutation analysis in families with discordant phenotypes of phenylalanine hydroxylase deficiency. Inheritance and expression of the hyperphenylalaninaemias. J Inherit Metab Dis 17, 645–651 (1994). https://doi.org/10.1007/BF00712004
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00712004