Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: Frequent mutation allows screening and early diagnosis

Zschocke, Johannes; Graham, Colin A.; Stewart, Fiona; Carson, Dennis; Nevin, N. C.

doi:10.1002/humu.1380040204

Cited by 22 publications

(17 citation statements)

References 10 publications

(9 reference statements)

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“…The pattern of MHP mutations, with a prevalence of A403V (16.7%), differs from that in other populations; in Denmark the predominant MHP mutation is D415N, 24 in Sicily the highest frequency corresponds to A300S 11 and in Ireland to T380M. 25 In the course of this study, four patients were found to present no mutations in the analysed regions of the PAH gene. Although mutations elsewhere in the gene Genotypes and phenotypes of PKU in Spain LR Desviat et al t could not be definitely ruled out, a PAH deficiency was finally discarded, considering that the phenylalanine levels were borderline (125-180 µM) with the generally accepted threshold for dietary intervention.…”

Section: Discussionmentioning

confidence: 54%

Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

et al. 1999

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We present an extensive study of the genetic diversity of phenylalanine hydroxylase deficiency in the Spanish phenylketonuria population. We have analysed 195 PKU patients by DGGE analysis identifying 67 different mutations which represent 89% of the total mutant chromosomes. Seventeen mutations first described in Spain have not yet been detected elsewhere; ten of these are reported here for the first time. The clinical significance of this high genetic heterogeneity was examined by analysing the genotype-phenotype correlations, mainly focusing on the mild hyperphenylalaninaemia (MHP) phenotype. The genotypes found in a group of 93 MHP patients, the largest analysed so far, are described in detail, as well as the relative frequencies of the MHP mutations identified. From the total pool of mutations, 27 can be considered severe, 18 can be defined as mild and 13 as associated with MHP. The prevalent mutations correspond to one severe mutation (IVS10nt-11), one MHP mutation (A403V) and two mild mutations (I65T and V388M). The high frequency of mutations with a low degree of severity can explain the relatively higher prevalence of MHP and mild PKU phenotypes in Spain compared with Northern European populations. We have looked at the geographical distribution in Spain of the more common mutations, finding evidence of local mutation clustering, which could be the result of differences in the ethnic background and/or of genetic drift within each region.

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Section: Discussionmentioning

confidence: 54%

Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

et al. 1999

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“…A322G appears to be a frequent MHP mutation in Sweden, but homozygosity for the mild PKU mutation Y414C was also identified . T380M is the prevalent MHP mutation in Northern Ireland [Zschocke et al, 1994]. Common MHP mutations in Germany include V245A, A403V, and I306V [Weglage et al, 2001].…”

Section: Mhp Mutationsmentioning

confidence: 99%

Phenylketonuria mutations in Europe

2003

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For the PKU Special IssuePhenylketonuria (PKU) is heterogeneous. More than 400 different mutations in the phenylalanine hydroxylase (PAH) gene have been identified. In a systematic review of the molecular genetics of PKU in Europe we identified 29 mutations that may be regarded as prevalent in European populations.Comprehensive regional data for these mutations were collated from all available studies. The spectrum of mutations found in individual regions results from a combination of factors including founder effect, range expansion and migration, genetic drift, and probably heterozygote advantage.

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“…[6][7][8][9] Correlations between the genotype and clinical phenotype of PKU have been demonstrated using predicted PAH activity, which is the average in vitro PAH activity for both mutations, 10 with several mutations related to non-classical PKU phenotypes (mild PKU and mild hyperphenylalaninemia (HPA)). 7,[11][12][13] Recently, BH 4 -responsive PAH deficiency was defined by decreased blood phenylalanine after a BH 4 loading test 14 and patients with this deficiency were treated with long-term BH 4 . [15][16][17][18][19][20] Blood phenylalanine levels were relatively well controlled by BH 4 therapy compared with dietary treatment involving improvement of patients' quality of life.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g4a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH 4 ) responsiveness. The frequency of BH 4 responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH 4 therapy, and genetic counseling in East Asia.

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Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: Frequent mutation allows screening and early diagnosis

Cited by 22 publications

References 10 publications

Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

Phenylketonuria mutations in Europe

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

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