Transient neonatal hyperphenylalaninaemia is not related to mutations at the phenylalanine hydroxylase gene.
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Amino Acid Metabolism, Inborn Errors↗
Biomedical subjects
J Zschocke
Publications and source records attributed to J Zschocke.
Discordant phenylketonuria phenotypes in one family: the relationship between genotype and clinical outcome is a function of multiple effects.
Four members spanning three generations of one family have phenylketonuria of varying degrees of severity. Two first cousins were screened in the neonatal period and have had dietary phenylalanine restriction since diagnosis, the older patient having been classified as having more severe PKU and the younger one as having mild PKU. Their mutual grandfather and his older brother also have a significant hyperphenylalaninaemia and are of normal intelligence despite never having had restricted phenylalanine intake. Mutation analysis of the phenylalanine hydroxylase (PAH) gene has established that there are four different mutations, two in exon 2 (F39L and L48S) and two in exon 3 (R111X and S67P), which give rise to PKU in this family. In order to establish their relative severity, we screened the PKU populations of western Scotland and the south west of England for these mutations. The exon 3 mutations are rare; however, F39L is relatively common in Scotland and L48S in England. A comparison of diagnostic blood phenylalanine concentrations in subjects carrying L48S/null or F39L/null mutations with those carrying two null mutations suggest that these exon 2 mutations are less deleterious. Thus, in this family, the different biochemical phenotypes can be explained, in part, by different genotypes at the PAH locus but our results show that the relationship between genotype and clinical outcome is more complex and is a function of multiple effects.
Aged↗
Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach.
We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, I65T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting.
Base Sequence↗
Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: frequent mutation allows screening and early diagnosis.
Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninaemia, i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different phenylalanine hydroxylase mutations in a particular population, non-PKU HPA is usually caused by the combined effect of a mild HPA mutation and a severe PKU mutation. Presented here is a comprehensive analysis of non-PKU HPA in Northern Ireland. Of particular interest is one prevalent HPA mutation (T380M), which is present in over 70% of non-PKU HPA patients in Northern Ireland. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU hyperphenylalaninaemia in the majority of cases at a very early stage. This may be clinically useful and reassuring for the parents. Other mutations described are V245A, L194P, and E390G.
Adolescent↗
Automated sequencing detects all mutations in Northern Irish patients with phenylketonuria and mild hyperphenylalaninaemia.
In the first phase of the Northern Ireland PKU Study, we used automated sequencing to identify the spectrum of mutations in a random group of 32 unrelated phenylketonuria (PKU) families. We also investigated 7 Northern Irish patients with mild hyperphenylalaninaemia not requiring dietary intervention (MHP, previously referred to as non-PKU HPA). Disease-causing mutations were identified on all 78 investigated chromosomes. We found 23 different mutations, including 20 missense, 1 nonsense and 2 splice site mutations. All mutations were located within exons or at intron-exon boundaries of the phenylalanine hydroxylase gene. Seven mutations occurred at CpG sites, confirming these sites as mutation hot-spots in PKU. Mutations R408W and I65T are the two commonest PKU mutations in the Northern Irish population. Two mutations (T380M and V245A) can be characterized as MHP mutations; they are quasi dominant markers for MHP since they cause mild hyperphenylalaninaemia even when occurring in conjunction with the most severe PKU mutations. The results have proven valuable for the development of a routine PKU mutation analysis system in Northern Ireland.
DNA Mutational Analysis↗
The STR system in the human phenylalanine hydroxylase gene: true fragment length obtained with fluorescent labelled PCR primers.
We present a simple, fast, non-radioactive method for the analysis of the polymorphic short tandem repeat (STR) system in the human phenylalanine hydroxylase gene. Previously, sizing of the STR marker involved radiolabelling of PCR amplified fragments and resolution on denaturing polyacrylamide gels using M13 sequencing ladder as a standard. However, this method consistently gave sizes 2 bp longer than the known sequence. The fluorescent method presented here employs internal lane standards and enables accurate sizing of the fragments. To avoid confusion, we suggest that the true fragment lengths are used as reference values in the future. The analysis of STR alleles is valuable for population genetic studies and for targeted mutation screening in phenylketonuria (PKU). It can replace RFLP-based haplotype analysis for carrier detection, and we report its use for prenatal diagnosis in a Northern Irish family with PKU. The analysis of 250 Northern Irish chromosomes, including 128 PKU alleles, showed no significant difference between normal and PKU alleles, with fragment lengths of 238 and 242 bp most common in both groups.
Genetic Testing↗
A molecular survey of phenylketonuria in Iceland: identification of a founding mutation and evidence of predominant Norse settlement.
Iceland was settled during the late 9th and early 10th centuries AD by Vikings who arrived from Norway and the British Isles. Although it is generally acknowledged that the Vikings brought with them Celtic slaves, the relative contribution of these peoples to the modern Icelandic gene pool has been a matter of considerable discussion. Most population genetic studies using classical markers have indicated a large Irish genetic contribution. We have investigated the molecular basis of phenylketonuria (PKU) in 17 Icelandic patients and found 9 different mutations in the phenylalanine hydroxylase gene. One novel mutation, Y377fsdelT, accounts for more than 40% of the mutant chromosomes. Haplotype data support a common ancestral origin of the mutation, and genealogical examination extending back more than 5 generations shows that this mutation has probably arisen in an isolated part of southern Iceland and was enriched by a founder effect. At least 7 PKU mutations have originated outside iceland. The almost exclusively Scandinavian background of these mutations and the complete absence of common Irish PKU mutations strongly support historical and linguistic evidence of a predominant Scandinavian heritage of the Icelandic people.
DNA Mutational Analysis↗