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F Güttler

Publications and source records attributed to F Güttler.

At least 19 recordsLinked to original sources
PubMed1998

Mild hyperphenylalaninemia and heterozygosity of the phenylalanine hydroxylase gene.

Newborn screening for phenylketonuria (PKU) is now the standard of practice. Initial phenylalanine blood levels of 240 mumol/L result in referral of affected newborns to medical facilities experienced in caring for patients with metabolic disorders. This case report concerns a female infant born in 1976 with a presumptive positive PKU screening test on the third day of life of 240 mumol/L phenylalanine. Follow-up levels while the mother was breast feeding on the sixth day of life were 324 and, on the 27th day, 312 mumol/L. She was subsequently lost to follow-up at age 11 years, but returned at 19 years of age due to pregnancy, with a blood phenylalanine level of 132 mumol/L. Mutation studies then were performed documenting that she was a carrier for the phenylalanine hydroxylase gene and did not have hyperphenylalaninemia. The mother's parents and the infant were also genotyped confirming heterozygosity. The infant on follow-up is completely normal, following a normal pregnancy.

Adult↗
PubMed1998

Aberrant phenylalanine metabolism in phenylketonuria heterozygotes.

The wide variation in phenylalanine hydroxylating capacity observed among patients with phenylketonuria (PKU) is primarily due to allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus. In this study, we examined phenylalanine metabolism after an oral phenylalanine load in 148 carriers of known PAH gene mutations. As a group, heterozygotes formed less tyrosine than normozygotes (p < 0.001), and there was a tendency that carriers of a severe PAH mutation formed less tyrosine than carriers of a mild mutation. Nevertheless, the interindividual variation was extensive, and we identified a group of individuals who formed no or very little tyrosine after the phenylalanine load. This tyrosine response was accompanied by a decreased ability to eliminate the phenylalanine test dose but did not correlate with the intrinsic severity of the mutant PAH allele. Examination of the entire coding region of the PAH gene revealed no additional sequence alterations in these subjects. Our data suggest that a subset of PKU heterozygotes have reduced phenylalanine hydroxylating capacity approaching or equalling the levels observed in genetic compounds with non-PKU mild hyperphenylalaninaemia (MHP). Awareness of this phenotypic overlap between PKU carriers and genetic compounds with two mutant alleles may be useful for clinicians and paediatricians involved in diagnosis and genetic counselling.

Adult↗
PubMed1998

A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Alleles↗
PubMed1997

[Hemoglobinopathy in the county of Copenhagen].

In Copenhagen County, haemoglobinopathy was centralized to the Department of Haematology L, Herlev University Hospital from January 1995. All pregnant women of relevant ethnic origin admitted to the obstetric departments of the Country in 1995, were examined by haemoglobin electrophoresis. furthermore, we performed haemoglobin electrophoresis on immigrants admitted on suspicion of haemoglobinopathy. 24 (4.8%) of 505 examinations in pregnant women were abnormal. 12 reflected a carrier condition for either beta-thalassaemia or sickle cell disease; 53 of 82 examinations in non-pregnant patients were abnormal; 29 had beta-thalassaemia minor and the rest included the haemoglobin variants C, D, E, H and S, mostly in a heterozygous from. The genetic lesions, all of which were mutations, were characterized by molecular genetic analysis in 13 cases with demonstrated beta-gene disorder. The gene frequency of haemoglobinopathies among immigrants to Denmark is common. The Danish health care system must therefore be prepared to address this problem including the clinical aspects, screening and molecular biological examinations, prenatal diagnosis and genetic counselling.

Adult↗
PubMed1997

The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency.

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.

Adult↗
PubMed1997

Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria.

Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as "classical" (>1200 micromol/L), "mild" (600-1200 micromol/L), or "non-phenylketonuria (PKU)-hyperphenylalaninemia" (<600 micromol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter (magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 micromol/L). As a consequence, a lifelong diet with serum phenylalanine levels below 400 micromol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 micromol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent "executive functions." In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.

Adolescent↗
PubMed1996

PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population.

The results of the neonatal screening for phenylalanine hydroxylase (PAH) deficiency in Sicily show that its incidence is higher than previously reported for mainland Italians and that non-PKU HPA is in excess of classical and mild PKU. The latter finding suggests that a high number of non-PKU HPA mutations would occur in the Sicilian population compared to populations with an inverted PKU/non-PKU HPA ratio. Previous studies have identified 40 mutations accounting for the majority (98%) of mutant alleles underlying PAH deficiency in Sicily. In order to study the molecular basis of the distribution of PAH deficiency phenotypes in the Sicilian population, we have correlated 31 of those mutations with clinical and metabolic phenotypes in 12 mentally retarded patients, 14 treated patients with classic or mild PKU, and 13 subjects presenting the non-PKU HPA phenotype. The present study proposes a tentative classification for a large number (26) of PAH gene mutations which may represent an additional tool for establishing a differential diagnosis for PAH deficiency in the Sicilian population.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency.

The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with a continuum of metabolic phenotypes ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). More than 200 mutations in the PAH gene are associated with PAH deficiency. From theoretical considerations or in vitro expression studies each mutation has a particular influence on enzyme activity, which explains the variation in dietary tolerance for phenylalanine (Phe). This paper gives a summary of the effect of each type of mutation on PAH activity and illustrates how the combination of mutations (the genotype) is associated with the Phe tolerance (the metabolic phenotype). Mutations within a population generally include a few prevalent mutations and a high number of rare mutations. The particular distribution of mutations implies that many PAH-deficient patients carry the same mutation combination, enabling the establishment of genotype-phenotype correlations by comparing clinical parameters in patients with identical genotypes. Because certain mutations always cause MHP irrespective of the mutation on the second allele, mutation typing of hyperphenylalaninaemic neonates will differentiate between PKU and MHP. In addition, genotyping will provide a tool for precise diagnosis of the metabolic phenotype of the neonate with PKU and thereby permit earlier implementation of dietary therapy better tailored to each individual patient.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.

The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g-->a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies < or = 1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency.

Alleles↗
PubMed1995

Phenylketonuric patients decades after diet.

Nineteen early-treated phenylketonuric patients, whose diet was discontinued between 4.5 and 13 years of age, and who have been off the diet for 12-28 years, were reassessed in 1992-93. There was little change in mean IQ between end of diet and follow-up, less than one IQ point on the average, with no change for any individual exceeding 12 IQ points. Both prior and current IQ correlated slightly negatively with mean phenylalanine (Phe) concentration, and positively with parents' education. The phenylalanine level at follow-up was significantly lower on average by about 900 mumol/L. Five of the subjects (26%) have evidence of mental disease. However, the data suggest that the discontinuation of the diet did not cause intellectual deterioration. Nonetheless, the patients' intellect cannot be the only consideration for maintenance of diet. The occurrence of psychopathology among phenylketonuric patients and the possible unknown effects of toxic elevation of phenylalanine during their lifetime suggest the need to maintain the diet. The use of DNA for diagnostic and prognostic purposes might assist in decisions about dietary quality and duration, and in anticipation of psychopathology.

Adult↗
PubMed1995

In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: characterization of seven common mutations.

UNLABELLED: Mutations in the gene encoding phenylalanine hydroxylase (PAH) cause persistent hyperphenylalaninaemia. To date, more than 200 point mutations and microdeletions have been characterized. Each mutation has a particular quantitative effect on enzyme activity and recessive expression of different mutant alleles results in a marked interindividual heterogeneity of metabolic and clinical phenotypes. In this paper we demonstrate how a simple clinical test can be used to evaluate the correlation between mutation genotype and phenylalanine metabolism. In hyperphenylalaninaemic patients with known PAH mutation genotype, we have investigated phenylalanine turnover in vivo by measuring the ability to eliminate a test dose of L-phenylalanine. All patients could be considered functionally hemizygous for one of their mutant alleles by carrying on the other allele a mutation that is known to completely abolish PAH activity and encode a peptide with no immunoreactivity. Seven mutations (R408W, IVS-12nt1, R261Q, G46S, Y414C, A104D, and D415N) were characterized by oral phenylalanine loading, each mutation being represented by at least three patients. The elimination profile determined for a 3-day period provides a measure to compare residual activity of the mutant proteins and to assign each mutation to a particular metabolic phenotype. The established relation between genotype and phenotype may enable prediction of the severity of the disease by genotype determination in the newborn period. This will aid in the management of hyperphenylalaninaemia and may improve prognosis. CONCLUSION: The possibility of predicting the residual enzyme activity by DNA analysis performed already in the newborn period allows the prompt implementation of a diet that is adjusted to the degree of PAH deficiency. This may improve management and prognosis of hyperphenylalaninaemia.

Alleles↗
PubMed1995

Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland.

The incidence of phenylketonuria (PKU) in Finland is extremely low, probably below 1 in 100,000. We describe the mutations and haplotypes in all four presently known patients. Mutation R408W was found on four mutant chromosomes (all haplotype 2), and IVS7nt1, R261Q, and IVS2nt1 were each found on a single chromosome. No mutation was found on the remaining chromosome. These findings support a pronounced negative founder effect as the cause of the low incidence of PKU in Finland, and are consistent with existing data regarding the European and Baltic origin of Finnish genes.

Adolescent↗