Severity of mutation in the phenylalanine hydroxylase gene influences phenylalanine metabolism in phenylketonuria and hyperphenylalaninaemia heterozygotes

Summary We examined whether the degree of residual activity from the mutant phenylalanine hydroxylase (PAH) allele affected phenylalanine metabolism in heterozygotes for phenylketonuria (PKU) or non-PKU hyperphenylalaninaemia (HPA). Discriminant analysis was carried out to find the function of fasting plasma concentrations of phenylalanine (PHE) and tyrosine (TYR) that best separated carriers from non-carriers. This function (0.103TYR –0.214PHE_CORR –4.499) was subsequently used as the dependent variable, with thein vitro activity of the expressed mutant PAH as the independent variable, in a regression analysis performed on heterozygotes for mutations that had been studied in a eukaryotic cell expression system. This analysis showed a significant correlation (r=0.40,n=140,p<0.001), although there was a wide spread of values within each of the two major groups of carriers and a considerable overlap between the groups. We conclude that the severity of the mutation, as determined byin vitro expression analysis, in the mutant PAH gene is reflected in the biochemical phenotype of heterozygotes. This result emphasizes the relevance of the cell expression system used for establishing the relative severities of most mutations at the PAH locus. Differences in the activities from the carried mutant PAH allele on phenylalanine metabolism in heterozygotes are, however, small compared to the activity from the normal PAH allele and are easily obscured by other factors leading to inter- or intra-individual variation in phenylalanine metabolism. Fasting plasma concentrations of phenylalanine and tyrosine thus can not be used to predict the severity of the carried PAH mutation in individual PKU or HPA heterozygotes.     

A twin study of amino acid concentrations in cerebrospinal fluid

The concentrations of amino acids in the cerebrospinal fluid (CSF) were measured in pairs of healthy mono- and dizygotic twins. Intraclass correlations were calculated. Genetic and cultural heritabilities were estimated using a path analytical model. CSF levels of glycine, tyrosine and arginine were shown to be influenced by genetic factors. Genetic variation was also shown for serine, alpha-aminobutyrate and leucine. The results were compared with results from a genetic analysis of the amino acids in serum.     

Formal genetics of isoniazid metabolism in man

Complex segregation analysis of the isoniazid inactivator phenotype has shown the existence of a recessive gene and a multifactorial background. The phenotype is also influenced by age, sex and weight. The relevance of these findings to the grouping of individuals into slow and rapid inactivators is stressed.     

A germline E-cadherin mutation in a family with gastric and colon cancer

Inactivating mutations have been found in the cell-cell adhesion molecule E-cadherin (CDH1), which acts as a tumor suppressor gene in different kinds of cancers, e.g. primarily diffuse gastric cancer and lobular breast cancer. In this study, we screened for germline alterations in familial gastric and colon cancer cases. In total, 20 gastric and 18 colon cancer patients with both familial gastric and colon cancer were tested for germline E-cadherin alterations by using PCR/SSCP, specific restriction digestion test and sequencing. No pathogenic mutations were identified in the gastric cancer patients. In two colon cancer patients, a missense mutation in exon 12, codon 592 (Ala592Thr) was found. This alteration segregated with diffuse gastric cancer and colon cancer in one of the families. The prevalence of this alteration in the general population and colon cancer cases was almost the same. However, the fact that this alteration (Ala592Thr) segregated with colon cancer and diffuse gastric cancer in one big family, suggests that this E-cadherin missense alteration, beside predisposing to diffuse gastric cancer, also may play a role in colorectal carcinogenesis.     

Von Hippel-Lindau disease: a genetic study.

Genetic aspects of von Hippel-Lindau (VHL) disease were studied in familial and isolated cases. Complex segregation analysis with pointers was performed in 38 kindreds with two or more affected members. Dominant inheritance with almost complete penetrance in the highest age classes (0.96 at 51 to 60 and 0.99 at 61 to 70 years) was confirmed and there was no evidence of heterogeneity between families ascertained through complete and incomplete selection. The point prevalence of heterozygotes in East Anglia was 1.89/100,000 (1/53,000) persons with an estimated birth incidence of 2.73/100,000 (1/36,000) live births. Reproductive fitness was 0.83. Direct and indirect estimates of the mutation rate were 4.4 (95% CI 0.9 to 7.9) x 10(-6)/gene/generation and 2.32 x 10(-6)/gene/generation respectively. There was no significant association between parental age or birth order and new mutations for VHL disease.     

Transmission of breast cancer - a controversy resolved

The Danish breast cancer data collected by Jacobsen (1946) have been reanalysed using morbid risks which incorporate mortality due to breast cancer. A dominant gene is favoured for familial breast cancer, supporting the conclusions of Williams & Anderson (1984) and later authors. Neglect of specific mortality does not greatly alter estimates of gene frequency and displacement, but the evidence for a major gene is inflated. No evidence for heterogeneity was found. Earlier claims of non-Mendelian transmission are in error since we have discovered that transmission probabilities are not correctly implemented in the computer program POINTER. Cases with bilateral breast cancer and males with breast cancer all belonged to families favouring a major gene. Of the cancer sites frequently reported to be associated with familial breast cancer, only ovarian cancer is significant in this material.     

Epidemiology of familial adenomatous polyposis in Sweden: changes over time and differences in phenotype between males and females

BACKGROUND: The Swedish Polyposis Registry was set up in Sweden in the late 1950s to promote screening of familial adenomatous polyposis (FAP). The aim of this study was to examine the epidemiology of FAP in Sweden, including the influence of screening on morbidity and mortality in colorectal cancer (CRC). METHODS: Four hundred and thirty-one patients (213 males and 218 females) with FAP from 145 families recorded by the Swedish Polyposis Registry were investigated. The effect of screening on morbidity and mortality in CRC was evaluated by comparing the 216 probands with the 215 call-up patients. Three different periods were studied: the pre-screening period (1912-1956), the first screening period (1957-1976), and the second screening period (1977-1996). RESULTS: The mean annual incidence rates during the three periods were 0.2, 1.38, and 0.86 per million, respectively. The birth frequency was calculated to be 1 in 18,000 between 1947 and 1966, and the prevalence was 32 per million at the end of 1996. The proportion of new mutants among the FAP patients born between 1927 and 1966 was estimated to be 11%. The median age at diagnosis of probands was 39 (range, 11-71) years and did not change over time, although an increase was seen in the subgroup with CRC at diagnosis (P = 0.02). In the call-up group the median age at diagnosis was 22 (range, 3-65) years. Sixty-seven per cent of the probands and 3.3% of the call-up patients had CRC at diagnosis, and the corresponding mortality figures were 44% and 1.9%. The risk among probands of having CRC at diagnosis decreased from 81% to 49% (P = 0.0006). Female probands were diagnosed with symptoms (P = 0.03) and CRC (P = 0.04) earlier than male probands. CONCLUSIONS: A nationwide screening program facilitates detection and early diagnosis of FAP. A decrease in CRC morbidity among probands contributed to the improved prognosis. An earlier onset of symptoms and CRC in females indicate that the course of FAP is influenced by sex.     

Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals--a genetic study

The concentrations of the major monoamine metabolites, homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), of platelet monoamine oxidase (MAO) and of dopamine beta-hydroxylase (DBH)-activity in serum and CSF were determined in pairs of healthy mono- and dizygotic twins, brothers and unrelated individuals. Intraclass correlations were calculated for each category of pairs. Of the monoamine metabolites, only MOPEG was found to be under any major genetic influence. Genetic heritability for MOPEG was 0.74 with no evidence of cultural heritability or environment common to twins. For HVA and 5-HIAA, a familial influence was found, where the cultural heritability was higher than the genetic. As in previous studies of MAO in blood platelets and of DBH activity in serum, there was strong evidence for a genetic component. The genetic heritability for MAO was 0.78. For DBH in serum the genetic component was 0.98, and for DBH in CSF, 0.83. The demonstration of a familial influence on 5-HIAA and HVA in CSF requires a more detailed analysis of the character of such environmental and genetic influences, using more direct techniques.     

Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations

Summary European data on the polymorphic metabolism of debrisoquine, sparteine, dextromethorphan and mephenytoin have been collected.No significant difference in phenotype frequencies was found between the separate series for debrisoquine, sparteine and dextromethorphan, which supports the claim that these probe drugs reflect the same enzyme polymorphism.The mean frequency of the phenotype slow debrisoquine metaboliser was 7.65% based on 5005 determinations. The overall mean reflecting all three drugs and 8764 determinations was 7.40%. This is consistent with a gene frequency of 0.27 (95% confidence interval 0.26–0.28).The overall mean of the phenotype slow metaboliser of mephenytoin was 3.52% corresponding to a gene frequency of 0.19 (confidence interval 0.17–0.20).The incidence of slow metabolism of debrisoquine and possibly also of S-mephenytoin was homogeneous in the samples from European populations. This is of considerable interest as interethnic differences are now being found both in the phenotypic characters as well as the genotypes of polymorphic drug oxidation.     

KAMEDO report no. 79: train accident in Germany, 1998

A train traveling at 200 kilometers per hour carrying 300 passengers crashed into a bridge. At leaset 85 doctors and 1889 persons were involved in the emergency response. A total of 101 persons were killed, 108 were injured, and 87 were transported to a hospital (27 by helicopter; 60 by land ambulance). Eighty percent of the severely injured were trasported to a hosptial within two hours of the crash. Coordination of the activities of the hoards of responders was an issue, as was the lack of a formal organization to provide psychosocial support. Preparedness plans should include management of the dead and for the provision of psychosocial support.