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Biomedical subjects

L P ten Kate

Publications and source records attributed to L P ten Kate.

At least 19 recordsLinked to original sources
PubMed2006

[Rapid prenatal diagnosis of chromosomal abnormalities; limitations and possibilities].

In the past, prenatal diagnosis of chromosomal abnormalities has been achieved using a microscope to make a visual assessment of the chromosomes in foetal cells which had been obtained by invasive procedures. The results were usually not available until 10-14 days later. Now molecular techniques have become available which provide a result within 24-48 hours. The first generation of these techniques combines speed with a focus on a limited number of frequent and important chromosomal abnormalities. Examples include fluorescence in-situ hybridisation (FISH), quantitative polymerase chain reaction (PCR) and multiple ligation-dependent probe amplification (MLPA). One drawback, therefore, is that other clinically significant chromosomal abnormalities will not be detected. More recently other new techniques have been making their appearance, such as array-comparative genomic hybridisation (CGH), which will allow the detection of clinically significant submicroscopic aberrations.

Chromosome Aberrations↗
PubMed2003

Possibilities and barriers in the implementation of a preconceptional screening programme for cystic fibrosis carriers: a focus group study.

OBJECTIVE: This qualitative study aimed to explore possibilities and barriers in the implementation of a nationwide preconceptional cystic fibrosis (CF) carrier screening programme. METHODS: Sessions were held with two focus groups of CF patients and CF relatives, one focus group of people from the target population (couples planning a pregnancy), and two focus groups of potential providers (general practitioners (GPs) and municipal health service workers). RESULTS: Important barriers in the implementation of a preconceptional CF carrier screening programme included the problem of reaching the target population, the heavy workload of GPs, the limited public knowledge about CF in general, and the absence of a preconceptional consultation setting. In general, there was a positive attitude among the participants towards CF carrier screening. CONCLUSION: This study revealed some important barriers in the implementation of CF carrier screening programmes. More research is needed to specify and quantify the importance of the various barriers. Eventually, different intervention strategies should be included in an implementation plan to overcome the most important barriers in the organization and execution of screening.

Adult↗
PubMed2002

Preconception cystic fibrosis carrier couple screening: impact, understanding, and satisfaction.

The impact, understanding of test-results, and satisfaction among participating couples in a preconception cystic fibrosis (CF) carrier screening project were assessed 6 months after testing. Questionnaire data were obtained from 17/18 identified carriers, 15 partners of carriers with negative test results, and 794 (73%) other participants. None of the carriers changed their reproductive plans because of their test results. Eight participants were worried about their results, including four carriers. Those who attended a general practitioner (GP) consultation for pretest education were less worried than those who attended an educational session. Seven carriers felt less healthy. Predictors of a correct understanding of test results (correct in 62% of participants) were: positive test results, high level of knowledge of CF, high level of education, attending an educational session, and previously heard of CF. All participants who reported that they were worried, all carriers, and 95% of the other participants said that they would make the same decision to be tested again. Although couples who were educated during a GP consultation were less worried, the results of the study suggest that understanding is more correct in couples attending an educational session. The results further suggest that since satisfaction with the screening was high, worries and feeling less healthy due to the test results are probably not a great burden.

Adult↗
PubMed2001

Attitudes towards reproductive issues and carrier testing among adult patients and parents of children with cystic fibrosis (CF).

Assessing the reproductive choices of parents of children with cystic fibrosis (CF) is important in getting a greater insight into the possible needs for counselling of carrier couples in the reproductive decision-making process. Also, parents' reproductive attitudes might indicate critical issues for discussion with regard to introducing general population screening programmes. Data were available from two groups of subjects: 287 adult patients with CF (mean age 27.5 years) and 288 parents of a child with CF (mean age of child 7.7 years) who participated in a Dutch national survey. Attitudes towards reproductive issues and carrier screening and parents' reproductive behaviour were analysed in terms of responses to questionnaires. To avoid having another child with CF, most parents decided against further pregnancies or used other reproductive options. Prenatal diagnosis was used by 72% of parents, whereas 76% of parents planning more children intended using this option. Intention to use prenatal diagnosis was associated with the strength of religious conviction, and was not associated with perceived severity of CF, health of the child, or future therapeutic possibilities. Respondents demonstrated difficulties in deciding to abort for CF. A majority of parents and adult patients supported carrier couple identification within CF families. The results suggest that those most closely involved with CF will accept the reproductive choices of carrier couples identified in population screening programmes.

Abortion, Induced↗
PubMed2001

Polymorphisms in the tumor necrosis factor and lymphotoxin-alpha gene region and preeclampsia.

OBJECTIVE: To investigate potential association or linkage among nine polymorphisms in the genes encoding tumor necrosis factor (TNF) alpha or lymphotoxin (LT) alpha and preeclampsia. METHODS: Four di-allelic polymorphisms and five microsatellite markers in the genes encoding TNF-alpha (TNF) and LTalpha (LTA) and their haplotypes were studied in 150 Dutch families. These families contained sib-pairs of women affected with preeclampsia; eclampsia; the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (strict criteria); or pregnancy-induced hypertension (mild criteria). Frequencies were compared with 98 healthy controls. Nonparametric affected sib-pair analyses for allele sharing among siblings were carried out for all nine markers. Each sibship was composed of an affected index woman and one or more affected sisters. RESULTS: Although we found a striking association with the TNF-I haplotype in 30 index women with (pre-)eclampsia or HELLP syndrome compared with controls (odds ratio [OR] 3.8; 95% confidence interval [CI] 1.6, 8.9), this association was not found in their 30 sisters meeting similar disease criteria. Analyses in all 150 families showed a similar TNF-I association in 122 index women meeting the strict criteria compared with controls (OR 1.9; 95% CI 1.1, 3.3), but, again, not in their 91 sisters meeting similar disease criteria. This association was stronger in a subgroup of 75 index women with preeclampsia only (OR 2.3; 95% CI 1.2, 4.2). No excess allele sharing for any marker was seen between the siblings. CONCLUSION: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia.

Case-Control Studies↗
PubMed2001

A genome-wide scan for preeclampsia in the Netherlands.

Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.

Chromosome Mapping↗
PubMed2001

Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia.

OBJECTIVE: This study was undertaken to assess frequencies of the methylenetetrahydrofolate reductase gene mutations cytosine-to-thymine substitution at base 677 (C677T) and adenine-to-cytosine substitution at base 1298 (A1298C) and their interactions with homocysteine and vitamin levels among Dutch women with preeclampsia. STUDY DESIGN: Mutations were studied in the following 5 groups: 47 consecutive women with preeclampsia, 49 women with preeclampsia and with hyperhomocysteinemia, 36 women with preeclampsia but without hyperhomocysteinemia, 127 women with familial preeclampsia (typed for C677T mutations only), and 120 control subjects. Plasma levels of homocysteine, folate, and vitamin B12 were measured. RESULTS: Although 10.6% of the consecutive women with preeclampsia had strictly defined hyperhomocysteinemia (values >97.5th percentile), neither mutation was found in excess relative to the control group. Women with preeclampsia who had mild hyperhomocysteinemia (values >75th percentile) had a significant excess of the TT genotype (homozygosity for C677T mutation) relative to the women with preeclampsia who did not have hyperhomocysteinemia (odds ratio, 8.2; 95% confidence interval, 1.8-39). They also had significantly lower vitamin levels. CONCLUSION: Hyperhomocysteinemia in women with preeclampsia was associated with mutations in the gene for methylenetetrahydrofolate reductase, but the high frequency of hyperhomocysteinemia itself cannot be explained by these mutations alone.

Birth Weight↗
PubMed1999

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Abnormalities, Multiple↗
PubMed1999

Efficacy of cascade testing for fragile X syndrome.

OBJECTIVE: Fragile X syndrome is the most common cause of mental retardation from a single gene defect, transmitted in an X-linked semidominant fashion. Cloning of the gene responsible for fragile X syndrome has made it possible to identify carriers who are at risk of giving birth to a child with fragile X syndrome. One of the proposed strategies for identifying carriers is cascade testing, in which relatives of a patient with fragile X syndrome (the index case) are tested. Because the effectiveness of this type of testing is unknown, the objective of this study was to develop a simulation model for studying the consequences of cascade testing for fragile X syndrome. METHODS: With this model, 100,000 five-generation pedigrees were simulated to assess the maximum number of carriers that would be detected for three scenarios: (a) only first degree relatives of the index case are tested; (b) relatives up to the third degree are tested; (c) relatives up to the fifth degree are tested. RESULTS: In the start-up phase of the testing programme, 18% of couples who will have a fragile X syndrome child are detected. After this phase the (stabilised) cascade testing programme detects 7% of undetected couples who would have a fragile X syndrome child if only first degree relatives were tested, 12% if first to third degree relatives were tested, and 15% if first to fifth degree relatives were tested. To detect 90% of all premutation and full mutation carriers at least eight consecutive generations need to be tested. CONCLUSIONS: The results of our analysis show that cascade testing is not very effective in detecting carriers.

Decision Support Techniques↗
PubMed1999

Preconceptional screening of couples for carriers of cystic fibrosis: a prospective evaluation of effects, costs and savings for different mutation detection methods.

OBJECTIVE: The aim of this study was to perform a prospective evaluation of the effects, costs and savings of a preconceptional screening programme of couples for carriers of cystic fibrosis (CF). METHODS: A decision model for both single-entry two-step (SETS) and double-entry two-step (DETS) couple screening was constructed. Two mutation detection methods were considered: allele-specific oligonucleotide (ASO) hybridisation screening of 32 mutations, with a sensitivity of 90%, and denaturing gradient gel electrophoresis (DGGE), with a sensitivity of 98%. In our model, the following combinations were used: (1) ASO for both steps; (2) DGGE for both steps, and (3) ASO for the first step and DGGE for the second step. The model is demonstrated using figures from the Netherlands, where there is a carrier frequency of 1:30. We estimated the value of different choices and probabilities in a decision tree and determined the costs of screening for CF and the costs of the illness itself. RESULTS: We found that with most of the combinations of mutation detection methods, SETS couple screening could offer positive net savings in the Netherlands. The ASO/DGGE combination resulted in the highest net savings. DETS couple screening for all combinations, including testing with DGGE in both steps, did not show a positive cost-savings balance at all, not even with an uptake rate of 100%. The maximum number of carrier couples identified when screening 100,000 couples with the ASO/DGGE combination was 98 (SETS). This could result in about 25 fewer children born with CF each year in the Netherlands, under the following assumptions: (1) each couple has two children and 10% of couples are unable to have children; (2) of detected carrier couples, 15% decide not to have children and 85% make use of prenatal diagnosis; (3) of those fetuses diagnosed with CF, 80% are aborted, and (4) prenatal diagnosis carries a 0.75% risk of iatrogenic abortion. CONCLUSIONS: The results of this evaluation show that there are no financial objections to the preconceptional screening of couples in the Netherlands when the above-mentioned assumptions apply; thus, further evaluation can concentrate on the balance of the non-economic consequences of screening for participants and for society.

Journal Article↗
PubMed1998

[Preconception screening of parents and carrier state of cystic fibrosis in the Netherlands: expenses and savings].

OBJECTIVE: To evaluate effects, costs and savings for a preconceptional couple screening programme for cystic fibrosis (CF) carriers. SETTING: State University Groningen, the Netherlands. DESIGN: Prospective theoretical evaluation. METHOD: A decision tree and an arithmetic model were constructed for two different strategies of preconceptional CF screening of couples: 'single entry two step' (SETS; start by testing one partner), and 'double entry two step' (DETS; test both partners). The difference between costs of screening and costs of CF illness prevented by screening was determined. RESULTS: DETS couple screening with the assumptions used for e.g. sensitivity and use of options can detect 81.5% of carrier couples in the Netherlands (against 70% for SETS), but results in twice as many positive/negative couples as SETS couple screening. The maximum number of carrier couples identified when screening 100,000 couples would be 88, resulting in a decrease of the number of children with CF of 25 each year. The costs of screening equal the savings if approximately 8,000 couples are screened yearly in the Netherlands. CONCLUSIONS: There are no financial objections to preconceptional couple screening in the Netherlands, even with an uptake ratio of around 10%. Whether screening for CF carriers should be offered or not should be decided on the basis of non-financial arguments.

Adult↗
PubMed1998

Relative frequencies of cystic fibrosis mutations in The Netherlands as an illustration of significant regional variation in a small country.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in white populations. Significant regional differences in CF mutations among affected individuals have been reported. We have studied the geographic distribution of the relative frequencies of the three most common Dutch CF mutations, deltaF508, A455E, and G542X, by analyzing data on area of residence of CF patients. Significantly higher relative frequencies of the A455E mutation and the G542X mutation were observed in the South-West and the South-East, respectively. A uniform distribution of relative frequencies was found for the deltaF508 mutation. The results of our study show that, even in a small country such as The Netherlands, certain CF mutations may be more common in one region than in another.

Cystic Fibrosis↗
PubMed1998

Screening for cystic fibrosis and its evaluation.

Cystic fibrosis (CF) is a recessively inherited disorder for which screening has been proposed. A number of different screening strategies have been suggested, including prenatal, preconceptional, school and neonatal carrier screening, as well as screening of newborns to identify affected infants. We discuss the advantages and disadvantages of these strategies, and identify gaps in knowledge relevant to decisions to introduce a screening programme for cystic fibrosis. Screening to identify carriers during the newborn period or among school age children is inadvisable, mainly on psychosocial and cost-effectiveness grounds. Although early diagnosis of CF may improve prognosis, current scientific evidence is not sufficient to support screening newborns to identify affected infants. of the remaining two options, prenatal screening has a practical advantage because of existing facilities, while with screening before conception all reproductive options are, in principle, open to detected carrier couples. If adequate pre- and post-test counselling can be provided, both two types of screening could be introduced.

Cystic Fibrosis↗
PubMed1998

Costs, effects, and savings of screening for cystic fibrosis gene carriers.

STUDY OBJECTIVE: Evaluating the costs, effects, and savings of several strategies for cystic fibrosis (CF) gene carrier screening. DESIGN: A general model for evaluating prenatal, preconceptional, school, and neonatal carrier screening was constructed. For prenatal and preconceptional screening, two strategies were evaluated: single entry and double entry two step couple screening. Firstly, the Dutch situation was evaluated prospectively; subsequently the results were generalised to other carrier frequencies. SETTING: Prospective simulation model. MAIN RESULTS: Of all screening strategies, neonatal carrier screening gives most carrier couples an informed choice concerning reproduction. If the parents of carrier newborns would not be tested however, prenatal screening detects most carrier couples. Prenatal and single entry preconceptional screening programmes have a favourable cost-savings balance in the Netherlands under a wide range of assumptions. For double entry preconceptional screening and neonatal screening, high enough values of uptake of screening, prenatal diagnosis, and induced abortion are necessary. School carrier screening does not have a favourable cost-savings balance. CONCLUSIONS: If a CF screening programme is judged to be useful on individual and social grounds, costs considerations are no obstacle for prenatal and single entry preconceptional screening.

Child↗
PubMed1998

Explorative study of costs, effects and savings of screening for female fragile X premutation and full mutation carriers in the general population.

OBJECTIVE: Evaluation of the costs, effects and savings of three strategies for female fragile X premutation and full mutation carrier screening in the general population. METHODS: We calculated the costs, effects and savings by using a general model for prenatal, preconceptional, and school carrier screening. Assumptions were based on literature data, expert opinions, prices and tariffs. RESULTS: Prenatal screening will detect most carriers and will lead to the highest number of avoided fragile X syndrome patients. The costs per detected carrier are quite similar for all screening programmes (around USD 45,000). All screening strategies have a favourable cost-savings balance (USD 14 million for prenatal screening, USD 9 million for preconceptional screening and USD 2 million for school screening). CONCLUSIONS: From an economic point of view, there is no obstacle to fragile X screening. The decision to screen or not can (and should) therefore concentrate on discussion of medical, social, psychological and ethical considerations.

Journal Article↗
PubMed1997

An atypical case of Fanconi anemia in elderly sibs.

We describe a 56-year-old woman suspected of Fanconi anemia on the basis of the following clinical findings: microcephaly, short stature, congenital deafness, and the clinical findings in her deceased brother. Hematologic or other signs of malignancy were absent. The diagnosis was confirmed by demonstrating hypersensitivity of her lymphocytes to mitomycin C (MMC). Cell fusion experiments indicated that the patient belongs to complementation group A. The patient's brother died at the age of 50 of heart and renal failure, and anemia. He had clinical findings similar to those of his sister, and a horseshoe kidney. From 31 years on he had thrombocytopenia and leucopenia. Both patients had insulin-dependent diabetes mellitus. A chromosomal breakage test carried out elsewhere before his death failed to demonstrate MMC hypersensitivity of his lymphocytes, which led to the investigation of his sister. To our knowledge these two cases are the oldest Fanconi anemia patients reported thus far.

Animals↗