New problems in testing for Huntington's disease: the issue of intermediate and reduced penetrance alleles.
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Alleles↗
Biomedical subjects
A Tibben
Publications and source records attributed to A Tibben.
[New insights in frontotemporal dementia].
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterised by progressive behavioural disturbance, aphasia and a decline in frontal cognitive functions. Frontotemporal atrophy on CT and MRI, and hypoperfusion of the frontal brain regions on single-photon emission computed tomography (SPECT), are characteristic findings. Neuropathological examination reveals deposition of abnormally phosphorylated tau protein in neurons and glial cells in a number of the sporadic and familial cases, while aspecific changes with neuronal loss, spongiosis and gliosis are found in the remaining cases. A familial form with an autosomal dominant pattern of inheritance is seen in 20% of FTD patients. Mutations in the tau gene have been identified in a number of families with deposition of abnormal tau protein in affected brain regions. Presymptomatic DNA testing is now available for relatives of patients with tau mutations, but must only be considered after extensive genetic counselling in a centre with neurogenetic expertise.
Cognition Disorders↗
Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692).
Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutation at codon 692 of the APP gene (APP692). Here we describe the clinical and pathological expression of APP692 in eight patients with the mutation. Furthermore, 21 first-degree relatives with an a priori risk of 50% of being a carrier were tested for the APP692 mutation and studied for presymptomatic signs by neurological examination, neuropsychological testing and brain MRI. Patients with APP692 presented with haemorrhage, dementia or both. The dementia in patients with the APP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-significant impairment of cognitive function compared with relatives without APP692. A significant increase in the number of periventricular and subcortical white matter lesions at young age was seen in presymptomatic carriers (mean age 26.4 years). The findings of this study suggest that a single (genetic) mechanism may underlie the pathology of Alzheimer's disease and CAA. These diseases are manifested subclinically by white matter pathology. Further insight into the relationship between CAA and Alzheimer's disease may provide clues about the aetiology of Alzheimer's disease.
Adult↗
High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands.
Mutations in microtubule-associated protein tau recently have been identified in familial cases of frontotemporal dementia (FTD). We report the frequency of tau mutations in a large population-based study of FTD carried out in the Netherlands from January 1994 to June 1998. Thirty-seven patients had >/=1 first-degree relative with dementia. A mutation in the tau gene was found in 17.8% of the group of patients with FTD and in 43% of patients with FTD who also had a positive family history of FTD. Three distinct missense mutations (G272V, P301L, R406W) accounted for 15.6% of the mutations. These three missense mutations, and a single amino acid deletion (DeltaK280) that was detected in one patient, strongly reduce the ability of tau to promote microtubule assembly. We also found an intronic mutation at position +33 after exon 9, which is likely to affect the alternative splicing of tau. Tau mutations are responsible for a large proportion of familial FTD cases; however, there are also families with FTD in which no mutations in tau have been found, which indicates locus and/or allelic heterogeneity. The different tau mutations may result in disturbances in the interactions of the protein tau with microtubules, resulting in hyperphosphorylation of tau protein, assembly into filaments, and subsequent cell death.
Dementia↗
Dilemmas in counselling females with the fragile X syndrome.
The dilemmas in counselling a mildly retarded female with the fragile X syndrome and her retarded partner are presented. The fragile X syndrome is an X linked mental retardation disorder that affects males and, often less severely, females. Affected females have an increased risk of having affected offspring. The counselling of this couple was complicated by their impaired comprehension which subsequently impaired their thinking on the different options. The woman became pregnant and underwent CVS, which showed an affected male fetus. The pregnancy was terminated. Whether nondirective counselling for this couple was the appropriate method is discussed and the importance of a system oriented approach, through involving relatives, is stressed.
Female↗
Prenatal consultation after a fetal anomaly scan: videotaped exploration of physician's attitude and patient's satisfaction.
The main aim of the study was to evaluate the relationship between the physician's attitude (using the non-verbal Global Affective Measure of the Roter Analaysis System and the Counselor Rating Form-short version) and the satisfaction of the pregnant women with the prenatal consultation. A secondary aim was to evaluate the women's recall of essential information (i.e. location, severity, prognosis and cause of the anomaly). To this end, 24 prenatal consultations (pregnant women, partners and physicians) were videotaped following a fetal anomaly scan, and a few days later, the pregnant women completed questionnaires to assess their perception of the physician's attitude and their satisfaction with the consultation and the extent to which they could recall the essentials of the information given about the fetal anomaly. In descending order, the physician's dominance/assertiveness (i.e. being self-confident and decisive) (assessment of the videotapes by two psychologists), trustworthiness (women's report) and expertise were significantly positively associated with the women's overall satisfaction, i.e. satisfaction with the information given and affective behaviour on the part of the physician during the prenatal consultation. All the women (n=24) recalled the essentials of the information given about the location of the fetal anomaly. The majority of them correctly reproduced the severity, the prognosis and the cause of the anomaly. Our findings indicate that women in whom a fetal anomaly has been detected derive particular benefit from a self-confident, decisive, expert and trustworthy physician.
Adult↗
Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? Rotterdam/Leiden Genetics Working Group.
Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy). We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC. Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.
Adult↗
Screening for the fragile X syndrome among the mentally retarded: a clinical study. The Collaborative Fragile X Study Group.
The fragile X syndrome is characterised by mental retardation with other features such as a long face with large, protruding ears, macro-orchidism, and eye gaze avoidance. This X linked disorder is caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene which is associated with shut down of transcription and absence of the fragile X mental retardation protein (FMRP). Molecular testing is used for detection of patients and carriers of the fragile X syndrome. In a screening programme for the fragile X syndrome in the south west of The Netherlands, 896 males and 685 females with an unknown cause for their mental retardation were scored on seven fragile X features. All were tested by DNA analysis and 11 new cases were diagnosed. The seven item checklist allowed exclusion from further testing in 86% of the retarded males (95% CI 0.83-0.88) without missing either any of the newly diagnosed cases or, in retrospect, any of the 50 previously diagnosed cases known to our department. These results showed that clinical preselection for DNA testing in mentally retarded males is feasible using a simple scoring list, which will increase the efficiency of further testing eightfold.
Adolescent↗
[A large-scale diagnostic program for the fragile X-syndrome among the mentally retarded. II. Implications for parents and family].
OBJECTIVE: Studying the attitudes and reactions of (non)consenting parents/guardians of mentally retarded patients regarding the screening programme for the fragile X syndrome in the Netherlands. DESIGN: Observative-descriptive. SETTING: Department of Clinical Genetics, University Hospital Dijkzigt and Erasmus University, Rotterdam, the Netherlands. METHOD: Since 1992 a screening program for the fragile X syndrome has been conducted in 5 institutions giving residential care (1869 individuals) and 16 special schools (1483 children) in the southwestern Netherlands. Patients with an unknown cause for their mental handicap were, after the parents/guardians' written consent, briefly examined physically and a blood sample for DNA analysis of the FMRI gene was taken. The attitude and reactions of (non)consenting parents/guardians were assessed by pre- and post-test questionnaires. Of the 1531 persons who consented, 1090 were sent a letter before the test (response: 860; 79%) and 1030 after the test results (response: 681; 66%); of the 435 parents/guardians who had not consented, 153 (35%) responded. RESULTS: Seventy percent (1531/2189) of the parents/guardians consented to testing. Major motives to participate in the screening were the wish to obtain a diagnosis (82%), the hereditary implications (80%), and the support of research into mental retardation (81%). The majority of consenting parents/guardians (84%) as well as of non-consenting parents/guardians (78%) discussed the DNA test with other relatives. Major reasons for non-consenting were the blood test which was considered too stressful for their relative (61%) and the opinion that a 'definite' cause of the mental handicap in their relative was already known (44%). These parents/guardians were not opposed to genetic testing in general (72%). Of the consenting parents/guardians 34% would actively seek further investigations after exclusion of the fragile X syndrome in their relative. CONCLUSION: The fragile X screening programme was rated positively by parents/guardians.
Adolescent↗
Distress in individuals facing predictive DNA testing for autosomal dominant late-onset disorders: comparing questionnaire results with in-depth interviews. Rotterdam/Leiden Genetics Workgroup.
In 50% risk carriers for Huntington disease (n = 41), hereditary cerebral hemorrhage with amyloidosis Dutch-type (n = 9) familial adenomatous polyposis coli (n = 45) and hereditary breast and ovarian cancer (n = 24), pretest intrusion and avoidance (Impact of Event Scale), anxiety and depression (Hospital Anxiety and Depression Scale), feelings of hopelessness (Beck Hopelessness Scale), and psychological complaints (Symptom Checklist) were assessed to determine their psychological well-being. The manner of discussing the genetic disorder, the test, and its implications during a semistructured interview (reflecting on one's emotions without getting carried away or dismissing or minimizing the subject) was judged in terms of coherence. Participants at risk for neurodegenerative disorders had higher anxiety and depression scores and more psychological complaints than did those at risk for cancer syndromes. Those reporting high intrusion/high avoidance had higher anxiety and depression scores and more psychological complaints than did those reporting low intrusion/low avoidance. However, the scoring of the interview showed that participants reporting high intrusion/high avoidance were more reflective about their emotions without getting carried away or dismissing the subject (e.g., more coherent) than those reporting low intrusion/low avoidance. This result suggests that participants with higher stress scores may be actively dealing with the emotional implications of the test, whereas those with low stress scores may (as yet) be unable to face these implications. It is important to identify the strategy of coping with threat to provide suitable counseling and necessary guidance. However, long-term follow-up is needed to learn the consequences of a denial coping strategy for those participating in a genetic testing program.
Adenomatous Polyposis Coli↗
Subtle involuntary movements are not reliable indicators of incipient Huntington's disease.
In the past, Huntington's disease was diagnosed when movement disturbances were present in concordance with a positive family history. Early motor signs, however, are often not found in a standard neurologic examination, and their expression is variable. Not until later stages of the disease could one be sure about the diagnosis. Since genetic diagnosis became available, the onset of symptoms and signs could be studied in the earliest phase. The aim of the study was to evaluate observer agreement of the assessment of early motor signs in Huntington's disease. A total of 17 gene carriers, 22 noncarriers, and eight partners were recorded on video performing several facial movements after instruction and engaging in a 5-minute conversation. Three experienced neurologists, unaware of the genetic status of the participants, judged and classified the video recordings independently. The cases with disagreement were judged a second time after the neurologists discussed these cases. The observer agreement after the first judgment is poor (kappas 0.09, 0.24, 0.45) and after the second judgment satisfactory (kappas 0.79, 0.90, 0.78). Consequences for clinical practice and research programs into early symptoms and signs are discussed.
Adult↗
Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup.
The first comparative study on predicting post-test distress (conceptualised by intrusion and avoidance, measured with the Impact of Event Scale) after presymptomatic genetic testing for Huntington's disease (HD, n=25), cancer syndromes (familial adenomatous polyposis (FAP, n=23)), and hereditary breast and ovarian cancer (HBOC, n=10) is reported. The variables with the highest predictive potential of post-test distress are presented. Participants who were depressed before the test were more distressed after testing, but we found that those who were anxious before the test were less distressed, that is, had less intrusive thoughts post-test. Other factors associated with a higher level of post-test intrusion were gender (being a woman), having children, and pre-test intrusion. Religion and being at risk for HBOC were associated with less post-test intrusion. Participants who showed avoidance behaviour before the test and those who had many people available for support showed more avoidance behaviour post-test. The test result did not additionally contribute to post-test distress. The prima facie simple notion that the test result, as such, determines the distress experienced seems to be a misrepresentation of the complex reality.
Adaptation, Psychological↗
BRCA1 in the family: a case description of the psychological implications.
Our experience with the first family in the Netherlands for whom predictive DNA-testing for Hereditary Breast and Ovarian Cancer (HBOC) became an option is described. This serves to illustrate the complex emotional impact on a family as a whole, and upon the members separately, of becoming aware that breast and ovarian cancer is hereditary, and the implications of undergoing predictive testing. All family members received genetic counseling and were offered pre- and post-test psychological follow-up. We observed two important roles within the family. One member became "the messenger of the news" informing the relatives of the hereditary character of cancer in the family. Another was "the first utilizer" of the new options; namely, the predictive DNA-test and preventive surgery. This first utilizer became the example to the rest of the family. Decisions made about preventive treatment (prophylactic ovariectomy and/or mastectomy) were based on the experiences within the family, whether one identified with an affected family member with breast or with ovarian cancer. The actions and reactions perceived were illustrative of what kind of support provisions should be provided in addition to the genetic and oncological counseling for HBOC. Moreover HBOC should be considered both as an individual and a family problem and be treated as such in genetic counseling.
Adult↗
Psychological consequences of presymptomatic testing for Huntington's disease.
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Anxiety↗
Early cognitive and motor symptoms in identified carriers of the gene for Huntington disease.
OBJECTIVE: To study early motor and cognitive symptoms in Huntington disease. DESIGN: A follow-up cohort study after a DNA test procedure in which gene carriers and noncarriers were identified among people genetically at risk for Huntington disease. SETTING: Leiden University Medical Center, Department of Neurology, Leiden, the Netherlands, in cooperation with the Clinical Genetics Center Leiden and the Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam, Rotterdam, the Netherlands. PARTICIPANTS: Thirty-three individuals: 9 unaffected gene carriers, 6 gene carriers with motor symptoms, and 18 noncarriers of the gene for Huntington disease. MAIN OUTCOME MEASURES: A neuropsychologic examination covering a broad area of cognitive functioning, reaction time procedures, and motor tasks. RESULTS: The neuropsychologic assessment showed no significant differences between presymptomatic gene carriers and noncarriers. Three motor tasks differentiated between these 2 groups on a liberal .05 P level (analysis of variance followed by the Student test). The affected gene carriers performed less well than the presymptomatic gene carriers and the noncarriers in 10 motor tasks and 7 cognitive tasks. These differences were significant at P < .05. CONCLUSION: Motor symptoms play a more prominent and unequivocal role than cognitive symptoms in early stages of Huntington disease.
Adult↗
Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families.
Hereditary frontotemporal dementia (HFTD) is a rare autosomal dominant form of presenile dementia characterized by behavioral changes and reduced speech. Three multigeneration kindreds with this condition, in the Netherlands, were investigated for clinicopathological comparison and linkage analysis. Frontotemporal atrophy on computed tomographic scanning and/or magnetic resonance imaging was usually present. Single-photon emission computed tomography (SPECT) showed frontal hypoperfusion in the early phase of the disease. Brain tissue showed moderate to severe atrophy of frontal and temporal cortex with neuronal loss, gliosis, and spongiosis. Pick bodies were lacking in all cases of the 3 families. The mean age of onset varied significantly between families. We report here evidence for linkage to chromosome 17q21-q22 with a maximum lod score of 4.70 at theta = 0.05 with the marker D17S932. Recombination analysis positions the gene for HFTD in a region of approximately 5 cM between markers D17S946 and D17S791. Three other neurodegenerative disorders with a strong clinical and pathological resemblance have recently been mapped to the same chromosomal region, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene.
Chromosomes, Human, Pair 17↗
Three-year follow-up after presymptomatic testing for Huntington's disease in tested individuals and partners.
The 3-year psychological effects of presymptomatic DNA diagnosis for Huntington's disease are described in 20 identified carriers of the Huntington's disease gene (mean age = 31 years), 29 noncarriers (mean age = 32 years), and 37 partners. The Intrusion and Avoidance subscales of the Impact of Event Scale (M. J. Horowitz, N. Wilner, & W. Alvarez, 1979) and the Beck Hopelessness Scale (A. T. Beck, 1986; A. T. Beck, A. Weissman, D. Lester, & L. Trexler, 1974) measured psychological distress at 4 time points: baseline (before disclosure of test results) and 1 week, 6 months, and 3 years after testing. Multivariate testing on course of distress revealed similar patterns of intrusive thoughts about Huntington's disease over the 3-year follow-up in carriers and noncarriers but showed opposite patterns of avoidance at the 6-month assessment. One week after disclosure, carriers had increased and noncarriers had decreased levels of hopelessness. These effects disappeared after 6 months and did not recur. Carrier partners followed the same course of distress as carriers. Carrier partners with children were significantly more distressed than those without offspring. Noncarrier partners were significantly less distressed than noncarriers after 3 years.
Adaptation, Psychological↗
Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group.
The fragile X syndrome is an X-linked mental retardation disorder caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene. Its frequency, X-linked inheritance, and consequences for relatives all prompt for diagnosis of this disorder on a large scale in all affected individuals. A screening for the fragile X syndrome has been conducted in a representative sample of 3,352 individuals in schools and institutes for the mentally retarded in the southwestern Netherlands, by use of a brief physical examination and the DNA test. The attitudes and reactions of (non)consenting parents/guardians were studied by (pre- and posttest) questionnaires. A total of 2,189 individuals (65%) were eligible for testing, since they had no valid diagnosis, cerebral palsy, or a previous test for the FMR1 gene mutation. Seventy percent (1,531/2,189) of the parents/guardians consented to testing. Besides 32 previously diagnosed fragile X patients, 11 new patients (9 males and 2 females) were diagnosed. Scoring of physical features was effective in preselection, especially for males (sensitivity .91 and specificity .92). Major motives to participate in the screening were the wish to obtain a diagnosis (82%), the hereditary implications (80%), and the support of research into mental retardation (81%). Thirty-four percent of the parents/guardians will seek additional diagnostic workup after exclusion of the fragile X syndrome. The prevalence of the fragile X syndrome was estimated at 1/ 6,045 for males (95% confidence interval 1/9,981-1/ 3,851). On the basis of the actual number of diagnosed cases in the Netherlands, it is estimated that >50% of the fragile X cases are undiagnosed at present.
Adolescent↗