Biomedical subjects
Publications and source records attributed to A D Sadovnick.
Birth order position for affected siblings was examined for 88 sibships having 2 or more cases of multiple sclerosis (MS). The data show that MS patients are randomly ordered by birth within these multiplex sibships. The data therefore do not support the hypothesis that MS occurs in siblings because of a common environmental exposure as defined by proximity in birth order position.
The cause of MS is unknown. There is considerable circumstantial evidence that MS is a complex trait, probably autoimmune in nature, and is determined by both genetic and environmental factors. At present, it must be acknowledged, however, that our understanding of the pathogenesis of MS is minimal. Very little is known about the genes determining disease susceptibility and perhaps even less is understood about environmental factors that influence penetrance or the geographic distribution. This lack of knowledge results neither from lack of effort nor from a shortage of fertile imaginations. Almost every imaginable hypothesis has, in the past, found some support. The intractability of the problem could well result from its complexity, because answers to testable hypotheses are commonly negative or ambiguous. Today, the opportunity exists for researchers to provide such answers because of recent major developments. The first development is the recognition that MS research requires a relatively large pool of well-ascertained, carefully diagnosed, and longitudinally well-characterized MS patients. The last two developments are the identification and successful application of statistical and molecular genetic techniques carrying sufficient power to allow the exploration of complex traits such as MS.
Amniocentesis is now commonly used in many countries; it is important to know whether there are any long-term adverse effects on children born after this procedure, in particular disabilities that may emerge during childhood or adolescence. We studied consecutive liveborn offspring of women who had had amniocentesis and compared them with matched controls whose mothers had not had amniocentesis. The controls were matched for age of mother, residence by geographic health unit, sex, and when the birth occurred. 1296 cases and 3704 controls were studied. With the exception of one disorder, the offspring of women who had had amniocentesis were no more likely than controls to have a registrable disability (such as hearing disabilities, learning difficulties, visual problems, and limb anomalies) during childhood and adolescence. The follow-up period was 7-18 years. Children of women who had amniocentesis had a significantly higher rate of haemolytic disease due to ABO isoimmunisation than matched controls. The results of this study should therefore be reassuring to women having amniocentesis, and be useful to women making decisions about having this procedure.
There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder. From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively. Morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, children--aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for "high-risk" families whose genetic pedigree is suggestive of "autosomal dominant" inheritance.
OBJECTIVE: To conduct a prospective assessment of pregnancy on women with multiple sclerosis (MS), focusing on pregnancy outcome and relapses during gestation and up to 6 months after delivery. DESIGN: Expected numbers of relapses were based on data for (1) "self-controls": the mothers ("cases") themselves prior to becoming pregnant and (2) "matched controls": female patients with MS "matched" to the mothers for year of birth, age of MS onset, MS type, MS course, and initial MS symptom(s). SETTING: Cases and controls were identified from an ambulatory care MS clinic that serves the province of British Columbia, Canada. PATIENTS OR OTHER PARTICIPANTS: Women with a diagnosis of MS who attended the MS clinic during 1982 through 1986 and subsequently became pregnant during 1982 through 1989 inclusive were included in this study as cases. Matched controls were women with MS who attended the MS clinic during the same period but did not become pregnant. RESULTS: No significant increase in relapse rate was found for cases during the first two trimesters of gestation. The number of relapses was significantly less than expected during the third trimester compared with matched controls (chi 2 = 6.80, df = 1, P < .02), but not compared with self-controls (chi 2 = 3.39, df = 1, P > .05). The observed number of relapses for the 6 months after delivery did not differ significantly from expected (self-controls: chi 2 = 2.84, df = 2, P > .05; matched controls: chi 2 = 1.76, df = 2, P > .05). CONCLUSION: These data suggest that neither pregnancy nor the 6-month period after delivery is a risk factor for relapse in MS. They are consistent with previous observations that, in the long term, pregnancy does not influence subsequent MS disability.
Since the inception of the MS Clinic, Vancouver Hospital and Health Sciences Centre, all consecutive, unrelated patients with multiple sclerosis (MS) have had their family histories documented by the Clinic's geneticist as part of the overall assessment. The family histories are updated annually. These data, along with the longitudinal clinical information on each patient, have resulted in a unique resource for clinical genetic/genetic epidemiological/molecular genetic research on MS. Analyses of these data have included the calculation of age-adjusted familial risks for MS; genetic modeling, necessary for molecular genetic research; and family studies involving affected relative pairs, studies of the nontransmitted parental haplotypes, and multiplex families. The results of the work to date are discussed. In addition, the impact of these data on the development of the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis is reviewed. This project involves all 14 MS "sites" across Canada, and the study's overall objective is to elucidate the roles of genetic and environmental factors in the causation of MS.
The possible role of genetic factors in the etiology of multiple sclerosis (MS) has been debated for over a century. It is now clear that genetic and environmental interactions must exist. It is likely that MS susceptibility is under the control of several genes encoded both within and outside the major histocompatibility complex (MHC). It is therefore unlikely that MS has a purely transmissible cause for these and other reasons, including the low concordance rate in dizygotic twins, low concordance rate in conjugal pairs, negative birth order in multiplex MS sibships, the relatively high rate of MS in second- and third-degree relatives of MS patients, and the identification of groups resistant to MS in otherwise high-risk areas.
Kaplan-Meier risks estimates are calculated and compared for two consecutive series (N1 = 840, N2 = 819) of first-degree relatives of Alzheimer disease (AD) patients diagnosed as either "probable" or "autopsy-confirmed" AD. The consistency of results increases confidence in estimates and suggests consistent case ascertainment over 8 years. Lifetime risk estimates to age 88 for the combined sample (23.4% +/- 3.0%) do not approach the 50% risk compatible with an autosomal dominant model of transmission. These results support our previous finding and suggest that an autosomal dominant gene(s) is not responsible for all cases of AD.
It has been suggested that older mothers are more likely to have a child with isolated cleft palate (CP) or cleft lip +/- cleft palate (CL +/- CP), but most of these studies have been based on fairly small sample sizes. Data from a population-based registry with multiple sources of case ascertainment were used to examine any association of maternal age with the incidence of these defects in infants without other congenital anomalies. The study group consisted of all cases with CP or CL +/- CP without other congenital anomalies from a series of over half a million consecutive livebirths during the period 1966 to 1981 inclusive in British Columbia. During the study period, the overall incidences of isolated CP and isolated CL +/- CP per 10,000 livebirths were 3.9 and 8.2, respectively. No association with maternal age was found when either isolated CP or isolated CL +/- CP was analyzed as a group. When analyzed by sex, and by CP or CL +/- CP, no significant maternal-age effect was observed for males and females with CP or CL +/- CP. Our population-based data, therefore, do not show that older mothers are more likely to have a child with cleft palate, or cleft lip +/- cleft palate.
In the search for candidate loci having a role in susceptibility to common diseases such as multiple sclerosis (MS), studies often look for an 'association' between one allele at a putative candidate susceptibility locus and the disease, e.g. MS. However, reproducibility of results from association studies has been difficult. In MS, despite numerous studies, association has been reproducibly confirmed only for the major histocompatibility complex, the MHC. The present paper is designed to review the allelic associations which have been reported in MS and suggest possible reasons for the difficulties in replicating these studies. We also outline some suggestions for improving the validity of future association studies in MS and in other complex traits.
There has been increasing evidence that genetic factors have a role in determining susceptibility to MS. Re-examination of results from prevalence and migration surveys reveals that there remains considerable ambiguity in interpretation. Some patterns previously thought to decisively support environmental determination may still be explained, at least in part, on a genetic basis. It seems inescapable that MS is probably due to an interaction of genetic and environmental factors. It remains undetermined whether or not genes exist which are truly necessary for the development of the disease. Existing data are consistent with the notion that the study of MS susceptibility will parallel the findings in experimental models of spontaneous autoimmunity and that at very least, two genes and almost certainly several genes will be found to influence susceptibility and interact in as yet unknown ways. One of these loci appears to be the Class II MHC, although its role may be minor at the germ line level. Roles for the T-cell receptor alpha and beta loci appear to be minor and may even be non-existent in contributing to heritable susceptibility. We predict that additional loci will be identified which influence both susceptibility and outcome and will be more important. Furthermore, it is clear that the understanding of the contribution of individual susceptibility loci will continue to be difficult because of the constraints of human pedigree data. It is likely that further resolution of the questions posed above related to genetic susceptibility in MS will require multicenter collaboration.
The identification of mutations in the amyloid precursor protein (APP) gene associated with the presence of early-onset familial Alzheimer disease (AD) raises the possibility of their practical clinical application, at least in some circumstances, in the diagnostic assessment for AD. As a stimulus for discussion, a hypothetical, illustrative case vignette is presented. A 48-year-old man, concerned about recent memory loss and with a family history of early-onset AD, requested testing for the APP717 Val-->Ile mutation, previously identified in his relatives affected with AD. Whether the testing should be undertaken is considered in the context of the current interpretation of potential test results as well as the competency of the individual who requested the test to provide informed consent. Informed consent includes an understanding of the foreseeable risks and benefits associated with disclosure of test results. Although molecular genetic testing in particular individuals, such as the man described herein, could be appropriate, it should not be interpreted to apply in general at this stage to individuals suspected of having AD. In view of a number of caveats, including the genetic heterogeneity of AD, which significantly limits the sensitivity and specificity of the currently available genetic tests, further research and discussion is strongly recommended before widespread introduction of molecular genetic testing for individuals with suspected AD.
It has been reported that the Down syndrome occurs more often than expected among relatives of individuals with Alzheimer disease. This study focused on 578 liveborn offspring of 206 females with Alzheimer disease. Controlling for maternal age at delivery, the frequency of the Down syndrome live births was as expected, based on data for the well-monitored general population of British Columbia (chi 2 = 5.39; df = 3; p > 0.05).
The monthly distribution of births of people who were later diagnosed with multiple sclerosis (MS) did not differ significantly from that of the general population in British Columbia, Canada. This is in contrast to a recent report on the Danish population.
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This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.
The decisive conclusions to be drawn from the available epidemiological data, mostly geography and prevalence, of MS are: (1) a north-south (as well as west-east in the United States) gradient exists independent of genetic/racial factors; (2) major differences in prevalence occur in the absence of latitude differences; (3) individuals from the same ethnic derivation have either similar prevalence rates or very different prevalence rates in widely separated geographical areas and (4) specific resistant isolates are shown to exist regardless of latitude. Existing information leads to the almost inescapable conclusion that the epidemiology of MS cannot be explained by any single known environmental or genetic factor(s) in isolation. A combination of a heterogeneous distribution of both genetic and environmental factors appears to be required to explain the available data on MS.
Clinical differentiation between forms of progressive dementia can prove difficult, particularly when relatively rare forms of dementia are involved. Factors such as family history of dementia, age at onset, presenting features such as personality change, cognitive deficits, psychiatric symptoms, and clinical course (progressive deterioration; retention of skills over time) may prove useful for directing investigations to identify underlying pathology and genetic implications. This is illustrated by two patient reports. Each patient had the onset of memory/behavioral problems at approximately age 40 years, was initially given a psychiatric, non-dementing diagnosis, and had a positive family history for early onset behavioral and memory problems. After longitudinal assessment, the diagnosis of Alzheimer disease was confirmed at autopsy in one patient and a diagnosis of familial, adult-onset metachromatic leukodystrophy in the other.