Background: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed... more Background: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis. Methods: Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed. Results: The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI ϭ 0.40 to 1.12; p for trend ϭ 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of Ն400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI ϭ 0.38 to 0.91; p for trend ϭ 0.006). No association was found between vitamin D from food and MS incidence. Conclusion: These results support a protective effect of vitamin D intake on risk of developing MS.
Multiple sclerosis (MS) is a chronic autoimmune complex trait with strong evidence for a genetic ... more Multiple sclerosis (MS) is a chronic autoimmune complex trait with strong evidence for a genetic component. A female gender bias is clear but unexplained and a maternal parent-of-origin effect has been described. X-linked transmission of susceptibility has been previously proposed, based on pedigree, association and linkage studies. We genotyped 726 relative pairs including 552 affected sib-pairs for 22 X-chromosome microsatellite markers and a novel dataset of 195 aunt-uncle/niece-nephew (AUNN) affected pairs for 18 markers. Parent-of-origin effects were explored by dividing AUNN families into likely maternal and paternal trait transmission. For the sib-pair dataset we were able to establish exclusion at a λ s = 1.9 for all markers using an exclusion threshold of LOD ≤—2. Similarly for the AUNN dataset, we established exclusion at λAV = 1.9. For the combined dataset we estimate exclusion of λ = 1.6. We did not identify significant linkage in either the sib-pairs or the AUNN dataset...
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Apolipoprotein E (APOE) is involved in neuronal remodelling and several studies have attempted to examine the effect of APOE on MS disease severity, but its function in modifying the course of MS is controversial. It has been suggested recently that PVRL2, not APOE, is the locus on chromosome 19 which influences clinical outcome of MS. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of APOE and PVRL2 on MS disease severity. The MS cases selected represent the prognostic best 5% (benign MS) and worst 5% (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that APOE or PVRL2 have any outcome modifying activity. We conclude that APOE and PVRL2 have little or no effect on the clinical outcome of MS.
1. Parker WD Jr, Boyson SJ, Luder AS, Parks JK. Evidence for a defect in NADH:ubiquinone oxidored... more 1. Parker WD Jr, Boyson SJ, Luder AS, Parks JK. Evidence for a defect in NADH:ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 1990;40:123 1-1234. 2. Parker WD, Boyson SJ, Parks JK. Electron transport chain abnormalities in idiopathic Parkinson’s disease. Ann Neural 1989;26:719723. 3. Ichiki T, Tanaka M, Nishikimi M, et al. Deficiency of subunits of complex I a n d mitochondria1 encephalomyopathy. Ann Neural 1988;23:287-294.
Multiple sclerosis (MS) is a lifelong disease typically affecting individuals in young to middle ... more Multiple sclerosis (MS) is a lifelong disease typically affecting individuals in young to middle adulthood. There are recognized sex differences in MS onset and clinical course. MS affects approximately three times more women than men, thus resulting in less attention to the male experience (i.e. diagnosis, management, societal dimensions). Here, we review current scientific evidence on sex differences in MS risk and course, highlight potential sources of bias, and suggest avenues of further inquiry. We then describe what is known about male experiences with MS diagnosis, treatment, and symptom management (particularly mood and sexual function). Finally, we consider ways in which healthcare providers might engage male patients in the broader aspects of living with MS (e.g. familial and societal relationships) to influence their long-term quality of life (QOL). When possible, we draw from published sources to underscore our collective clinical and scientific experiences.
Introduction: Conventional multisession genetic counseling is currently recommended when disclosi... more Introduction: Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. Methods: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. Results: Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n 5 115), CP-GC protocol (n 5 116), or CP-MD protocol (n 5 112). Mean postdisclosure scores on all outcomes were well below cutoffs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P ,.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. Conclusions: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.
To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women.... more To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women. We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: "multiple sclerosis" and "pregnancy." We manually searched the reference lists of identified studies. Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team. The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be ...
Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting... more Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting as infectious mononucleosis (IM) are recognized as risk factors for multiple sclerosis (MS). However, their combined effect and possible interaction on MS risk is not known. Objective To assess the association between HLA-DRB1*15 and risk of MS in persons with and without IM. Methods We compared the prevalence of DRB1*15 in MS patients with ( n = 76) and without ( n = 1,836) IM with the corresponding distributions in blood donors with ( n = 62) and without ( n = 484) IM histories. This allowed us to estimate the relative risk of MS associated with DRB1*15 in the presence and absence, respectively, of previous IM. We then estimated the interaction between DRB1*15 and IM as the ratio of the two individual odds ratios. Results In IM-naïve individuals, DRB1*15 carried a 2.4-fold (95% confidence interval [CI], 2.0–3.0) increased MS risk. In contrast, among persons with IM history, DRB1*15 wa...
Background Evidence of an association between multiple sclerosis (MS) and other autoimmune diseas... more Background Evidence of an association between multiple sclerosis (MS) and other autoimmune diseases would substantiate the hypothesis that MS is an autoimmune disease, and implicate a common mechanism. We aimed to investigate and compare the rate of autoimmune disease in MS patients, in their fi rst-degree relatives, and in their unrelated spouses. Methods We used data from a national, multicentre, population-based sample to investigate the rate of autoimmune disease in 5031 MS patients, 30 259 of their fi rst-degree relatives, and 2707 spousal controls. We asked patients and controls whether they had any of ten autoimmune diseases: Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anaemia, systemic lupus erythematosus, autoimmune thyroid disease, vitiligo, and myasthenia gravis. MS probands were also asked whether their fi rst-degree relatives had Crohn's disease, ulcerative colitis, rheumatoid arthritis, or type 1 diabetes. Findings After correction for age and sex, we did not identify any increased risk of autoimmune diseases in MS patients compared with their spousal controls (odds ratio [OR]=1•07, 95% CI 0•86-1•23, χ²=0•47, p=0•49), or in the fi rst-degree relatives of MS probands compared with controls (OR=0•89, 0•63-1•17, χ²=1•11, p=0•29). However, the reported frequency of autoimmune diseases did diff er according to the sex of the interviewee (female vs male patients χ²=92•2, p<0•0001; female vs male spousal controls χ²=87•1, p<0•0001). MS patients had slightly higher rates of thyroid disease and pernicious anaemia than did controls, which is consistent with MHC associations for these diseases, but this eff ect disappeared when results were adjusted for sex. For eight other diseases the rates were similar in MS patients and controls. Families with multiple cases of MS were no more likely to report autoimmune diseases than families with single MS cases. Interpretation When data were adjusted for sex, no excess of common autoimmune diseases could be identifi ed in MS patients or their families, including multicase pedigrees. Our results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratifi ed data for a sex-limited disease. Family histories should thus be taken from male patients in the presence of a spouse.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out.
Life expectancy in Down syndrome was calculated to 68 years, using data for 1610 Down syndrome li... more Life expectancy in Down syndrome was calculated to 68 years, using data for 1610 Down syndrome liveborn individuals among over 1.5 million consecutive British Columbia livebirths. Overall, although survival is significantly poorer than for the general population, over half of Down syndrome individuals can be expected to survive into their fifties, and 13.5% will still be alive at age 68. The data are presented as a life table, a practical format for the clinician and planner.
Background and purpose: Genetic and environmental factors have important roles in multiple sclero... more Background and purpose: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Given a potential role for sex hormones in MS, we have investigated whether or not the age of puberty influences the risk of developing MS in a population-based cohort. Methods: We identified 5493 MS index cases and 1759 spousal controls with age of puberty information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Age of puberty was compared between index cases and controls, and any effect of age of puberty on the age of onset of MS was also investigated. Results: There were no significant differences between male index cases and controls with respect to age of puberty, P = 0.70. However, a significant difference was observed between female index cases and female controls, with average age of puberty being 12.4 and 12.6 years respectively, P = 0.00017, providing a relative risk decrease of 0.9 per year increase of age of puberty. There was no effect of the age of puberty on the age of MS onset in either sex. Conclusions: Earlier age at menarche increases the risk of MS in women. Whether this association is a surrogate for a disease causative factor or directly involved in MS disease aetiology needs to be uncovered.
This study is a 7.5 year follow‐up of a population‐based series of twins with multiple sclerosis ... more 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 Cabadian 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 an 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 date 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 date also have importatnt implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age...
The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflamma... more The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflammatory disease that is disseminated in space and time, as evidenced clinically or by magnetic resonance imaging (MRI). The 2010 McDonald criteria simplified MRI requirements, and newly proposed that the criteria are also suitable for the diagnosis of pediatric MS. Methods: In a national prospective incident cohort study of children with acute demyelination observed for a minimum of 24 months, baseline and serial clinical and MRI examinations were used to retrospectively evaluate the 2010 and 2005 McDonald criteria using clinically relapsing disease as the gold standard. Results: Of 212 eligible participants, 34 experienced 2 or more clinical attacks, 58 met the 2010 criteria, and 42 met 2005 McDonald criteria. The 2010 criteria demonstrated high sensitivity (100%), specificity (86%), positive predictive value (76%), and negative predictive value (100%) for children older than 11 years with non-acute disseminated encephalomyelitis (ADEM) presentations, as did the 2005 McDonald criteria. In younger children with a non-ADEM presentation,
There is increasing evidence that genetic factors play a role in the etiology of mood disorders. ... more 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 ...
Background: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed... more Background: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis. Methods: Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed. Results: The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI ϭ 0.40 to 1.12; p for trend ϭ 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of Ն400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI ϭ 0.38 to 0.91; p for trend ϭ 0.006). No association was found between vitamin D from food and MS incidence. Conclusion: These results support a protective effect of vitamin D intake on risk of developing MS.
Multiple sclerosis (MS) is a chronic autoimmune complex trait with strong evidence for a genetic ... more Multiple sclerosis (MS) is a chronic autoimmune complex trait with strong evidence for a genetic component. A female gender bias is clear but unexplained and a maternal parent-of-origin effect has been described. X-linked transmission of susceptibility has been previously proposed, based on pedigree, association and linkage studies. We genotyped 726 relative pairs including 552 affected sib-pairs for 22 X-chromosome microsatellite markers and a novel dataset of 195 aunt-uncle/niece-nephew (AUNN) affected pairs for 18 markers. Parent-of-origin effects were explored by dividing AUNN families into likely maternal and paternal trait transmission. For the sib-pair dataset we were able to establish exclusion at a λ s = 1.9 for all markers using an exclusion threshold of LOD ≤—2. Similarly for the AUNN dataset, we established exclusion at λAV = 1.9. For the combined dataset we estimate exclusion of λ = 1.6. We did not identify significant linkage in either the sib-pairs or the AUNN dataset...
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Apolipoprotein E (APOE) is involved in neuronal remodelling and several studies have attempted to examine the effect of APOE on MS disease severity, but its function in modifying the course of MS is controversial. It has been suggested recently that PVRL2, not APOE, is the locus on chromosome 19 which influences clinical outcome of MS. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of APOE and PVRL2 on MS disease severity. The MS cases selected represent the prognostic best 5% (benign MS) and worst 5% (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that APOE or PVRL2 have any outcome modifying activity. We conclude that APOE and PVRL2 have little or no effect on the clinical outcome of MS.
1. Parker WD Jr, Boyson SJ, Luder AS, Parks JK. Evidence for a defect in NADH:ubiquinone oxidored... more 1. Parker WD Jr, Boyson SJ, Luder AS, Parks JK. Evidence for a defect in NADH:ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 1990;40:123 1-1234. 2. Parker WD, Boyson SJ, Parks JK. Electron transport chain abnormalities in idiopathic Parkinson’s disease. Ann Neural 1989;26:719723. 3. Ichiki T, Tanaka M, Nishikimi M, et al. Deficiency of subunits of complex I a n d mitochondria1 encephalomyopathy. Ann Neural 1988;23:287-294.
Multiple sclerosis (MS) is a lifelong disease typically affecting individuals in young to middle ... more Multiple sclerosis (MS) is a lifelong disease typically affecting individuals in young to middle adulthood. There are recognized sex differences in MS onset and clinical course. MS affects approximately three times more women than men, thus resulting in less attention to the male experience (i.e. diagnosis, management, societal dimensions). Here, we review current scientific evidence on sex differences in MS risk and course, highlight potential sources of bias, and suggest avenues of further inquiry. We then describe what is known about male experiences with MS diagnosis, treatment, and symptom management (particularly mood and sexual function). Finally, we consider ways in which healthcare providers might engage male patients in the broader aspects of living with MS (e.g. familial and societal relationships) to influence their long-term quality of life (QOL). When possible, we draw from published sources to underscore our collective clinical and scientific experiences.
Introduction: Conventional multisession genetic counseling is currently recommended when disclosi... more Introduction: Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. Methods: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. Results: Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n 5 115), CP-GC protocol (n 5 116), or CP-MD protocol (n 5 112). Mean postdisclosure scores on all outcomes were well below cutoffs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P ,.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. Conclusions: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.
To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women.... more To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women. We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: "multiple sclerosis" and "pregnancy." We manually searched the reference lists of identified studies. Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team. The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be ...
Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting... more Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting as infectious mononucleosis (IM) are recognized as risk factors for multiple sclerosis (MS). However, their combined effect and possible interaction on MS risk is not known. Objective To assess the association between HLA-DRB1*15 and risk of MS in persons with and without IM. Methods We compared the prevalence of DRB1*15 in MS patients with ( n = 76) and without ( n = 1,836) IM with the corresponding distributions in blood donors with ( n = 62) and without ( n = 484) IM histories. This allowed us to estimate the relative risk of MS associated with DRB1*15 in the presence and absence, respectively, of previous IM. We then estimated the interaction between DRB1*15 and IM as the ratio of the two individual odds ratios. Results In IM-naïve individuals, DRB1*15 carried a 2.4-fold (95% confidence interval [CI], 2.0–3.0) increased MS risk. In contrast, among persons with IM history, DRB1*15 wa...
Background Evidence of an association between multiple sclerosis (MS) and other autoimmune diseas... more Background Evidence of an association between multiple sclerosis (MS) and other autoimmune diseases would substantiate the hypothesis that MS is an autoimmune disease, and implicate a common mechanism. We aimed to investigate and compare the rate of autoimmune disease in MS patients, in their fi rst-degree relatives, and in their unrelated spouses. Methods We used data from a national, multicentre, population-based sample to investigate the rate of autoimmune disease in 5031 MS patients, 30 259 of their fi rst-degree relatives, and 2707 spousal controls. We asked patients and controls whether they had any of ten autoimmune diseases: Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anaemia, systemic lupus erythematosus, autoimmune thyroid disease, vitiligo, and myasthenia gravis. MS probands were also asked whether their fi rst-degree relatives had Crohn's disease, ulcerative colitis, rheumatoid arthritis, or type 1 diabetes. Findings After correction for age and sex, we did not identify any increased risk of autoimmune diseases in MS patients compared with their spousal controls (odds ratio [OR]=1•07, 95% CI 0•86-1•23, χ²=0•47, p=0•49), or in the fi rst-degree relatives of MS probands compared with controls (OR=0•89, 0•63-1•17, χ²=1•11, p=0•29). However, the reported frequency of autoimmune diseases did diff er according to the sex of the interviewee (female vs male patients χ²=92•2, p<0•0001; female vs male spousal controls χ²=87•1, p<0•0001). MS patients had slightly higher rates of thyroid disease and pernicious anaemia than did controls, which is consistent with MHC associations for these diseases, but this eff ect disappeared when results were adjusted for sex. For eight other diseases the rates were similar in MS patients and controls. Families with multiple cases of MS were no more likely to report autoimmune diseases than families with single MS cases. Interpretation When data were adjusted for sex, no excess of common autoimmune diseases could be identifi ed in MS patients or their families, including multicase pedigrees. Our results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratifi ed data for a sex-limited disease. Family histories should thus be taken from male patients in the presence of a spouse.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. As little is conclusively known about MS disease mechanisms, we have selected a variety of candidate genes that may influence the prognosis of the disease based on their function. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of on MS disease severity. The MS cases selected represent the prognostic best 5 % (benign MS) and worst 5 % (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that the genes selected have any outcome modifying activity, although small effects of these genes cannot be ruled out.
Life expectancy in Down syndrome was calculated to 68 years, using data for 1610 Down syndrome li... more Life expectancy in Down syndrome was calculated to 68 years, using data for 1610 Down syndrome liveborn individuals among over 1.5 million consecutive British Columbia livebirths. Overall, although survival is significantly poorer than for the general population, over half of Down syndrome individuals can be expected to survive into their fifties, and 13.5% will still be alive at age 68. The data are presented as a life table, a practical format for the clinician and planner.
Background and purpose: Genetic and environmental factors have important roles in multiple sclero... more Background and purpose: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Given a potential role for sex hormones in MS, we have investigated whether or not the age of puberty influences the risk of developing MS in a population-based cohort. Methods: We identified 5493 MS index cases and 1759 spousal controls with age of puberty information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Age of puberty was compared between index cases and controls, and any effect of age of puberty on the age of onset of MS was also investigated. Results: There were no significant differences between male index cases and controls with respect to age of puberty, P = 0.70. However, a significant difference was observed between female index cases and female controls, with average age of puberty being 12.4 and 12.6 years respectively, P = 0.00017, providing a relative risk decrease of 0.9 per year increase of age of puberty. There was no effect of the age of puberty on the age of MS onset in either sex. Conclusions: Earlier age at menarche increases the risk of MS in women. Whether this association is a surrogate for a disease causative factor or directly involved in MS disease aetiology needs to be uncovered.
This study is a 7.5 year follow‐up of a population‐based series of twins with multiple sclerosis ... more 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 Cabadian 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 an 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 date 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 date also have importatnt implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age...
The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflamma... more The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflammatory disease that is disseminated in space and time, as evidenced clinically or by magnetic resonance imaging (MRI). The 2010 McDonald criteria simplified MRI requirements, and newly proposed that the criteria are also suitable for the diagnosis of pediatric MS. Methods: In a national prospective incident cohort study of children with acute demyelination observed for a minimum of 24 months, baseline and serial clinical and MRI examinations were used to retrospectively evaluate the 2010 and 2005 McDonald criteria using clinically relapsing disease as the gold standard. Results: Of 212 eligible participants, 34 experienced 2 or more clinical attacks, 58 met the 2010 criteria, and 42 met 2005 McDonald criteria. The 2010 criteria demonstrated high sensitivity (100%), specificity (86%), positive predictive value (76%), and negative predictive value (100%) for children older than 11 years with non-acute disseminated encephalomyelitis (ADEM) presentations, as did the 2005 McDonald criteria. In younger children with a non-ADEM presentation,
There is increasing evidence that genetic factors play a role in the etiology of mood disorders. ... more 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 ...
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Papers by A. Sadovnick