Multiple sclerosis (MS) most commonly affects individuals of Northern European descent who live in countries at high latitude. The relative contributions of ancestry, country of birth and residence as determinants of MS risk have been studied in adult MS, but have not been explored in the pediatric MS population. In this study, we compare the demographics of pediatric- and adult-onset MS patients cared for in Toronto, Ontario, Canada, a multicultural region. The country of birth, residence during childhood, and ancestry were compared for 44 children and 573 adults. Our results demonstrate that although both the pediatric and adult cohorts were essentially born and raised in the same region of Ontario, Canada, children with MS were more likely to report Caribbean, Asian or Middle Eastern ancestry, and were less likely to have European heritage compared with individuals with adult-onset MS. The difference in ancestry between the pediatric and adult MS cohorts can be explained by two hypotheses: (1) individuals raised in a region of high MS prevalence, but whose ancestors originate from regions in which MS is rare, have an earlier age of MS onset, and (2) the place of residence during childhood, irrespective of ancestry, determines lifetime MS risk -- a fact that will be reflected in a change in the demographics of the adult MS cohort in our region as Canadian-raised children of recent immigrants reach the typical age of adult-onset MS.
We have evaluated genetic and environmental influences in multiple sclerosis (MS) by comparing age of onset in 99 sibling pairs concordant for the disease. We used three methods of analysis: (1) comparison of mean differences in age of onset and year of onset, (2) linear regression of differences in age or year of onset vs difference in ages, and (3) intraclass correlation of age of onset which is also used for monozygotic twins concordant for MS. Comparison of the mean differences in age of onset or year of onset is found to be inappropriate and potentially misleading. No significant results were found in linear regression of the age of onset or year of onset vs differences in ages, although a trend towards onset at the same age is present. However, nontwin siblings show a significant intraclass correlation for age of onset (P less than 0.01) as is seen in genetic disorders. A stronger intraclass correlation in age of onset in concordant monozygotic twins vs concordant sibling pairs further suggests that age of onset is partly under genetic control, assuming common exposure to an environmental agent. The results give little support for common exposure to an environmental trigger in concordant MS sibling pairs. They are consistent with a mixture of random independent exposures and common exposures leading to the development of the disease, with the former predominating.
Microchimerism, the persistence of foreign cells thought to derive from previous pregnancies, has been associated with autoimmune diseases. A maternal parent-of-origin effect in MS remains unexplained. We tested for microchimerism in monozygotic and dizygotic twin-pairs with MS. Microchimerism was associated with MS in affected females from monozygotic concordant pairs when compared to both affected (p=0.020) and unaffected (p=0.025) females in monozygotic discordant pairs. Microchimerism was increased in affected females of dizygotic discordant pairs (p=0.059). The rate of microchimerism was significantly higher in affected twins than in unaffected co-twins (p=0.0059). These observations show an association in twins between the presence of microchimerism and having MS.
Results from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (MS)-Phase 1 (CCPGSMS-Phase 1) together with other family data published since 1982 have led to the following conclusions about the etiology of MS: (i) genetic and non-genetic (environmental) factors are involved in the etiology of MS on a population basis; (ii) the familial aggregation of MS is genetic; (iii) maternal factors do not influence the risk for siblings to develop MS; and (iv) MS appears to be oligogenic. The present paper describes the rationale and methodology for the CCPGSMS-Phase 2.
The CCPGSMS-Phase 2 is a nation-wide collaborative effort involving all the 15 Canadian MS clinics. A series of structured questionnaires is administered to MS index cases, spouse controls and mothers of index cases and spouse controls (if available) by trained interviewers. Blood samples are taken for molecular genetic studies. This national effort is coordinated by the MS Clinics in Vancouver and London.
The CCPGSMS-Phase 2 is in progress so specific results are not available. The study is designed to (i) increase the database for genetic epidemiological/molecular genetic research and (ii) gather population-based data to further our understanding of the non-genetic factors in the etiology of MS.
It is anticipated that the results from this study will impact on the eventual prevention, cure and treatment of MS.
To look at the underlying cause of death (U.C.O.D.) data for Down syndrome (DS), we studied 324 DS individuals who died out of a total of 1,337 DS births occurring in 1,066,508 consecutive live births during the years 1952-81 inclusive. U.C.O.D. rates, separated into ICD-9 classifications, for the DS population were compared with those of the age-matched general population. In general, an individual with DS is significantly more likely to die than the age-matched general population over all ages studied up to age 30. The greatest absolute likelihood of dying is under 1 year, but the age group with the greatest relative risk of dying (17.2) is very definitely between ages 1-9. In order, the three categories for causes of death in DS with the greatest relative risk are congenital anomalies, circulatory system, and respiratory system.
Cites: Med Inform (Lond). 1980 Apr-Jun;5(2):121-307453270
Cites: J Epidemiol Community Health. 1982 Jun;36(2):127-96214602
Cites: Dev Med Child Neurol. 1982 Dec;24(6):817-296218002
Cites: Am J Hum Genet. 1983 Jan;35(1):110-66218752
Cites: Oncology. 1983;40(4):280-36223254
Cites: J Med Genet. 1984 Feb;21(1):72-36229636
Cites: Am J Med Genet. 1978;2(1):1-5162533
Cites: J Pediatr. 1984 Aug;105(2):235-426235337
Cites: Psychol Med. 1984 Aug;14(3):691-56494374
Cites: Am J Epidemiol. 1986 Aug;124(2):161-793524199
Cites: Am J Epidemiol. 1986 Aug;124(2):180-13728435
To characterize the neuropsychiatric symptoms (NPS) of subjects classified as not cognitively impaired (NCI), cognitively impaired-not demented (CIND), and dementia.
A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD) is a longitudinal investigation of individuals referred to eight Canadian dementia centers for evaluation of cognitive impairment and neurobehavioral symptoms. Of the inception cohort of 804 subjects for whom the informant-based Neuropsychiatric Inventory (NPI) was completed at study entry, 35 were classified as NCI, 193 as CIND, and 576 as dementia. The three diagnostic groups were compared on each of the 12 NPI items. Within each diagnostic group, comparisons were also made between symptomatic (NPS+; total score > 1) and asymptomatic (NPS-; total score = 0) subjects on measures of general cognitive status and functional disability. A subset of the NCI and CIND individuals were also compared on a comprehensive neuropsychological test battery.
There was at least one NPI item reported in 60% of subjects with NCI, 74% with CIND, and 89% with dementia. The item scores for delusions, hallucinations, agitation, apathy, disinhibition, aberrant motor behavior, and problems with appetite were greater in dementia subjects than in NCI or CIND. There were no significant differences between subjects with NCI and CIND on any NPI item. For each diagnostic group, NPS+ subjects were more impaired on functional but not neuropsychological measures.
Across all levels of cognition, neuropsychiatric symptoms (NPS) are an important feature in individuals referred to dementia clinics. The current data suggest that NPS may precede cognitive deficits in individuals classified as not cognitively impaired and cognitively impaired-not demented.
There has been a suggestion that esophageal atresia with tracheoesophageal fistula (EA/TEF) may be related to the occurrence of infectious disease in the population during the time of early gestation. There is therefore a need for further data on trends in incidence related to infectious diseases. Data on the occurrence of EA/TEF with and without additional congenital malformations may also be relevant. The British Columbia Health Surveillance Registry is population-based with excellent case ascertainment of birth defects, and data are available on the incidence of infectious diseases for B.C., allowing comparison of trends to be made. One hundred forty-nine cases of EA/TEF occurred among 534,834 consecutive livebirths during the period 1966-1980 for an incidence rate of 1/3,590. No significant (p less than 0.05) annual, seasonal or monthly incidence trends were observed. In addition, the occurrence of EA/TEF could not be correlated with the prior incidence of infectious hepatitis, rubella, salmonella, or rubeola. Fifty-five percent of individuals with EA/TEF had congenital malformations in other systems, most frequently cardiovascular, gastrointestinal, and genitourinary. Most individuals with additional congenital malformations had multiple system involvement.
From a population-based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty-three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%-0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease.
Comment In: Ann Neurol. 2001 Oct;50(4):552-311601510
BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p
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.