Biomedical subjects
Publications and source records attributed to G C Ebers.
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Flu-like symptoms and injection site reactions are adverse effects of treatment with interferon beta-1b in patients with MS. We compared gradual dose escalation, ibuprofen treatment, or their combination in an open-label study. The combination reduced the incidence of flu-like symptoms to rates comparable with the placebo group in the pivotal trial but increased the frequency of injection site reactions, albeit modestly and transiently.
We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.
The natural history of primary progressive multiple sclerosis (PP-multiple sclerosis) recently has been defined in a geographically based multiple sclerosis population. For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible. Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints. Hypothetical entry criteria were based on the practical considerations which would attend the execution of clinical trials in progressive multiple sclerosis. We then developed a series of sample size tables giving the number of patients with PP-multiple sclerosis and the length of observation that would be required to detect a significant result (P = 0.05) for a 25, 50 and 75% decrease in the median time to progression with 80 or 90% power, with treatment efficacy based upon the ability to slow progression on the disability status score. It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-multiple sclerosis which will require multi-centre collaborative efforts.
BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: It is anticipated that the results from this study will impact on the eventual prevention, cure and treatment of MS.
Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system affecting primarily young adults. Evidence from genetic epidemiological studies demonstrate that the observed familial clustering of MS is primarily due to shared genes between family members. Molecular investigations have failed to elucidate susceptibilty loci with the exception of the HLA DRB1*1501, DQA1*0102, DQB1*0602 haplotype of the major histocompatibility complex. Results from genomic screens stress the complexity of MS genetics and that there is no one single locus contributing significantly to familial risk. To overcome the confounding effects of genetic complexity, MS genetic research needs to take advantage of clinical and epidemiological information to better homogenize study samples. In addition, the continued collection and genotyping of MS families may shed some light on the mild to moderate susceptibility loci affecting the MS patient population.
MS is believed to be a complex trait determined by genetic and nongenetic factors. Data suggest that MS susceptibility and age at onset are each, at least to some extent, under genetic control. The present study carefully examined five covariates (sex of the index case, sex of the sibling, birth cohort of the sibling [< or = 1919, 1920 to 1939, > or = 1940], age of MS onset in the index patient (< or = 20 years, 21 to 30 years, 31 to 40 years, > 40 years), and MS disease status of the parents [i.e., MS present in one parent or no parent with MS]) that may influence the familial risk of MS in a large cohort of 1,896 MS patients and 8,878 of their first-degree relatives. Of these, sex of the sibling, parental MS status, and index patient onset age were the important factors influencing MS risks to siblings. The results of this study are (1) the index-patient-onset-age effect suggests that individuals with a greater genetic loading (i.e., a greater contribution of susceptibility alleles) have an earlier age at onset and (2) genetic loading is substantially increased in individuals with an affected parent. These data are important both for genetic counseling and gene identification studies.
OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.
Multiple Sclerosis (MS) is a common chronic central nervous system disease in young adults. Relative familial risk appears to be determined largely by genes while population risk is strongly influenced by environmental factors. This is supported by genetic epidemiological studies which also suggest an oligogenic inheritance of susceptibility. The HLA DRB1*1501, DQA1*0102, DQB1 0602 haplotype is associated with the disease but HLA contributes only modestly to overall susceptibility. The results of three genomic searches are concordant with the genetic epidemiology and imply a number of genes with interacting effects will be found. Importantly, no single region has been identified with a major influence on familial risk.
The continuing search for genetic loci which may influence multiple sclerosis susceptibility has probably been more complex and exciting than Spielman and Nathanson (4) could have imagined in 1982. Restriction fragment length polymorphisms no longer represent the "cutting edge" of technology. This entire area of research has gained incredible impetus with advances in molecular genetics and the advent of the "Human Genome Project." Readers must be cautioned that identification of a gene does not equate with a cure. Nevertheless, we are entering into a very exciting era with respect to the genetics and treatment of common complex disorders such as breast cancer, Alzheimer disease, and multiple sclerosis. Given the increasing awareness of the public about the role of genetics in the etiology of such disorders, a better understanding is needed of the legal, social, ethical, and psychologic implications of genetic research in multiple sclerosis.
It has been previously shown that ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor. To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis, cerebellar degeneration, or drug toxicity. The principal outcome measures were the change in blind assessment of a writing task (spiral copying) and the timed completion of a nine hole peg test. Thirteen of 19 patients were deemed to have improved spiral copying after treatment with ondansetron when compared with baseline performance. One patient had a better response to the placebo compared with baseline performance (P = 0.00024). Patients completed the nine hole peg test in less time after ondansetron than after placebo (P = 0.08). Twelve patients thought that their tremor was functionally improved with the ondansetron treatment. None thought that the placebo gave improvement (P = 0.00098). The efficacy of orally administered ondansetron in tremor control is currently under study.
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<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
Multiple sclerosis appears to be a complex trait determined by genes and environmental factors. This hypothesis is increasingly supported by genetic epidemiological studies of large populations. Well ascertained studies of adoptees and half siblings indicate that familial aggregation is genetic. These results have important implications for the nature of environmental factors influencing susceptibility to multiple sclerosis. These appear to act at a population level and probably exert an influence on risk that matches or exceeds that from any single genetic locus. The identification of susceptibility genes in multiple sclerosis will be difficult.
Genetic-environmental interactions probably underlie spontaneous human autoimmune disorders, a category of complex traits thought to include multiple sclerosis (MS). The geographical distribution and familial aggregation of this disease have often been ascribed to the role of infectious agents, but there is no consensus. Increased family risks range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives over the general population prevalence of 0.1% (ref. 6). We screened a population-based sample of 15,000 individuals with MS by using standardized, personally administered questionnaires to identify adopted index cases and/or those who had adopted relatives. The frequency of MS among first-degree non-biological relatives living with the index case was no greater than expected from Canadian population prevalence data and significantly less than for biological relatives. These findings indicate that familial aggregation of MS is genetically determined: no effect of shared environment was detectable.
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The cause of several familial muscular diseases have recently been linked to mutations within skeletal muscle sodium and chloride channel genes. Thomsen's and Becker's diseases are autosomal dominant and recessive, respectively, and are caused by at least seven different mutations in the CLCN1 (ClC-1) skeletal muscle chloride channel gene on chromosome 7q35. Hyperkalaemic periodic paralysis, paramyotonia congenita and a small heterogeneous group of related 'pure' myotonias are autosomal dominant disorders and are due to at least 16 different mutations in the SCN4A (SkM1) adult skeletal muscle sodium channel gene on chromosome 17q23-25. There is generally little correlation between the position of a mutation in the channel and the phenotype. Indeed, identical sodium channel mutations in unrelated subjects and sometimes in different members of the same family can have different clinical expressions. It seems, however, that mutations of the inactivation gate (ID3-4 loop) of the sodium channel tend to produce paramyotonia or pure, sometimes severe, myotonia and respond most favourably to the same medications (tocainide and mexiletine). The structure and polarity of substituted amino acids at a mutation site, especially in highly evolutionally conserved regions of the gene, are undoubtedly important to the expression of a channel disease and may partly explain phenotypic variability. In addition, genetic polymorphisms elsewhere, either in the gene or other channel-related loci, and the net effect of other types of muscle ion channels on the electrical potential of the plasma membrane probably contribute to disease expression.
Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated and the APCA locus was found to be linked to the short arm of chromosome 19 in two large kindreds. The microsatellite marker UT705 was found to be linked to the APCA locus with two point analysis yielding a maximum lod score of 8.20 at theta max = 0.000 in a five generation pedigree. Linkage to this region was confirmed in a second kindred. The absence of known candidate genes in the region may necessitate a positional cloning approach in order to identify the gene for this disorder.