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Biomedical subjects

G C Ebers

Publications and source records attributed to G C Ebers.

At least 19 recordsLinked to original sources
PubMed2003

Twin concordance and sibling recurrence rates in multiple sclerosis.

Size and ascertainment constraints often limit twin studies to concordance comparisons between identical and fraternal twins. Here we report the final results of a longitudinal, population-based study of twins with multiple sclerosis (MS) in Canada. Bias was demonstrably minimized, and an estimated 75% of all Canadian MS twin pairs were ascertained, giving a sample sufficiently large (n = 370) to permit additional informative comparisons. Twinning was not found to affect prevalence, and twins with MS did not differ from nontwins for DR15 allele frequency nor for MS risk to their siblings. Probandwise concordance rates of 25.3% (SE +/- 4.4) for monozygotic (MZ), 5.4% (+/-2.8) for dizygotic (DZ), and 2.9% (+/-0.6) for their nontwin siblings were found. MZ twin concordance was in excess of DZ twin concordance. The excess concordance in MZ was derived primarily from like-sexed female pairs with a probandwise concordance rate of 34 of 100 (34 +/- 5.7%) compared with 3 of 79 (3.8 +/- 2.8%) for female DZ pairs. We did not demonstrate an MZ/DZ difference in males, although the sample size was small. We observed a 2-fold increase in risk to DZ twins over nontwin siblings of twins, but the difference was not significant.

Canada↗
PubMed2003

Genetic loading in familial migraine with aura.

Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi(2)=6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi(2)=9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.

Adult↗
PubMed2002

Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.

Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.

Calcium Channels↗
PubMed2002

No evidence to support CTLA-4 as a susceptibility gene in MS families: the Canadian Collaborative Study.

Two polymorphisms of the CTLA-4 gene were genotyped in 232 sibling pairs affected with multiple sclerosis (MS) from 185 families. The CTLA-4 polymorphisms genotyped were a 3' untranslated (AT)(n) microsatellite and an alanine/threonine RFLP of exon 1. There was no evidence observed for linkage by either identity-by-descent (ibd) or identity-by-state (ibs) methods. A transmission disequilibrium test (TDT) was performed and no preferential transmission of alleles was observed. Upon stratification of patients, there was no preferential transmission observed based upon gender, by presence or absence of HLA*DRB1*15, by ethnicity or by clinical course of the disease. CTLA-4 does not appear to be a major MS susceptibility locus in Canadian multiplex families.

Abatacept↗
PubMed2002

A multigenerational family with multiple sclerosis.

We report a family with 15 individuals affected with multiple sclerosis present in three and possibly four generations. The segregation of multiple sclerosis within this pedigree is consistent with an autosomal dominant mode of inheritance with reduced penetrance. The clinical characteristics of the affected individuals are indistinguishable from those seen in sporadic multiple sclerosis with respect to sex ratio, age at onset, onset symptom, MRI and clinical course. Eleven of 14 cases (78.6%) were positive for the known multiple sclerosis-associated major histocompatibility complex (MHC) Class II HLA DRB1*15 allele. Parametric linkage analysis gave a non-significant LOD score of 0.31 (theta; = 0.33) for the DRB1 gene. However, among 11 affected children with at least one DRB1*15 bearing parent, all 11 out of 11 received at least one copy of this known susceptibility allele. A transmission disequilibrium test analysis was significant for the DRB1*15 allele within this single family; P = 0.0054. The inheritance pattern in this family suggests the presence of a single major locus responsible for multiple sclerosis susceptibility, with DRB1 acting as an important modifier. This family could be an important resource for the identification of a multiple sclerosis susceptibility gene.

Adolescent↗
PubMed2001

An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus.

The authors report an autosomal dominant episodic ataxia that is clinically distinct from the other episodic ataxias. Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide. Linkage analyses of markers flanking the EA1 and EA2 loci demonstrate genetic exclusion from the other autosomal dominant episodic ataxias. The authors suggest EA3 for periodic vestibulocerebellar ataxia and EA4 for the disorder described here.

Adolescent↗
PubMed2001

Recurrence risks to sibs of MS index cases: impact of consanguineous matings.

Using population-based data, the authors identified 24 MS index cases whose parents were related. Twenty-two had 67 sibs of whom 6 also had MS, yielding a recurrence risk of approximately 9%, significantly higher than for sibs of MS index cases from nonconsanguineous parents. These findings support the concept that multiple interacting genes increase the risk of MS.

Consanguinity↗
PubMed2001

Genetic susceptibility to MS: a second stage analysis in Canadian MS families.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

Canada↗
PubMed2000

Genetic analysis of vitamin D related genes in Canadian multiple sclerosis patients. Canadian Collaborative Study Group.

The objective of this study was to investigate genes involved in the metabolism and function of vitamin D as candidate genes for genetic susceptibility to MS. Restriction fragment length polymorphisms and highly polymorphic microsatellite markers within or very close to the 1,25(OH)2D3 receptor (VDR) [12q14], the vitamin D binding protein (DBP) [4q12], and the 25(OH)D2 1alpha-hydroxylase [12q13] loci were analyzed for linkage or association with MS. We found no evidence for linkage or association of these candidate genes with MS in the Canadian population.

Alleles↗
PubMed2000

Bone marrow transplantation in multiple sclerosis.

There is strong circumstantial evidence that multiple sclerosis (MS) is an autoimmune disease. Nonspecific immunosuppressive therapy has not been successful in altering the natural course of the illness. Bone marrow transplantation has heretofore been a radical therapy used in patients with life-threatening malignancies but has potential as a treatment for human autoimmunity. In MS there have been no controlled studies. We report here four patients with MS undergoing bone marrow transplantation with 6-48 months of follow-up. In three this was carried out for co-existing malignancy and in one as an experimental treatment for MS using the patient's unaffected identical twin as a donor. The limited outcome that can be evaluated in these patients supports further experimentation into this treatment modality in MS patients with poor prognostic indications.

Adult↗
PubMed2000

The natural history of multiple sclerosis.

The natural history of chronic diseases is generally poorly understood. Multiple sclerosis is one of the best-studied diseases and we outline here some of the information obtained from 25,000 patient-years of observation. This population-based cohort received almost no treatment and certainly none known to alter the long-term natural course of the illness. There is a possibility that such data will prove useful in new generation clinical trials which are observational in nature.

Cohort Studies↗
PubMed2000

Factors influencing sib risks for multiple sclerosis.

Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non-genetic (environmental) factors. The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1,083 MS index cases, 2,166 of their parents and 3,112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS. These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.

Adolescent↗
PubMed2000

The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis.

We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.

Adult↗
PubMed2000

Susceptibility to multiple sclerosis: interplay between genes and environment.

Multiple sclerosis is a complex trait of unknown etiology. Epidemiological data have shown that susceptibility to multiple sclerosis is determined by both genetic and environmental factors. It is unknown whether the clinical subcategories of multiple sclerosis are separate diseases with separate etiologies and causes. Recent theories of the pathogenesis of multiple sclerosis and candidate genes are discussed. Other potential nonchromosomal factors involved in multiple sclerosis susceptibility such as mitochondrial DNA and viral factors such as Chlamydia pneumoniae are reviewed.

Environmental Exposure↗
PubMed2000

Evidence favoring genetic heterogeneity for febrile convulsions.

PURPOSE: Two large Canadian kindreds appearing to segregate febrile convulsions as an autosomal dominant trait were evaluated for linkage to three known FC loci, as well as other epilepsy loci. METHODS: Members of the two families were genotyped with microsatellite markers linked to the previously identified febrile convulsion loci, FEB1, FEB2, and GEFS+, and we performed two-point linkage analyses by assuming an autosomal dominant mode of inheritance. RESULTS: We report the exclusion of the FC trait in our families to FEB1 on 8q13-21 and to a second febrile convulsion locus on 19p13. Furthermore, we also excluded the GEFS+ locus on 19q13.1 as the cause of febrile convulsions in both kindreds. Microsatellite markers linked to juvenile myoclonic epilepsy (EJM1), benign neonatal familial convulsions EBN1 and EBN2, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), idiopathic generalized epilepsy (EGI), progressive myoclonic epilepsy of Unverricht-Lundborg (EPM1), and partial epilepsy with auditory features (EPT), were also excluded as potential loci linked to the FC trait in our families. CONCLUSIONS: These findings favor considerable genetic heterogeneity for febrile convulsions.

Age of Onset↗