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G C Ebers

Publications and source records attributed to G C Ebers.

At least 19 recordsLinked to original sources
PubMed2006

Follow-up investigation of 12 proposed linkage regions in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease with overwhelming evidence for genetic determination, and for which a maternal parent-of-origin effect has been reported. As with many complex diseases, multiple suggestive linkage signals have been observed. However, the only unambiguous association and linkage identified to date is with alleles of the human lymphocyte antigen (HLA) class II region. We have now carried out high-density microsatellite genotyping for 12 of the most promising regions (1p, 1q, 2q, 4q, 5p, 9q, 10p, 11p, 12q, 17q, 18p, 19p) from a whole-genome scan in 552 affected sibling pairs. This has been carried out in 194 families containing avuncular pairs. These permit examination of parent-of-origin effects in non-colineal pairs when divided into likely maternal and paternal trait transmission. The results do not confirm any non-major histocompatibility complex linkage in the overall subset nor in the maternal, paternal or HLA-DRB1*1501 subsets. We were able to establish exclusion for a locus with lambda(AV) > or = 1.3 for all the previously suggested regions. These results again raise the possibility that the paradigm of multiple genes of small individual effect used to justify genome searches in MS is incorrect.

Alleles↗
PubMed2006

The contribution of demyelination to axonal loss in multiple sclerosis.

The traditional notion that multiple sclerosis is a primary demyelinating disease has led to a plaque-centred view of both aetiology and the pathogenesis of disease progression. The presence of axonal loss has received increasing recognition. However, the relative roles of demyelination and axonal loss have not been fully clarified in multiple sclerosis nor have their possible interrelationships been elucidated. Post-mortem material from the cerebrum, brainstem and spinal cord of 55 multiple sclerosis patients (29 males) with an age range of 25-83 years (mean = 57.5 years) and length of disease history ranging from 2 to 43 years (mean = 17.1 years) was stained for myelin. Plaque load was calculated by summing the relative proportion of plaque area compared with total white matter area of the corticospinal and sensory tracts at each level. This was related to estimates of axonal density and of total axon number in these tracts in the spinal cord. Our results indicate that plaque load did not correlate with brain weight. Unexpectedly, after adjusting for sex, age and duration of disease, correlations between total plaque load and axonal loss in both the corticospinal tract and sensory tracts were weak or absent at each level investigated. Since there was little correlation between plaque load and axonal loss, the possibility that demyelination is not the primary determinant of spinal cord axonal loss warrants consideration.

Adult↗
PubMed2006

The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.

The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.

Adolescent↗
PubMed2006

Multiple sclerosis in stepsiblings: recurrence risk and ascertainment.

Reports implicating specific transmissible agents in multiple sclerosis (MS) susceptibility continue to appear. We therefore re-evaluated MS risk in 687 step-siblings of 19 746 MS index cases. We found the risk of MS to be indistinguishable from that of the general population after diagnostic verification. These results are coherent with studies of adopted children, half siblings and conjugals, showing no risk attributable to the familial microenvironment. This family based genetic epidemiological approach found no trace of transmissibility other than genetic from one affected individual to another in the high prevalence area of Canada. This adds to existing data showing that the action of environment in influencing MS risk is operative at a population level.

Adolescent↗
PubMed2005

A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia.

Episodic ataxias are ion channel disorders characterized by attacks of incoordination. The authors performed a genome-wide screen in a large pedigree segregating a novel episodic ataxia and found significant linkage on 1q42 with a multipoint lod score of 3.65. Haplotype analysis and fine mapping yielded a peak 2-point lod score of 4.14 and indicated a 4-cM region on 1q42 that is likely to harbor an episodic ataxia gene.

Adolescent↗
PubMed2005

Maternal - offspring HLA-DRB1 compatibility in multiple sclerosis.

Major histocompatibility complex (MHC) compatibility has been reported to facilitate the long-term tolerance of fetal or maternally derived stem cells exchanged during pregnancy. Furthermore, such compatibility has been suggested to play a role in fetal viability. An increase in maternal - fetal human leukocyte antigen (HLA) compatibility for class II DR alleles has previously been observed in the autoimmune disease scleroderma. Here, we examined the hypothesis that increased maternal - fetal MHC class II DR compatibility was associated with multiple sclerosis (MS) risk. HLA-DRB1 typing was performed in 2170 affected individuals and 2894 unaffected relatives from 1006 families with MS in at least two members. We found no evidence for increased HLA compatibility between affected individuals and their mothers, compared with unaffected individuals and their mothers, nor compared with affected individuals and their fathers. We also observed no excess of homozygosity of mothers compared with fathers of individuals with MS. In families in which the father shared exactly one allele with the mother, we found no excess in transmission of this allele to affected or unaffected offspring. These findings do not support a role for an excess maternal - fetal HLA-DRB1 compatibility in MS susceptibility.

Alleles↗
PubMed2005

A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis.

BACKGROUND: Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis (MS) prevalence. OBJECTIVE: To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study. METHODS: 15 ambulatory patients with relapsing-remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol (target dose: 2.5 microg/d) for 48 weeks. Dietary calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the expanded disability status scale (EDSS), and brain magnetic resonance imaging (MRI). RESULTS: Two patients withdrew because of symptomatic hypercalcaemia (serum calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion. Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia. Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point. Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks. CONCLUSIONS: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.

Administration, Oral↗
PubMed2004

Parent-of-origin effect in multiple sclerosis: observations in half-siblings.

Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20-50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (chi2 test, p=0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility.

Female↗
PubMed2004

Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts.

Clinical, imaging, and pathological studies in multiple sclerosis have generally emphasized the relative preservation of axons in comparison with myelin. Recent evidence, however, demonstrates that axonal loss is also significant, affects long tracts such as the corticospinal and sensory tracts and relates closely to functional disability. Accordingly, the distribution and extent of this axonal loss is the focus of the current investigation. Post-mortem material of 55 multiple sclerosis patients and 32 matched controls was used to examine quantitatively the population of axons in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to the upper cervical spinal cord. Myelin- and axon-stained sections have been prepared to estimate the notional area and axon density, respectively of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction of the area and axon density at all levels investigated in multiple sclerosis cases when compared with controls. In contrast, the sensory tracts in multiple sclerosis cases showed a significant reduction in area and axon density only in the upper regions of the spinal cord. As has been found with MRI plaque load and T2 burden, correlations of axonal loss with duration of disease were not strong. Of the fibres lost in multiple sclerosis, we have found that small fibres (<3 microm2) seem to be particularly affected, with large fibres remaining relatively preserved in both the corticospinal and sensory tracts. In multiple sclerosis, axonal loss is widespread, and its extent is tract specific and size selective.

Adult↗
PubMed2004

TCR beta polymorphisms and multiple sclerosis.

A total of 267 families with two or more siblings with multiple sclerosis (MS) were genotyped with 14 restriction fragment length polymorphisms at the TCR beta locus. A nonparametric linkage analysis of the data showed no evidence for linkage to this locus (mlod=0.11). No significant allelic or haplotype transmissions were observed in the total sample of 565 patients. After stratification for the presence of HLA DRB1*15, an association was observed between the BV25S1*1-BV26S1*1-BV2S1*1 haplotype and MS (P=0.00089). This was not significant upon correction for multiple comparisons. It was also not significant when the haplotype frequency in affected individuals was compared to a normal control sample (P=0.77). Furthermore, the associated haplotype was followed-up in an independent sample of 97 nuclear families with a single DRB1*15-positive child with MS. The BV25S1*1-BV26S1*1-BV2S1*1 haplotype did not show significant evidence for transmission distortion but the same trend was seen (P=0.21). There were no significant associations observed in the DRB1*15-negative patients and no detectable difference was seen in the DRB1*15-positive BV25S1*1-BV26S1*1-BV2S1*1 association when comparing different subgroups based on clinical course of MS. These results show no evidence for linkage and fail to establish an association between MS susceptibility and the TCR beta locus.

Female↗
PubMed2004

The extent of axonal loss in the long tracts in hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) comprises a group of inherited neurodegenerative disorders with the shared characteristics of progressive weakness and spasticity predominantly affecting the lower limbs. Limited pathological accounts have described a 'dying back' axonal degeneration in this disease. However, the distribution and extent of axonal loss has not been elucidated in a quantitative way. We have studied post-mortem material from six HSP patients and 32 controls in detail. The population of axons was examined quantitatively in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to upper cervical spinal cord. Myelin and axon-stained sections were employed to estimate the notional area and axonal density, respectively, of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction in area and axonal density at all levels investigated in HSP compared to controls. In the corticospinal tracts, the ratio of medulla and lumbar total axonal number was significantly greater in HSP cases compared to controls suggesting more pronounced axonal loss in the distal neuraxis in HSP than in controls. The sensory tracts in HSP, in contrast, showed a significant reduction in area and axonal density only in the upper regions of the spinal cord. Similar to the corticospinal tracts, the ratio of lumbar and upper cervical cord total axonal number in the sensory tracts was increased in HSP cases compared to controls. These findings are consistent with a length-dependent 'dying back' axonopathy. Nerve fibre loss was not size-selective with both small and large diameter fibres affected. In HSP, axonal loss is widespread and symmetrical and its extent tract-specific. The characterization of the nature of axonal loss in HSP, where this is a primary phenomenon, may help the interpretation of axonal loss in conditions such as multiple sclerosis where the sequence of events is less clear.

Adult↗
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↗