Multiple sclerosis: postlinkage genetics

Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.     

多发性硬化人类白细胞抗原易感基因研究进展

多发性硬化为一种免疫相关性中枢神经系统脱髓鞘疾病,临床表现呈异质性,好发于青壮年女性,病残率高,给患者家庭及社会造成沉重负担.遗传因素和环境因素共同参与其发病机制,而HLA基因复合体为重要的遗传学决定因素,占易感风险的60%,对其研究是目前多发性硬化遗传学研究的热点和难点.     

Searching for needles in haystacks—the genetics of multiple sclerosis and other common neurological diseases

Recent years have witnessed considerable advances in our understanding of monogenic neurodegenerative diseases, such as hereditary motor sensory neuropathy and Huntington’s Chorea. Progress has been slower in the genetic dissection of other more common neurological diseases with a complex mode of inheritance. The identification of relevant genes in some, such as Alzheimer’s disease (AD) or Parkinson’s disease (PD), has been facilitated by characteristic pathological findings and autosomal dominant inheritance in a proportion of early onset families. Attempts to identify relevant genes for multiple sclerosis have highlighted the role of the major histocompatibility complex, but so far failed to unequivocally implicate other immunologic or structural candidate genes. Six linkage-based whole genome screens have been completed in multiple sclerosis and several regions of interest have been identified. As technology and progress in the human genome project advance, it has become clear that future studies of common neurological diseases will depend critically on the availability of large sample sizes and will have to address issues of disease heterogeneity.     

Multiple sclerosis: genetic versus environmental aetiology: epidemiology in Israel updated

The incidence and prevalence of multiple sclerosis (MS) were compared, controlling for age, in native-born Israelis of different origins and in immigrants to Israel. This comparison was carried out in two populations, countrywide and in Jerusalem. In the countrywide population, ascertainment was based mainly on hospitalizations; it included 252 patients who were native-born and 150 who had immigrated from Africa-Asia (AA immigrants). The 89 MS patients of Jerusalem also included patients diagnosed in outpatient clinics. In native-born Israelis whose father was born in Europe-America (I-EA), the incidence and prevalence of MS were found to be as high as or even higher than that found previously in immigrants from Europe-America. Among native-born Israelis whose father was born in Africa or Asia (I-AA), the yearly age-adjusted incidence and prevalence rates were found to be 1.4- to 1.8-fold higher than among AA immigrants, pointing to environmental factors. The incidence and prevalence rates in the I-EA were 1.2- to 1.6-fold higher than in the I-AA, pointing to genetic factors. These results seem to point to both environmental and genetic factors in the aetiology of MS. Further research is needed, however, to disentangle the genetic factors from possible environmental differences in the two ethnic groups.     

Multiple sclerosis in G: genes and geography

Multiple sclerosis (MS) shows uneven geographic distribution globally as well as within countries. In epidemiological studies we have previously demonstrated that there is a high-risk focus for MS in the southern Ostrobothnian region of western Finland. In genetic studies we recently identified haplotypes that associate with MS specifically in patients originating from southern Ostrobothnia suggesting a founder effect. Such haplotypes can be used as molecular tools for tracing common ancestry between patients in different geographic locations. In addition to providing clues to the historical origin, such a genetic archeological approach should help narrow the size of the shared haplotype, thus facilitating the identification of etiological variants and possibly define a superfamily of MS patients with common pathogenetic mechanisms.     

Multiple sclerosis and the HLA-D region: linkage and association studies

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.     

Multiple system atrophy masking multiple sclerosis

Multiple system atrophy (MSA) and multiple sclerosis (MS) are progressive neurological disorders with overlapping clinical signs and symptoms. However, due to the course of the disease and the age of onset both disorders are rarely differential diagnosis for each other. We here report the remarkable association of the two diseases in one patient. As MSA dominated the clinical presentation, diagnosis and therapy of MS were delayed. We discuss the clinical symptoms in our patient and highlight the features that allow to differentiate both diseases.     

多发性硬化康复治疗

<正>多发性硬化(MS)是一种以中枢神经系统白质脱髓鞘为主要病理改变的自身免疫性疾病,常见病变部位位于脑或脊髓,临床表现为病变多发和反复复发-缓解病程,即空间和时间多发性,以髓鞘脱失、神经胶质增生、不同程度轴索病变和进行性神经功能障碍为主要特点,常累及脑室周围白质、视神经、脊髓、脑干和小脑,尤以侧脑室体部和脊髓前角多     

Genetics for understanding and predicting clinical progression in multiple sclerosis

Introduction

Multiple sclerosis (MS) is a dys-immune disease of the central nervous system with highly variable and unpredictable long-term outcome.

State of the art

In the early 1970s association between HLA alleles and MS was established. Very recently, the power of Genome Wide Association Studies (GWAS) enabled the identification of several loci involved in immune functions as genetic risk factors in MS. Recent data suggest that common genetic variations might modulate the clinical phenotype of MS through a regulation of key pathophysiological pathways.

Perspectives

Identification of modifier genes might offer an opportunity to explore new relevant therapeutic targets and early prognostic markers. To date, studies of modifier genes in MS are numerous but results are still unclear. This research field may now benefit from large cohorts of patients available for association studies.

Conclusion

In this context, we propose a review of epidemiological and association studies of genetic modifying effect in MS.     

The genetic aspects of multiple sclerosis

The epidemiology of multiple sclerosis has been extensively investigated and two features have consistently emerged: marked geographical variation in prevalence and substantial familial clustering. At first sight, geographic variation would seem to imply an environmental cause for the disease, while familial clustering would seem to suggest that genetic factors have the predominant etiological effect. However, given that geographic variation in prevalence could result from variation in the frequency of genetic risk alleles and that familial clustering might result from shared environmental exposure rather than shared genetic risk alleles, it is clear that these crude inferences are unreliable. Epidemiologists have been resourceful in their attempts to resolve this apparent conflict between “nurture and nature” and have employed a whole variety of sophisticated methods to try and untangle the etiology of multiple sclerosis. The body of evidence that has emerged from these efforts has formed the foundation for decades of research seeking to identify relevant genes and this is the obvious place to start any consideration of the genetics of multiple sclerosis.     

Multiple sclerosis in American blacks

In the period 1968 through 1977, multiple sclerosis (MS) was diagnosed in 349 patients at the Henry Ford Hospital. Of these, 312 were accepted in the study and 53 were blacks. In this medical center where the overall population consists of approximately 50% blacks, the MS blacks comprised only 17 % of the total MS population. White and black MS patients did not differ significantly for clinical characteristics of MS or for death rates. The MS black patients were divided in two groups, Northern-and Southern-born. The mean age of migration was 11.9 years. Southern-born blacks lived an average of 20 years in the North before the symptoms of MS began. Northern-born MS patients had a 5.5 earlier age of onset and the diagnosis was made 9 years sooner when compared with the Southern-born MS blacks. The Southern-born MS group more often showed a chronic progressive course wither initially or following a few exacerbations and remissions. These findings suggest that a possible genetic predisposition, as well as a geographically determined exposure to an environmental agent, may be related not only to the risk of developing MS, but in the American blacks may also influence the age of onset, the age of diagnosis, and even the clinical course of MS.     

Cognitive rehabilitation in Multiple sclerosis

Cognitive impairments are frequent in Multiple sclerosis (MS). However, most studies about efficacy of cognitive rehabilitation interventions have been criticized in terms of methods and/or design. The aim of this study is to evaluate the efficacy of cognitive rehabilitation in MS patients with a cognitive intervention (ProCogSEP* program), compared to a control intervention (discussion program). Twenty MS patients have completed this simple blind study: 10 patients followed 13 sessions (2 hours) of the ProCog-SEP¹ program. Ten other patients followed 13 sessions (2 hours) of a discussion program (Control Group). All patients underwent neuropsychological assessment, before and after their program, in order to evaluate cognitive functions. Two neuropsychologists respectively assessed the patients and conducted the group sessions. Compared to its own baseline, ProCog-SEP Group show improvements in verbal memory [free recall (p = .02), learning (p = .002)], in visual memory [free (p = .05) and delayed recall (p = .007)], in working-memory (p = .03), in verbal fluency (p = .05) and in language (p = .01). Inter group analysis show a benefit of cognitive program mainly in verbal and visual memory, and in verbal fluencies. These results support the interest of a cognitive therapeutic management of MS patients.     

Multiple sclerosis and pain

Abstract

Despite the common belief that multiple sclerosis (MS) is a painless disease, several studies contradict this. There are a significant number of MS patients who actually suffer from painful conditions such as central and peripheral neuropathy, migraines, trigeminal neuralgia, painful tonic spasms, complex regional pain syndrome, glossopharyngeal neuralgia, and transverse myelitis. In addition, MS relapses are usually painful with many patients complaining of paroxysmal dystonia and neuropathic pain during these episodes. Additionally, treatments for MS such as use of beta-interferons may be associated with headache and pain at the injection site. The pathophysiology of pain in MS is poorly understood, but may be related to the development of demyelinating lesions involving certain neuroanatomic pathways such as the spinothalamic tract. Management of pain in MS patients is a therapeutic challenge for clinicians. Currently, various pharmacological agents such as antiepielptics, non-steroidal anti-inflammatory agents, and even corticosteroids are used to suppress various painful conditions associated with MS. Non-pharmacological procedures such as massage therapy have also been used in the treatment of MS patients. The authors present a review of recent findings in pathophysiology and management of pain in MS patients.     

Multiple sclerosis and parainfluenza 1 virus

Summary 54 cultures were established from brain tissue obtained 2–3 hrs after death from 1 case of multiple sclerosis and 30 cultures from another case. Following fusion with indicator cells in the presence of lysolecithin, a parainfluenza type 1 virus (6/94 virus) was isolated from cultures representing one plaque area in the first case and one plaque area in the second case. A cell line chronically infected with the 6/94 virus has been maintained for more than 100 passagesin vitro. A close relationship to the Sendai Hemagglutinating Virus of Japan (HVJ) is indicated from RNA-RNA hybridization and the patterns of electrophoretic mobilities of viral polypeptides. Conversely, differences in optima for growth-requirement temperatures, hemolytic activity and the capability to fuse mammalian cells, distinguishes 6/94 virus and HVJ as distinct phenotypic entities of a closely related genotype.Supported in part by funds from the National Multiple Sclerosis Society; USPHS Research Grant NS-11036 from the National Institute of Neurological Disease and Stroke and RR 05540 from the Division of Research Resources; by Deutsche Forschungsgemeinschaft AZ, Me270/10, Schwerpunkt Multiple Sklerose und verwandte Erkrankungen.     

Multiple sclerosis and Hashimoto's thyroiditis

Summary A case of multiple sclerosis and Hashimoto's thyroiditis confirmed by cytology is reported. The association of multiple sclerosis with other autoimmune diseases is infrequent but supports the immune hypothesis of the pathogenesis of multiple sclerosis. The authors suggest the inclusion of immunological tests in the screening of all patients diagnosed as having multiple sclerosis.     

Multiple sclerosis: Symptomatic treatment

Reports of new therapeutic agents designed to suppress inflammatory processes in multiple sclerosis have excited much interest but, thus far, have had little influence on symptoms, disability and handicap in patients. The clinical application of recent advances in physical, pharmacological and surgical approaches to management will, at least in the medium-term future, therefore offer significantly greater opportunities for improving the quality of life of patients with multiple sclerosis. Here, symptomatic treatment of the whole range of difficulties encountered by patients with multiple sclerosis is reviewed in the context of the multidisciplinary strategy crucial to an optimal outcome.     

多发性硬化与乙肝病毒感染

应用ELISA法,配对检测46例(确诊和拟诊各23例)多发性硬化(MS),43例其它神经科疾病(其它组)和34例非神经科病对照组的血清和CSF的HBsAg,抗—HBs,HBeAg,抗—HBe和抗—ABc。结果为:(1)血清中有HBV感染者:确诊MS组18例(78％),可疑MS组13例(56％),其它组13例(30％),对照组16例(47％)。(2)各组血清中仅含有抗—HBs和/或抗—HBe阳性者在确诊MS组的阳性率与其它组及对照组有极显著性差异(P<0.01)。本研究提示:MS血清中HBV感染显著增高。     

多发性硬化诊断与治疗进展

随着越来越多的疾病修正药物应用于临床,多发性硬化的治疗已向前迈出了可喜的一步,同时也为患者提供了更多的选择。本文重点介绍多发性硬化当前临床研究热点,包括临床表现、辅助检查、诊断标准和治疗进展等内容。。     

Multiple sclerosis: infectious hypothesis

In the search for the etiology of multiple sclerosis (MS), consideration has been given in turn to infectious agents, to genetic markers, and more recently to a combination of genetic and environmental factors, but after over a century of research, a definite conclusion has not been reached. The hypothesis that an infectious agent is responsible for triggering MS is perhaps one of neurology's most enduring notions. Interest in an infectious etiology has waxed and waned over the last two centuries since Pierre Marie first proposed that MS often starts as an infectious process. The possible role of infectious agents has been suggested by: the different geographic gradients in frequency among Caucasians; changes in prevalence due to migration, and the effect of age at migration; the suggestion of epidemics and clusters of cases in some small communities; and the remarkably low degree of concordance in monozygotic twins. The infectious hypothesis is strongly supported by the different temporal patterns of the disease in different geographic areas. Incidence rates have remained stable in some areas, but have changed over time in other regions. On the other hand, the hypothesis is hampered by the lack of evidence for a specific agent, and the weakness of the results of analytical studies that have tested the association between MS and previous infections. Despite these drawbacks, recent studies of a few select pathogens suggest that viral or bacterial infections or reactivations may trigger clinical exacerbations in relapsing-remitting MS.