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PubMed1996

A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).

Chromosome Mapping↗

PubMed2004

Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference to systemic sclerosis and multiple sclerosis.

Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.

Anthracyclines↗

PubMed1999

Chromosome 17q22-q24 and multiple sclerosis genetic susceptibility. American-French Multiple Sclerosis Genetic Group.

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.

Chromosome Mapping↗

PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON-associated genes.

The occurrence of mitochondrial mutations with primary pathogenic significance for Leber's hereditary optic neuropathy in patients with a multiple sclerosis-like phenotype and the preferential maternal transmission points to an involvement of the mitochondrial genome in conferring increased susceptibility to MS. To evaluate the link between MS and mtDNA variations we investigated a total of thirteen children with MS as well as twenty controls by sequencing eight mitochondrial encoded genes which are known to be the loci for LHON-associated mutations. Numerous synonymous nucleotide substitutions and common polymorphisms were excluded from comparative analyses. No primary LHON mutations were found. Secondary LHON mutations were identified more frequently in control subjects than in the children with MS. The remaining eight discrete missense mutations were chosen for further characterization. Only two of them were found in more than one patient. Our results suggest that nucleotide substitutions within the ND1, ND2, ND4, ND5, ND6, COI, COIII or cytochrome b genes of mtDNA do not contribute to the etiology of typical MS. However, the association of LHON mutations with visual impairment in MS as well as the relationship between phenotypic diversity in certain subgroups of patients with individual mtDNA genotypes merits further investigations.

Adolescent↗

PubMed1988

[Early detection of multiple sclerosis: MR findings in the initial manifestations of multiple sclerosis].

The MR results in 21 patients showing the initial manifestations of multiple sclerosis (MS) were compared with those in 45 patients with a long history of MS. As in the old cases, MR proved a very sensitive technique during the early manifestations, with abnormal findings in 20 out of the 21 patients. The relatively characteristic MR findings in long-standing MS (predominant peri-ventricular involvement with a relatively typical pattern) was seen in the early stages is only rare cases. The value of MR during the initial manifestations of MS is in cases where the clinical findings are not conclusive and laboratory diagnosis (evoked potentials, CSF findings) are indefinite. In these patients the findings of multiple lesions in the brain can confirm the suspected diagnosis of MS.

Adult↗

PubMed1990

Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors.

A panel of 20 human myelin basic protein (hMBP)-specific T-lymphocyte lines was generated from the peripheral blood of eight multiple sclerosis (MS) patients and two healthy donors, most of them expressing the HLA-DR2 haplotype, which is associated with an increased susceptibility to MS. Using HLA-DR gene-transfected mouse L-cell lines as antigen-presenting cells, we established that of the 20 hMBP-specific T-lymphocyte lines, 7 were restricted by the DR2a gene products of the DR2Dw2 haplotype. Four T-cell lines recognized hMBP in the context of the DR2b products of the DR2Dw2 haplotype. DR2b-restricted T-cell responses were demonstrable only in T-cell lines derived from MS patients. The hMBP epitopes presented by the DR2a heterodimer were mapped to peptides covering amino acid residues 1-44, 76-91, 131-145, or 139-153 and to a region spanning the thrombin-cleaved bond at Arg130-Ala131. DR2b-restricted T-cell lines recognized epitopes within amino acids 80-99 and 148-162. Peptide 139-153 was also presented in the context of HLA-DR1 molecules. Our data show that (i) in MS patients both the DR2a and DR2b products of the DR2Dw2 haplotype function as restriction elements for the myelin autoantigen hMBP, (ii) the DR2a molecule presents at least five different epitopes to hMBP-specific T lymphocytes, and (iii) anti-hMBP T-cell lines derived from individual donors can differ in their antigen fine specificity as well as in their HLA restriction.

Adult↗

PubMed1997

Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis.

The partial molecular characterization of multiple sclerosis (MS)-associated retrovirus (MSRV), a novel retrovirus previously called LM7, is reported. MSRV has been isolated repeatedly from leptomeningeal, choroid plexus and from Epstein-Barr virus-immortalized B cells of MS patients. A strategy based on reverse transcriptase PCR with RNA-purified extracellular virions yielded an initial pol fragment from which other regions of the retroviral genome were subsequently obtained by sequence extension. MSRV-specific PCR primers amplified a pol region from RNA present at the peak of reverse transcriptase activity, coinciding with extracellular viral particles in sucrose density gradients. The same sequence was detected in noncellular RNA from MS patient plasma and in cerebrospinal fluid from untreated MS patients. MSRV is related to, but distinct from, the endogenous retroviral sequence ERV9. Whether MSRV represents an exogenous retrovirus with closely related endogenous elements or a replication-competent, virion-producing, endogenous provirus is as yet unknown. Further molecular epidemiological studies are required to determine precisely the apparent association of virions containing MSRV RNA with MS.

Amino Acid Sequence↗

PubMed1998

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.

Alleles↗

PubMed2002

Interictal EEG, hippocampal atrophy, and cell densities in hippocampal sclerosis and hippocampal sclerosis associated with microscopic cortical dysplasia.

The EEG characteristics of isolated hippocampal sclerosis (HS) and HS associated with other types of temporal lobe pathology are not well defined. The pathologic substrate may be an important variable in determining seizure-free outcome. The objective of this study was to define the distribution of epileptiform discharges in patients with HS and HS associated with microscopic dysplasia, and to examine their relationship with hippocampal atrophy and cell loss. Thirty-four patients (15 women and 19 men; mean age, 30.6 +/- 11.2 years), all with good outcomes after temporal lobectomy (Engel classes I and II), were included. The characteristics studied were frequency and distribution of spikes, MRI-based hippocampal volume ratios, and quantitative hippocampal cell density in various subregions. The isolated HS group showed a trend to a higher percentage of epileptiform discharges maximal at the anterior temporal electrodes (89.87 +/- 17.0%; 79.5 +/- 28.2% in the dual-pathology group). The isolated HS group had, on average, significantly more cell loss (P < 0.001). There was a significant negative correlation between the amount of cell loss in the CA1 area and both anterior temporal spikes and hippocampal ratios (P < 0.05). Isolated HS and dual pathology show minimal differences in interictal spike distribution and frequency. More widespread spike distributions in severe isolated HS compared with patients with less cell loss is probably the result of less organized limbic circuitry.

Adult↗

PubMed1998

Immunohistochemical localization of brain-derived neurotrophic factor in the spinal cords of amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis patients.

Brain-derived neurotrophic factor (BDNF) has a trophic effect on several neuronal subtypes including motor neurons. To localize and assess BDNF in the human spinal cord with particular reference to amyotrophic lateral sclerosis (ALS), we immunohistochemically studied spinal cords from 8 ALS and 13 non-ALS patients. Punctate staining for BDNF was observed in neuronal somata and proximal processes of large-sized anterior horn cells of non-ALS patients, as were distal axons immunolabeled in the neuropil. The same immunostaining pattern was found in the anterior horn cells of ALS patients. Neurons of the dorsal nucleus of Clarke, intermediolateral nucleus, and posterior horn sensory system were also stained in both groups. The results suggest that BDNF may act widely as a trophic factor in the human spinal cord, and motor neurons in ALS patients might be sufficiently supplied with endogenous BDNF from other neuronal subpopulations in the spinal cord.

Adult↗

PubMed2006

Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is a multi- system disorder with complex genetics. The neurodevelopmental manifestations of TS are responsible for considerable morbidity. The prevalence of epilepsy and intellectual disabilities among individuals with TS have been well described. Ours is the first study that explores the prevalence and pattern of psychopathology in a population-based sample of adults with TS. METHODS: Sixty subjects were identified through a capture-recapture analysis of TS. Information was gathered as to seizure history, cognitive functioning (WISC-III) and psychopathology (SADS-L, SAPPA). Lifetime psychopathology was categorized according to Research Diagnostic Criteria. The overall pattern of mental illness (MI) was examined as well as how this varied with IQ and seizure history. RESULTS: Twenty-four (40.0%) subjects had a history of MI. The most common diagnosis was that of an affective disorder [18 (30.0%)], the majority of which were major depressive episodes. Alcoholism [4 (6.7%)] and anxiety disorders [3 (5.0%)] were the next most common diagnoses. Two (3.3%) subjects had had a tic disorder. Only one individual had a diagnosis of schizophrenia. MI was found in 75.0% of those with a history of epilepsy and 37.5% of those without epilepsy. MI was significantly more prevalent in those with a full-scale IQ above 70. CONCLUSIONS: A significant proportion of adult with TS experience MI. MI was significantly more [corrected] prevalent in subjects with a full-scale IQ above 70. Reasons for such a finding are explored, and related methodological considerations for future research outlined.

Adult↗

PubMed1982

Multiple sclerosis-lymphocyte transformation with multiple sclerosis and normal brain myelin basic protein and subcellular fractions.

Possible sensitisation of peripheral blood mononuclear cells from multiple sclerosis (MS) patients was studied in the presence of both normal and MS brain subcellular fractions. Myelin, synaptosomal and microsomal fractions and myelin basic protein were prepared by sucrose density gradient centrifugation from normal and MS brain. These preparations were added to mononuclear cell microcultures from the peripheral blood of nine acute and six chronic MS patients, 10 patients with other neurological diseases and 10 normal subjects. There was no significant increment in the peripheral blood mononuclear cell transformation of any of the acute MS patients with any of the fractions. Therefore there is no evidence that immunity to antigens in any of the fractions of MS or normal brain is of primary pathogenetic importance. A small increment in peripheral blood mononuclear cell transformation in the presence of several fractions was observed in two of six chronic MS patients, which might indicate the development of a secondary immune response after prolonged disease.

Acute Disease↗

PubMed1988

Epidemiology of multiple sclerosis: incidence and prevalence rates in Denmark 1948-64 based on the Danish Multiple Sclerosis Registry.

The Danish Multiple Sclerosis Registry (DMSR) is a national register based upon the ethnically homogeneous Danish population of about 5 millions. The DMSR was founded in 1956 following a nationwide Danish prevalence survey of MS in 1949 and a continuous registration of incident cases of MS since January 1, 1948. Included in DMSR are all Danish cases of MS (or suspicion of MS) diagnosed by a neurologist or a department of neurology. The sources of notification are the 22 neurological departments in Denmark, the National Patient Registry, the neuropathological departments, the Registry of Causes of Death, and, up to 1975, the Disablement Insurance Court. Notified cases which do not comply with the standardized diagnostic criteria of the DMSR are excluded. An estimate of the completeness of the DMSR is 90-95% and the validity is around 94%. Age- and sex-specific incidence rates of MS for the interval 1948-64 are presented. The crude annual incidence rate of MS in Denmark was in the year 1948-64 4.42 per 100,000 population, 22% higher in females than males. There was a significant geographical variation of incidence rates and a significant downward trend in incidence rates during the interval, whereas the prevalence rates showed a slight increase.

Adolescent↗

PubMed2007

Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score.

AIM: To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS). METHODS: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). RESULTS: The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001). CONCLUSIONS: The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.

Adult↗

PubMed1992

Treatment of lower urinary tract dysfunction in patients with multiple sclerosis. Committee of the European Study Group of SUDIMS (Sexual and Urological Disorders in Multiple Sclerosis)

Bladder symptoms in patients with multiple sclerosis (MS) are common and usually arise as a result of spinal lesions which interrupt the neural pathways connecting the pontine micturition centre to the sacral spinal cord. Thus these symptoms are particularly likely to occur in those with lower limb neurological deficits. Fortunately bladder dysfunction in MS is rarely associated with serious upper tract disease so that the problem is usually one of symptomatic management. Lower urinary tract symptoms may be both "irritative" or "obstructive" in nature and can be explained in terms of underlying detrusor hyperreflexia and incomplete bladder emptying. Treatment is aimed at minimising both these effects. Oral anticholinergic medication can be effective in reducing detrusor hyperreflexia and intermittent catheterisation is used to reduce abnormally high post micturition residual volumes. With this simple treatment, often used in combination, many less severely affected patients with MS can gain considerable improvement in controlling urinary continence.

Administration, Oral↗

PubMed2003

Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre.

BACKGROUND: The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial. OBJECTIVES AND METHODS: Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy. RESULTS: During a median treatment period of 26 months (range 2-85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment. CONCLUSION: IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression.

Adjuvants, Immunologic↗

PubMed2005

CD30 antigen and multiple sclerosis: CD30, an important costimulatory molecule and marker of a regulatory subpopulation of dendritic cells, is involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. The role of IFNbeta-1a in the treatment of multiple sclerosis.

OBJECTIVES: The immunological effect of CD30 on dendritic cells (DCs) was examined in a comparative study of patients with relapsing-remitting multiple sclerosis (RRMS). The patients were divided into two groups on the basis of interferon (IFN)beta-1a treatment: IFNbeta-1a-treated patients and untreated patients. We have already shown that CD30 is a marker of cells involved in the regulation of the balance between TH1 and TH2 immune responses and so the aim of this study was to confirm this role in DCs and, consequently, to clarify the immunopathological mechanisms of MS and the causes of immunosuppressive drug failure. METHODS: We studied network interactions between soluble (s) CD30 and TH1/TH2 cytokines in the supernatants of CD14+-derived immature DC (IDC) and DC cultures from treated and untreated patients. Network interactions between the sCD30 and cytokines in IDC and DC supernatants were also evaluated in relation to TH1/TH2 cytokine serum levels. RESULTS: Our overall results show that CD30 is expressed on IDCs and DCs, indicating an immunological role in resting and activated physiological conditions. This role would appear to be the regulation of the resting and activated physiological balance between the TH1/TH2 immune functions as abnormal increases in sCD30 levels result in impaired regulation. Further studies are undoubtedly required to clarify this situation. IFNbeta-1a treatment was found to determine a fall in sCD30 levels, leading to the restoration of the normal functional selection of IDCs from progenitor cells and the regulation of the TH1/TH2 network balance. However, IFNbeta-1a treatment may also be responsible for the in vivo suppression of CD30-mediated TH1-DC functions in immune activation. TH1-DC functions are involved in the induction of T-regulatory cells for the physiological deletion of self-aggressive cells. CONCLUSION: We conclude that CD30 is an important costimulatory molecule and marker of a regulatory subpopulation of DCs which induces and modulates immune cells involved in the maintenance of the physiological balance between TH1/TH2 immune responses and tolerance. Elucidating the mechanisms restoring DC and T-regulatory cell function could lead to more effective therapy and strategies for the prevention and treatment of immunopathological conditions such as autoimmunity, transplant rejection, allergy and tumors.

Adult↗

PubMed1995

Epidemiology of multiple sclerosis in US veterans. 6. Population ancestry and surname ethnicity as risk factors for multiple sclerosis.

Previously, we studied the effect of population ancestry on the risk of multiple sclerosis (MS) in US veterans of World War II, comparing by state 1980 US census ancestry data with MS case/control ratios. Here, the joint effects of population ancestry and surname-derived ethnicity on MS risk are examined in the same series. Census data are used again to characterize the population ancestry of the state from which each subject entered active duty (EAD)--that is, the proportions of the populace reporting various ancestries--and subjects were also individually categorized into a single ethnic group, without knowledge of case/control status, based on surname. In this study population, categorized ethnicity was strongly correlated with population ancestry, as expected. Although univariate analyses showed statistically significant associations between MS risk and several surname-derived ethnicities and ethnic groups, when residence at EAD was accounted for as well, there was almost no ethnic variation in MS risk. A logistic regression analysis further showed that variations in MS risk are associated most strongly with latitude and population ancestry group; in particular, subjects who entered military service from states with higher proportions of Swedish or French ancestry had higher risks of MS. After adjustment for characteristics of place, the only significant individual ethnicity factor found was Southern European ethnicity. In general, we conclude that an individual's ethnicity seems to be of less relative importance in determining MS risk than is the population ancestry of the state of EAD. These findings underscore the fact that MS is a disease of place, with 'place' including not only attributes of the locale (e.g., latitude), but also of its populace (e.g., ancestry).

Adult↗