J. Reboul

Familial factors influence disability in MS multiplex families

Background: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease. Objective: To determine the contribution of familial factors to the clinical expression of MS. Methods: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features). Results: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03). Conclusion: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP)

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome 1q31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome 1q31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPP.

Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

A systematic study of oligodendrocyte growth factors as candidates for genetic susceptibility to MS

Objective: To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis. Background: Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS. Methods: Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA. Results: Negative results were obtained for all candidate genes. The lower limits of the relative risk (λs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFβ3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA. Conclusions: Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFβ3, the only gene highlighted by this study, deserves further analysis.

Intrathecal Synthesis of β2-Microglobulin and Lysozyme: Differential Markers of Nervous System Involvement in Patients Infected with Human Immunodeficiency Virus Type 1

beta 2-Microglobulin and lysozyme were determined in paired serum and cerebrospinal fluid samples from 137 patients, using immunofluorometry and ELISA, respectively. Of these patients, 54 were infected by human immunodeficiency virus type 1 (HIV1) (including 20 AIDS dementia patients), 73 were HIV1-seronegative with neurological diseases (meningitis (n = 10), multiple sclerosis (n = 29), other neurological diseases (n = 34)) and 10 were controls. Intrathecal synthesis of beta 2-microglobulin occurred in each group. Conversely, lysozyme intrathecal synthesis was found only in meningitis (10/10) and in HIV1-infection (24/54). A pathological increase in beta 2-microglobulin intrathecal synthesis (> or = 2 mg/l) was observed in 45 patients (34 HIV1-infected patients and 11 HIV1-seronegative patients with neurological diseases). Serum concentration and intrathecal synthesis of beta 2-microglobulin were correlated only in the 20 AIDS dementia patients. The cerebrospinal fluid beta 2-microglobulin and lysozyme concentrations were correlated in the 54 HIV1-infected patients only. Blood CD4 + T-cell count was correlated negatively with beta 2-microglobulin intrathecal synthesis but not with lysozyme intrathecal synthesis. These data suggest that in the absence of any central nervous system opportunistic process the increase of beta 2-microglobulin intrathecal synthesis (> or = 2 mg/l) may be a reliable marker of central nervous system involvement in HIV1-infected patients. Intrathecal synthesis of lysozyme was related principally to HIV1-encephalitis and central nervous system opportunistic processes.

Exclusion of the candidate locus FSP1 in six families with late-onset autosomal dominant spastic paraplegia.

Hereditary spastic paraplegias are neurological hereditary conditions of unknown aetiology. In pure spastic paraplegia, most of the pedigrees display an autosomal dominant mode of inheritance. A gene for pure autosomal dominant spastic paraplegia (ADSP), termed FSP1, was mapped to chromosome 14q in a large pedigree with early-onset disease. This locus was tested by linkage analysis in six large French kindreds of ADSP with late-onset disease, using four microsatellites spanning a 9 cM interval including FSP1. FSP1 could be excluded in five of the six families, while no evidence for linkage was found in the remaining family. These results suggest that FSP1 is not involved in late onset ADSP, at least in the six families studied.

Frequency and relevance of IgM intrathecal synthesis in multiple sclerosis

Using a new ELISA method we have measured the IgM concentration in the serum and the cerebrospinal fluid CSF from 110 neurological patients. Among there, 41 had multiple sclerosis (MS), 48 other inflammatory diseases (OID), including 30 AIDS, and 21 non‐inflammatory neurological diseases (NID). A highly significant correlation was established between results with native IgM and the dithiothreitol reduced IgM. An intrathecal synthesis (ITS) of IgM was detected using the CSF IgM/CSF albumin ratio, the IgM index and a quantitative formula in 33 patients: nine MS, 23 OID (including 18 AIDS) and one NID. The frequency of IgM ITS was 22% in MS patients, 48% in the OID (60% in AIDS) and 5% in the NID groups. This ITS was not impaired by an increase in serum IgM concentration or by a blood–CSF barrier damage. These facts confirm that intrathecal immunity is not a “steady‐state” related to the general immunity but a specific response restricted to the central nervous system. Conversely, CSF IgM increase and IgM ITS were closely related (p < 10−6). In addition, IgM ITS and IgG ITS were found to be highly correlated in OID, especially in AIDS patients: such correlation was not observed in the MS group. No significant correlations were observed between IgM ITS and any of the clinical parameters in MS patients. These results suggest the probable specificity of IgM ITS in MS patients.

Genetic susceptibility to multiple sclerosis: a candidate gene approach

5 9 3 Relevance of an Intronie Polymorphism in Myasthenia Gray(s: a Preliminary Study C. Ferri, V. Casadei, F. Sciacea, SanRaffaele Science Institute, Italy, D. Franc(oats, G. eiccolo, lstituto Neurologico Mondino Pavia, Italy, L.M.E. Grim aldL San Raffaele Science Institute, Italy 5 9 6 Association Between Susceptibility to Asia Type (Opt(e-spinal Form) of Multiple Sclerosis and HLA-DPBl*0501Allde in the Japanese J. K ir& Kyushu University, Japan, H. lto, Kumamoto University, Japan, Y. Kawano, I. Horiuchi, Kyushu University, Japan, Y. Nishimura, Kurnamoto University, Japan, K. Yamasaki, K yushu Univer,~ity, Japan