The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

The identification of activated T cells in the brain of individuals with multiple sclerosis (MS) indicates that these cells are critical in the pathogenesis of this disease. In an attempt to elucidate the nature of the lymphocytic infiltration, we used the polymerase chain reaction to amplify T-cell antigen receptor (TCR) V alpha sequences from transcripts derived from MS brain lesions. In each of three MS brains, only two to four rearranged TCR V alpha transcripts were detected. No V alpha transcripts could be found in control brains. Sequence analysis of transcripts encoded by the V alpha 12.1 region showed rearrangements to a limited number of J alpha region segments. These results imply that TCR V alpha gene expression in MS brain lesions is restricted.

This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.

We report a trial of minocycline in people with relapsingremitting multiple sclerosis (RRMS) that evaluates safety and estimates its effect on magnetic resonance imaging (MRI). Ten subjects with active RRMS received oral minocycline 100mg twice daily for 6 months after a 3-month run-in period. A 30-month treatment extension is ongoing. Clinical and laboratory assessments were completed at enrollment and then at 3-month intervals. MRI was performed at enrolment and then every 4 weeks. Patients without MRI activity during the run-in phase continued in the study, including completion of all MRI scans, to confirm lack of MRI worsening. The primary outcome was change in the mean number of gadolinium-enhancing lesions per scan during the first 6 months of treatment compared with the run-in period (Wilcoxon signed rank test, two-sided alpha of 0.05).Eighty percent of participants were women. Mean age was 42.8 years (SD 4.0). Mean MS duration was 11.8 years (SD 6.3). Median baseline extended disability status score (EDSS) was 2.5 (range 1.5-5.5). Mean relapse number in the two prior years was 2.6 (range 2-4). During the trial, there were no serious adverse events or laboratory abnormalities and no change in EDSS. Three relapses occurred during the run-in phase, five during the first 6-month treatment phase, and none during the following 6 months. On-treatment relapses included one associated with MRI enhancement (during month 1), two without enhancement (one scan was a postrelapse scan, and one scan was missed because the patient was taking steroids), and two mild truncal sensory attacks unassociated with MRI enhancement (both at 5 months).Mean total enhancing lesion number decreased from 1.38 lesions per scan during the run-in phase to 0.22 during the treatment phase (z ϭ 2.204, p ϭ 0.0276), representing a relative reduction of greater than 84%. During the run-in phase, 47.5% of MRI scans (19/40) were active, whereas 9.3% (5/54) were active during the minocycline phase. There were no active scans after month 2 (Fig) and no new active lesions after month 1. Although five patients accounted for all MRI activity before and after treatment, all patient data were included in all analyses.This study provides preliminary evidence that minocycline may be useful in MS and supports its safety. The MRI results are consistent with the ability of minocycline to inhibit matrix metalloproteinases, 1,2 thus reducing lymphocyte access to the central nervous system. In addition, minocycline may have other beneficial properties including neuroprotection.3 Small sample size and short trial duration limit conclusions, but reduced MRI activity is encouraging and calls for definitive studies to establish minocycline efficacy in MS. Departments of

No abstract