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Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established.Objective: We aimed to identify genetic variants associated with progressive MS (PrMS).Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10−4) in two independent sets of primary progressive MS cases and controls.Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934T, pcombined=6.7×10-16, OR=2.34, 95% CI=1.90–2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343G, pcombined=2.4×10-5, OR=0.70, 95% CI=0.59–0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a ‘cis’ effect on RNA expression in lymphoblastic cell lines, but pathway analyses of ‘trans’ effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02).Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role. [ABSTRACT FROM PUBLISHER]

Abstract: Identification of novel targets and biomarkers, such as microRNAs, is extremely helpful to understand the pathogenetic mechanisms in a disease like multiple sclerosis (MS). We tested the expression profile of 1145 microRNAs in peripheral blood mononuclear cells (PBMCs) of 19 MS patients and 14 controls, and we further explored their function by performing a whole-genome mRNA profiling in same subjects and using bioinformatic prediction tool. A total of 104 miRNAs have been identified as deregulated in MS patients; 2/10 which ranked highest (let-7g and miR-150) have been validated in a replication sample, leading to the identification of putative target genes. [Copyright &y& Elsevier]

Fatigue is considered to be one of the most common and disabling symptoms among individuals with multiple sclerosis (MS). The aim of this study is to investigate if an intensive, short-term inpatient rehabilitation program is able to improve fatigue in MS, and if fatigue is able to negatively influence the clinical and functional outcome of rehabilitation in MS. One-hundred eighty six consecutively recruited MS patients underwent an intensive, short-term inpatient rehabilitation program. Sixty-four of them were selected for this study according to our inclusion criteria and compared to a control group of 22 MS patients who did not follow a rehabilitation program. We measured fatigue symptoms with the Fatigue Severity Scale (FSS) before and after rehabilitation, and classified patients into fatigued (FMS) in the case of an FSS score ≥36 and into non-fatigued MS (NFMS) in the case of an FSS <36. Expanded Disability Status Scale (EDSS) and Functional Independence Measure (FIM) were used as clinical outcome measures of the efficacy of the rehabilitation program. In our sample, an intensive, short-term rehabilitation treatment is able to determine a significant reduction of fatigue symptoms compared to untreated MS patients ( p < 0.0001); however, the presence of fatigue at the beginning of the rehab program seems not to have any impact on the clinical and functional outcome of rehabilitation. An intensive inpatient rehabilitation trial decreases symptom of fatigue in MS patients; furthermore fatigue seems not to modify the amelioration of disability and impairment determined by a rehabilitation program. [ABSTRACT FROM AUTHOR]

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63. [ABSTRACT FROM AUTHOR]

Background and purpose The Rio score ( RS) and the modified Rio score ( MRS) are two scoring systems that can identify the early predictive factors of disability progression in relapsing−remitting multiple sclerosis ( RRMS) patients treated with interferon-β ( IFN-β). The objective of the study was to validate the usefulness of the RS and MRS in a large cohort of multiple sclerosis patients treated with IFN-β in daily clinical practice. Methods The analysis included a cohort of RRMS patients treated with different formulations of IFN-β for at least 1 year. The RS and MRS were used to classify the patients after 1 year of treatment. Multivariate analysis was performed to identify predictive variables of suboptimal response at 5 years, defined as Expanded Disability Status Scale confirmed progression or switching to a second-line therapy. Results Sixty-nine of 416 included patients were considered as suboptimal responders at 5-year evaluation. The possible score range was 0-3. A higher risk of suboptimal response was found for RS and MRS in the presence of ≥2 scores (hazard ratio 3.0, P = 0.002, and hazard ratio 5.0, P < 0.0001, respectively). Conclusions Our study confirmed, in a daily clinical setting, that MRS had a better specificity and accuracy than RS in identifying the patients who will have a poor response to long-term IFN-β treatment. [ABSTRACT FROM AUTHOR]

Background: Mitoxantrone (MTX) is an immunosuppressive drug approved for multiple sclerosis (MS) treatment. Objective: The aim of this study is to evaluate and to compare the clinical and neuroradiological responses to MTX in relapsing—remitting (RR) and secondary progressive (SP) MS patients.Methods: We conducted a retrospective, non-randomized, open-label, observational study to evaluate the clinical and neuroradiological response to the drug in 79 patients with RR MS and 210 patients with SP MS.Results: A statistically significant reduction (p < 0.001) in the number of relapses was observed during MTX treatment and in the year after in both RR and SP MS patients. On the contrary, an opposite behavior in terms of disease progression was found in RR compared with SP MS patients, resulting in a statistically significant improvement of the Expanded Disability Status Scale score during the MTX treatment (p < 0.001) and in the year after (p < 0.001) for RR MS patients compared with a continuous, although mild, worsening of the disability in SP MS patients (p < 0.001). Finally, a significant reduction (p < 0.001) of new Gd-enhanced lesions in both RR and SP MS patients was observed in a subgroup of 224 individuals who underwent a brain MRI evaluation before and after MTX treatment.Conclusions: MTX should be considered as an effective therapeutic option in RR MS patients with evidence of relevant disease activity, but the potential life-threatening adverse events and the overall benefit—risk ratio must be carefully evaluated at individual patient level. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex disease triggered by environmental and genetic agents, and clinically characterized by bout onset (BOMS) or progressive onset (PrMS). We collected clinical and familial aggregation data in a cohort of 518 Italian PrMS patients, and compared with 400 BOMS cases. An increased prevalence of MS in first-degree relatives of Italian PrMS was found. Familial aggregation is not influenced by probands' clinical course, and there is no disease course concordance within MS families. These data are useful in counseling MS patients affected with different clinical courses of the disease. [ABSTRACT FROM AUTHOR]