Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models

Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial

Background: Evidence supporting the effectiveness of aerobic training, specific for fatigue, in severely fatigued patients with multiple sclerosis (MS) is lacking. Objective: To estimate the effectiveness of aerobic training on MS-related fatigue and societal participation in ambulant patients with severe MS-related fatigue. Methods: Patients (N = 90) with severe MS-related fatigue were allocated to 16-week aerobic training or control intervention. Primary outcomes were perceived fatigue (Checklist Individual Strength (CIS20r) fatigue subscale) and societal participation. An improvement of ≥8 points on the CIS20r fatigue subscale was considered clinically relevant. Outcomes were assessed by a blinded observer at baseline, 2, 4, 6 and 12 months. Results: Of the 89 patients that started treatment (median Expanded Disability Status Scale (interquartile range), 3.0 (2.0–3.6); mean CIS20r fatigue subscale (standard deviation (SD)), 42.6 (8.0)), 43 received aerobic training and 46 received the control intervention. A significant post-intervention between-group mean difference (MD) on the CIS20r fatigue subscale of 4.708 (95% confidence interval (CI) = 1.003– 8.412; p = 0.014) points was found in favour of aerobic training that, however, was not sustained during follow-up. No effect was found on societal participation. Conclusion: Aerobic training in MS patients with severe fatigue does not lead to a clinically meaningful reduction in fatigue or societal participation when compared to a low-intensity control intervention