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Background: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia.Methods: Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates.Results: Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites.Discussion: The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture. [ABSTRACT FROM AUTHOR]

Objectives: To assess the potential contribution of genetic factors to clinical phenotype in multiple sclerosis.Methods: Using a cohort of 262 pairs of coaffected siblings from 250 families with multiple sclerosis, intersibling concordance analysis was used to explore underlying genetic mechanisms in disease pathogenesis by assessing parameters of disease course, clinical presentation, age and year of onset, and measures of disability and handicap.Results: Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom. One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant. However, course type was identical in 50% of the sibling pairs (kappa=0.17 (95% confidence interval (95% CI) 0.08 to 0.26)) indicating a significant result. Severity of the disease at assessment, using the Kurtzke and CAMBS scales, demonstrated that whereas there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (kappa=0.11 (95% CI 0.04 to 0.19)), progression (kappa=0.09 (95% CI 0.01 to 0.18)) and handicap (kappa=0.08 (95% CI 0.02 to 0.14)).Conclusions: Within a sibship, the clinical presentation tends to be different. However, once established, concordance is more likely to be seen for the ultimate course, leading in the end to similar disability and handicap scores. These results are consistent with the hypothesis that genes influence both disease susceptibility and evolution in multiple sclerosis. [ABSTRACT FROM AUTHOR]

The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families with multiple sclerosis were genotyped and exon 3 and exon 4 of the gene were directly sequenced in a subset of the index members from these families (n=93). No evidence for association was found in any of the three markers and none of the commoner mutations causing CADASIL were found in the sequenced patients. [ABSTRACT FROM AUTHOR]

Objective: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination., Methods: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients., Results: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077)., Conclusion: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation., Competing Interests: Competing interests: Dr SR has received research funding from the National Health and Medical Research Council, the Petre Foundation and the Brain Foundation (Australia). Dr SM has received a scholarship from the National Health and Medical Research Council (Australia) and funding from the National Blood Authority IVIg grant. SB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen-Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen-Idec. JL-S has accepted travel compensation from Novartis, Biogen and Merck-Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Health Care, Biogen, Sanofi-Genzyme, Merck, Novartis and Teva. SR reports grants and personal fees from Sanofi-Genzyme, personal fees and departmental support from the Government of Australia, Baxter, Biogen, CSL and Merck; and departmental support from Novartis, outside the subject of the submitted work. Associate Professor FB has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia and the National Health Medical Research Council (Australia). RD has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia, the Petre Foundation and the National Health Medical Research Council (Australia). Dr RCD has received honoraria from Biogen-Idec as an invited speaker. Dr JLB has received compensation for education travel, honoraria for talks and advisory boards from Biogen, Teva, Merck-Serono, Sanofi-Genzyme, Novartis and Roche. Dr AC has received honoraria for attendance at advisory boards from Biogen and is an investigator in clinical trials sponsored by Biogen and Pfizer. Dr PC has accepted travel compensation from, Biogen and Merck Serono, and fellowship funding from Novartis/Biogen. Associate Professor CLF has received payment from Roche as a consultant. Dr MPM has received travel grants, speaking honoraria and unconditional research funding from Bayer, Biogen and Merck. Professor IES is supported by NHMRC Program Grant (1091593, 2016–2020) and Senior Practitioner Fellowship (1104831, 2016– 2020). IES serves on the editorial boards of Neurology and Epileptic Disorders; may accrue future revenue on a pending patent report: therapeutic compound; has received speakers honoraria from Athena Diagnostics, UCB, GSK, Eisai and Transgenomics; has received scientific advisory board honoraria from Nutricia and GSK, has received funding for travel from Athena Diagnostics, UCB and GSK and receives/has received research support from the NHMRC, ARC, NIH, Health Research Council of New Zealand, March of Dimes, the Weizmann Institute, CURE, US Department of Defense and the Perpetual Charitable Trustees. Dr EY is supported by an NHMRC Early Career Fellowship (APP1073323)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)