Cerebral hypomyelination associated with biallelic variants of FIG4

The lipid phosphatase gene FIG4 is responsible for Yunisâ Varón syndrome and Charcotâ Marieâ Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same Gâ >â A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in readâ through from exon 20 into intron 20 and truncation of the final 115 Câ terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149294/1/humu23720-sup-0001-Supp_Mat_Lenk_2018.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149294/2/humu23720.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149294/3/humu23720_am.pd

Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort

Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery

Background: Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. Objectives: The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. Methods: Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing-remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing-remitting multiple sclerosis patients were evaluated using linear mixed models. Results: Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline (p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test (p<0.001). In relapsing-remitting multiple sclerosis patients, reaction time slowed over 12 months (p<0.001) for the CogState Brief Battery Detection (mean change -34.23 ms) and Identification (-25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. Conclusions: The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting

The MSBase pregnancy, neonatal outcomes, and women's health registry.

Family planning and pregnancy decisions are key considerations in the management of women with multiple sclerosis (MS), who are typically diagnosed between the ages of 20-40 years. Despite a strong evidence base that pregnancy is not harmful for women with MS, many knowledge gaps remain. These include: best management strategies through pregnancy in the era of highly effective disease-modifying therapies (DMT); foetal risks associated with DMT exposure in utero or in relation to breastfeeding; knowledge base around the use of assisted reproductive technologies; the long-term impact of pregnancy on disease outcomes, as well as the impact of long-term DMT use on women's health and cancer risk. Here, we describe the new MSBase pregnancy, neonatal outcomes and women's health registry. We provide the rationale for, and detailed description of, the variables collected within the registry, together with data acquisition details. The present paper will act as a reference document for future studies

Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: an MSBase registry substudy

Background/objective: Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS. Methods: A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment. Results: Mean age on starting cladribine was 47 years; mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years. Conclusion: These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings

Multispectral sensing of biological liquids with hollow-core microstructured optical fibres

The state of the art in optical biosensing is focused on reaching high sensitivity at a single wavelength by using any type of optical resonance. This common strategy, however, disregards the promising possibility of simultaneousmeasurements of a bioanalyte’s refractive index over a broadband spectral domain. Here, we address this issue by introducing the approach of in-fibre multispectral optical sensing (IMOS). The operating principle relies on detecting changes in the transmission of a hollow-core microstructured optical fibre when a bioanalyte is streamed through it via liquid cells. IMOS offers a unique opportunity to measure the refractive index at 42 wavelengths, with a sensitivityup to ~3000 nm per refractive index unit (RIU) and a figure of merit reaching 99 RIU−1 in the visible and near-infra-red spectral ranges. We apply this technique to determine the concentration and refractive index dispersion for bovineserum albumin and show that the accuracy meets clinical need

Prediction of relapse activity when switching to cladribine for multiple sclerosis.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. OBJECTIVE: To determine predictors of relapse hazard when switching to cladribine. METHODS: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. RESULTS: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03-5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01-4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65-14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35-12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91-0.99). CONCLUSION: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard