The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

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Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.

Background Mesenchymal Stem Cells (MSCs) are multipotent cells with low immuonogenecity, and dynamic tissue repair potential, which explains the overwhelming attention they have attracted in regenerative therapy. One notable challenge in MSCs therapy is the bench to bed timeline of freshly cultured MSCs; it does not exceed 24 h. For use after 24 h, MSC need to be cryopreserved - which can preserve the cells for years - but it is a costly and damaging process. Here we introduce a method to extend the bench to bed lifetime of MSCs up to 4 days without the high cost and cell damaging effects of cryopreservation. Our method is based on preserving the MSCs in human plasma. Methods MSCs of 12 tissue samples - 4 adipose, 4 bone marrow and 4 Wharton’s jelly- were cultured and expanded in standard conditions. Cells harvested from passage 2 or 3 were washed, centrifuged, pelleted, and re-suspended in human plasma. Cell suspensions were refrigerated (5 ± 3 °C) or stored at room temperature (22 ± 3 °C) in a sterile, temperature controlled room. During the next 7 days, two tubes (one from each group) were examined every 24 h to assess MSCs viability and growth potential. On day 3, we assessed MSC cell surface markers and its differentiation potential to adipocyte and osteocyte tissues. Results were analyzed by computing the overall mean and applying the independent-samples t-test to those means. Results The sample means for both cell expansion and cell viability were compared between the two “refrigerator” and “room temperature” groups. Although there was a gradual decrease in cell growth potential between the cells stored for 1 day to those stored for 7 days, we show more than 80% of the cells remain alive for up to 4 days of storage in both groups. The cells reached 80% confluency in under 20 days for all samples stored up to 4 days. No significant differences were observed between the two groups (room temperature and refrigerator stored). The differentiation potential to adipocyte and osteocyte tested on day 3 were positive in all samples. The analysis of cell surface markers tested on day 3 were positive for CD90, CD105, CD73 and negative for CD34, CD45 and HLA-DR. Conclusion We present a method of MSC culture medium using human plasma that can preserve their viability and growth potential for up to 4 days in both room and refrigerator temperatures without losing their stemness characteristics (we recommend use of 5 ± 3 °C). This novel method will allow rapid expansion and therapeutic use of MSCs. Since the cells can be maintained in clinical grade, injection ready state for several days, they can be transported across the globe.