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Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017., (© 2024. The Author(s).)

The aim of this study was to establish whether bumetanide can abort an acute attack of weakness in patients with HypoPP. This was a randomised, double-blind, cross-over, placebo-controlled phase II clinical trial. Focal attack of weakness was induced by isometric exercise of ADM followed by rest (McManis protocol). Participants had two study visits and received either placebo or 2 mg bumetanide at attack onset (defined as 40 % decrement in the abductor digiti minimi CMAP amplitude from peak). CMAP measurements assessed attack severity and duration. Nine participants completed both visits. CMAP percentage of peak amplitudes in the bumetanide (40.6 %) versus placebo (34.9 %) group at 1hr following treatment did not differ significantly (estimated effect difference 5.9 % (95 % CI: (-5.7 %; 17.5 %), p = 0.27, primary outcome). CMAP amplitudes assessed by the area under the curve for early (0-2hr post-treatment) and late (2-4 h post-treatment) efficacy were not statistically different between bumetanide and placebo (early effect estimate 0.043, p = 0.3; late effect estimate 0.085, p = 0.1). Two participants recovered from the attack following bumetanide intake; none recovered following placebo. Bumetanide was well tolerated but not efficacious to rescue a focal attack in an immobilised hand in the majority of patients, although data supports further studies of this agent., Competing Interests: Declaration of competing interest I certify that all the co-authors have seen and agreed with the contents of this manuscript, and none of the authors have any financial interest to disclose. This manuscript has not been submitted to any other journal., (Copyright © 2024. Published by Elsevier B.V.)

Background: The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry., Methods: Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ)., Results: Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted., Conclusions: The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain., (© 2023. The Author(s).)

Background and Purpose: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein., Methods: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured., Results: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg., Conclusions: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment., (© 2023. The Author(s).)

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam., Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment., Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles., Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients., (© 2023. The Author(s).)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by homozygous deletion or loss-of-function mutations of the survival of motor neuron 1 (SMN1) gene, resulting in reduced levels of SMN protein throughout the body. Patients with SMA may have multiple tissue defects, which could present prior to neuromuscular symptoms., Objective: To assess the signs, comorbidities and potential extraneural manifestations associated with SMA in treatment-naïve patients., Methods: This observational, retrospective and matched-cohort study used secondary insurance claims data from the US IBM® MarketScan® Commercial, Medicaid and Medicare Supplemental databases between 01/01/2000 and 12/31/2013. Treatment-naïve individuals aged≤65 years with≥2 International Classification of Diseases, Ninth Revision (ICD-9) SMA codes were stratified into four groups (A-D), according to age at index (date of first SMA code recorded) and type of ICD-9 code used, and matched with non-SMA controls. The occurrence of ICD-9 codes, which were converted to various classifications (phecodes and system classes), were compared between groups in pre- and post-index periods., Results: A total of 1,457 individuals with SMA were included and matched to 13,362 controls. Increasing numbers of SMA-associated phecodes and system classes were generally observed from pre- to post-index across all groups. The strongest associations were observed in the post-index period for the youngest age groups. Endocrine/metabolic disorders were associated with SMA in almost all groups and across time periods., Conclusions: This exploratory study confirmed the considerable disease burden in patients with SMA and identified 305 unique phecodes associated with SMA, providing a rationale for further research into the natural history and progression of SMA, including extraneural manifestations of the disease.

Background: ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA., Methods: Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support., Results: Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9-10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9-16.4) months and at death was ~ 41.2 (7.3-not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking., Interpretation: Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease's devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation., (© 2022. The Author(s).)

Introduction/aims: Data regarding weight, height/length, and growth status of patients with spinal muscular atrophy (SMA) who have received only supportive care are limited. This cross-sectional study describes these measurements in patients with Type 1 and Types 2/3 SMA and compares them with reference values from typically developing children., Methods: Retrospective baseline data from three sites in the Pediatric Neuromuscular Clinical Research Network (Boston, New York, Philadelphia) were used. Descriptive statistics for weight, height/length, body mass index-for-age, as well as weight-for-length and absolute and relative deviations from reference values (ie, 50th percentile from World Health Organization/Centers for Disease Control growth charts) were calculated. Furthermore, growth status was reported., Results: A total of 91 genetically confirmed patients with SMA receiving optimal supportive care and without any disease-modifying treatment were stratified into Types 1 (n = 28) and 2/3 SMA (n = 63). Patients with Type 1 SMA weighed significantly less (median = -7.5%) compared with reference values and patients with Types 2/3 SMA were significantly shorter (mean = -3.0%) compared with reference values. The median weight was considerably below the 50th percentile in both groups of patients, even if they received a high standard of care and proactive feeding support., Discussion: More research is needed to understand which factors influence growth longitudinally, and how to accurately capture growth in patients with SMA. Further research should investigate the best time to provide feeding support to avoid underweight, especially in patients with Type 1, and how to avoid the risk of overfeeding, especially in patients with Types 2/3 SMA., (© 2022 F. Hoffmann-La Roche Ltd. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy., Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing., Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group)., Interpretation: Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests EM has received fees for serving on scientific advisory boards; speaker fees from F Hoffmann-La Roche, Biogen, AveXis/Novartis, Scholar Rock, and Cytokinetics; and grants from Biogen during the conduct of the study. ND served on scientific advisory boards for F Hoffmann-La Roche and Novartis pharmaceuticals; he has received personal fees from Biogen for congress and travel support. ESM reports that she has served on advisory boards for Biogen and Scholar Rock. She has received consulting fees, travel support, and speaker honoraria as an independent contractor from F Hoffmann-La Roche, Biogen, AveXis, and Scholar Rock. AN has received fees for serving on scientific advisory boards and speaker fees from F Hoffmann-La Roche. MO reports grants from F Hoffmann-La Roche during the conduct of the study and has received grants as a clinical trial investigator from Biogen. KS reports grants from F Hoffman-La Roche/Chugai Pharmaceutical during the conduct of the study and grants from Biogen Japan and lecture fees from Novartis Pharmaceuticals, outside the submitted work. CV reports personal fees and financial support to her institution from F Hoffmann-La Roche for activities outside the submitted work. GB received consultancy fees and speaker honoraria from F Hoffmann-La Roche and AveXis and speaker fees from PTC Therapeutics. NG reports fees for serving on advisory boards and presentations at symposia from F Hoffmann-La Roche, Biogen, and AveXis. JK received grants or contracts from Novartis Gene Therapies and Biogen. He has received consulting and speaker fees from F Hoffmann La Roche, Biogen, and Novartis Gene Therapies and consulting fees from Scholar Rock. AK-P reports that she received an institutional support grant from Biogen; serving on scientific advisory boards for and receiving speaker honoraria from Biogen, F Hoffmann-La Roche, Novartis, and PTC Therapeutics; and receiving personal fees from Biogen and F Hoffmann-La Roche for travel support. LS received grants and personal fees from F Hoffman-La Roche, Biogen, and AveXis/Novartis Gene Therapy and personal fees from Cytokinetics, outside the submitted work. OK reports that he was previously an employee and stockholder in F Hoffmann-La Roche during the submitted work and that he now holds the position of honorary chief medical officer at The Spinal Muscular Atrophy Foundation. JWD has received fees for serving on scientific advisory boards from Biogen, Novartis, Sarepta, and Avidity; has received consulting fees from Affinia Therapeutics and Shift Therapeutics for a therapeutic platform; and has received grant support for clinical trials from F Hoffman-La Roche, Biogen, Novartis Gene Therapies, Cytokinetics, Scholar Rock, and Sarepta. CM, PF, MG, KG, HK, HS, RSS, and WYY report that they are current employees and stockholders in F Hoffmann-La Roche. OB-T declared no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Whether the modified shuttle test (MST) achieves maximal effort in children and adolescents with asthma is unclear. The aim was to compare the physiological responses of MST to the cardiopulmonary exercise test (CPET) in pediatric patients with asthma, to observe its convergent validity., Patients and Methods: A cross-sectional study with volunteers with asthma (6-17 years of age) under regular treatment. The MST is an external-paced test, and the participants were allowed to walk/run. CPET was performed on a cycle ergometer to compare with MST. Gas exchange (VO 2 , VCO 2 , and VE) and heart rate (HR) were the outcomes and were continuously assessed in both tests., Results: Forty-seven volunteers were included, normal lung function expiratory forced volume at 1st second/forced vital capacity (FEV 1 /FVC) 88.6 (7.7). VO 2peak was higher at MST (2.0 ± 0.6 L/min) compared to CPET (1.6 ± 0.5 L/min), p < 0.001. Similar results was observed to VE at MST (50 ± 16 L/min) versus VE at CPET (40 ± 13 L/min), and to VCO 2 at MST (2.1 ± 0.8 L/min) versus VCO 2 at CPET (1.7 ± 0.6 L/min), p < 0.001. HR was also higher at MST (94 ± 6%pred) versus CPET (87 ± 8%pred), p = 0.002. VO 2peak in MST correlated to the CPET (r = 0.78, p < 0.001). The ICC of VO 2peak between tests was 0.73 (0.06-0.89), p < 0.001, and VO 2peak Bland-Altman analysis showed a bias of 0.46 L/min., Conclusion: The MST showed a maximal physiologic response in children and adolescents with asthma. It is a valid test and can be used as an alternative to evaluating exercise capacity., (© 2021 Wiley Periodicals LLC.)

Background: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood., Methods: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA., Results: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure., Conclusions: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein., Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds., Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study., Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.)., (Copyright © 2021 Massachusetts Medical Society.)

Not too long ago, the concept of selectively targeting mRNA with small molecules was perceived as a formidable scientific challenge. The discovery of small molecule splicing modifiers and the development of risdiplam for the treatment of spinal muscular atrophy (SMA) have firmly established proof of concept for this exciting new platform and transformed a scientific curiosity into a viable technology to target disease. Today, several approaches to target mRNA with small molecules, supported by biophysical and screening methods, are in place to deliver new drugs with high therapeutic relevance., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU., Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study., Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment., Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed., Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease)., Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders., Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients., Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO 2 peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO 2 peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings., (© 2020 SSIEM.)

Two retrospective audits were undertaken across several hospitals to understand the frequency and preventability of emergency admissions in people with neuromuscular disease (NMD). Following audit 1 (A1), a number of preventable themes emerged on the basis of which recommendations were made to improve quality and co-ordination of care and a network approach was developed to improve awareness and education amongst patients and non-expert professionals. Audit 2 (A2) was undertaken to determine the effect of these measures. The central NHS IT database identified emergency NMD admissions. Case notes were reviewed and audited against pre-agreed criteria. A1 included 576 admissions (395 patients) A2 included 361 admissions (314 patients). Preventable admissions (where an NMD was known) accounted for 63% in A1 and 33% in A2, with more patients followed up at a specialised neuromuscular centre in A2. There were fewer re-admissions in A2 (12%) compared with A1 (25%) and lower mortality (A1: 4.5%, A2: 0.3%). A2 showed a significant rise in patients admitted under the care of neuroscience during the acute admission and fewer preventable ITU admissions. These audits demonstrate a significant impact for both patient care and potential for financial savings following the implementation of recommendations made after A1., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cisplatin has dramatically improved the survival rate of cancer patients, but it has also increased the prevalence of hearing and neurological deficits in this population. Cisplatin induces ototoxicity, peripheral (most prevalent) and central (rare) neurotoxicity. This review addresses the ototoxicity and the neurotoxicity associated with cisplatin-based chemotherapy, providing an integrated view of the potential protective agents that have been evaluated in vitro, in vivo and in clinical trials, their targets and mechanisms of protection and their effects on the antitumor activity of cisplatin. So far, the findings are insufficient to support the use of any oto- or neuroprotective agent before, during or after cisplatin chemotherapy. Despite their promising effects in vitro and in animal studies, many agents have not been evaluated in clinical trials. Additionally, the clinical trials have limitations concerning the sample size, controls, measurement, heterogeneous groups, several arms of treatment, short follow-up or no blinding. Besides that, for most agents, the effects on the antitumor activity of cisplatin have not been evaluated in tumor-bearing animals, which discourages clinical trials. Further well-designed randomized controlled clinical trials are necessary to definitely demonstrate the effectiveness of the oto- or neuroprotective agents proposed by animal and in vitro studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The modified shuttle test is a field test that avoids the ceiling effect, and there are no reports of a multidimensional assessment concerning physical activity in asthmatic patients. Thus, the aim was to evaluate functional capacity by MST, additionally to perform a multidimensional assessment as physical activity in daily life, muscle strength, and cytokine levels in children and adolescents with asthma, and to correlate these variables., Method: This cross-sectional study included volunteers aged between 6 and 18 years who were divided into two groups: asthma group (n=43) that received regular treatment and control group (n=24). Functional capacity was evaluated by distance walked during the MST; physical activity in daily life was evaluated using an accelerometer by the number of steps. Quadriceps femoris strength was evaluated by load cell., Results: Distance walked was lower for the asthma group (790m [222m]) when compared with the control group (950m [240m]; p=0.007); however, the number of steps was similar between the two groups (asthma group: 7743 [3075]; control group: 7181 [3040]; p=0.41), and both groups were classified as sedentary behavior. There was no difference in muscle strength. Tumor necrosis factor-α differed, but interleukin levels were similar between groups. Quadriceps strength was correlated to distance walked (r=0.62; p<0.001) and tumor necrosis factor-α to the number of steps taken (r=-0.54, p=0.005)., Conclusion: Children and adolescents undergoing regular asthma treatment showed reduced functional capacity and sedentary behavior. The lower the quadriceps strength, the shorter the distance walked; the higher the tumor necrosis factor-α levels, the lower their daily physical activity levels., (Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Glycogen storage disease type XIII (GSDXIII) is a very rare inherited metabolic myopathy characterized by autosomal-recessive mutations in the ENO3 gene resulting in muscle β-enolase deficiency, an enzymatic defect of the distal part of glycolysis. Enzyme kinetic studies of two patients presenting with exertion intolerance and recurrent rhabdomyolysis are reported. Next generation sequencing confirmed patient 1 was homozygous for p.E187K in ENO3 , while patient 2 was homozygous for p.C357Y. ENO3 variants pathogenicity was confirmed by functional studies in skeletal muscle. p.E187K caused extremely low total enolase activity. p.C357Y was associated with a higher level of residual activity but kinetic studies showed a lower maximum work rate ( V max ). This study illustrates that GSDXIII may be caused by either null mutations leading to β-enolase deficiency or by mutations that alter the enzyme's kinetic profile. This study highlights the importance of carrying out functional studies as part of the diagnostic process following the identification of variants with next generation sequencing., Competing Interests: Ralph Wigley, Renata S. Scalco, Alice R. Gardiner, Richard Godfrey, Suzanne Booth, Richard Kirk, David Hilton‐Jones, Henry Houlden, Simon Heales, and Ros Quinlivan declare that they have no conflict of interest., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Peripheral sensory neuropathy (PSN) is a well-known side effect of cisplatin characterized by axonal damage. In the early stage of neurotoxicity, cisplatin affects proteins that modulate neurite outgrowth and neuroplasticity, without inducing mitochondrial damage or apoptosis. There are no preventive therapies for cisplatin-induced peripheral neuropathy; therefore, measures to improve axonal growth and connectivity would be beneficial. Caffeic acid phenethyl ester (CAPE) is a bioactive component of propolis with neurotrophic and neuroprotective activities. We have recently showed that CAPE protects against cisplatin-induced neurotoxicity by activating NGF high-affinity receptors (trkA) and inducing neuroplasticity. We have now assessed other potential early targets of cisplatin and additional mechanisms involved in the neuroprotection of CAPE. Cisplatin reduced axonal cytoskeletal proteins (F-actin and β-III-tubulin) without inducing oxidative damage in PC12 cells. It also reduced energy-related proteins (AMPK α, p-AMPK α, and SIRT1) and glucose uptake. At this stage of neurotoxicity, glutamate excitotoxicity is not involved in the toxicity of cisplatin. CAPE attenuated the downregulation of the cytoskeleton and energy-related markers as well as SIRT1 and phosphorylated AMPK α. Moreover, the neuroprotective mechanism of CAPE also involves the activation of the neurotrophic signaling pathways MAPK/Erk and PI3k/Akt. The PI3K/Akt pathway is involved in the upregulation of SIRT1 induced by CAPE, but not in the upregulation of cytoskeletal proteins. Altogether, these findings suggest that the neuroprotective effect of CAPE against cisplatin-induced neurotoxicity involves both (a) a neurotrophic mechanism that mimics the mechanism triggered by the NGF itself and (b) a non-neurotrophic mechanism that upregulates the cytoskeletal proteins.

Objective: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases., Methods: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible., Results: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants., Conclusions: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.

Background: Oxygen uptake (VO 2 ) evaluations by cardiopulmonary exercise test is expensive and time-consuming. Estimating VO 2 based on a field test would be an alternative. Objective: To develop and validate an equation to predict VO 2peak based on the modified shuttle test (MST). Methods: Cross sectional study, with 97 children and adolescents with asthma. Participants were divided in two groups: the equation group (EG), to construct the equation model of VO 2peak , and the cross-validation group (VG). Each subject performed the MST twice using a portable gas analyzer. The peak VO 2peak during MST was used in the equation model. The patients' height, weight, gender, and distance walked (DW) during MST were tested as independent variables. Results: The final model [-0.457 + (gender × 0.139) + (weight × 0.025) + (DW × 0.002)] explained 87% of VO 2peak variation. The VO 2peak predicted was similar to VO 2peak measured by gas analyzer (1.9 ± 0.5 L/min and 2.0 ± 0.5 L/min, respectively) ( p = 0.67), and presented significant ICC 0.91 (IC95% 0.77 to 0.96); p < 0.001. The Bland-Altman analysis showed low bias (-0.15 L/min) and limits of agreement (-0.65 to 0.35 L/min). There was no difference in DW between EG (760 ± 209 m) and VG (731 ± 180 m), p = 0.51. Conclusion: The developed equation adequately predicts VO 2peak in pediatric patients with asthma.

Cisplatin is a highly effective chemotherapeutic drug that is toxic to the peripheral nervous system. Findings suggest that axons are early targets of the neurotoxicity of cisplatin. Although many compounds have been reported as neuroprotective, there is no effective treatment against the neurotoxicity of cisplatin. Caffeic acid phenethyl ester (CAPE) is a propolis component with neuroprotective potential mainly attributed to antioxidant and anti-inflammatory mechanisms. We have recently demonstrated the neurotrophic potential of CAPE in a cellular model of neurotoxicity related to Parkinson's disease. Now, we have assessed the neurotrophic and neuroprotective effects of CAPE against cisplatin-induced neurotoxicity in PC12 cells. CAPE (10 μM) attenuated the inhibition of neuritogenesis and the downregulation of markers of neuroplasticity (GAP-43, synapsin I, synaptophysin, and 200-kD neurofilament) induced by cisplatin (5 μM). This concentration of cisplatin does not affect cell viability, and it was used in order to assess the early neurotoxic events triggered by cisplatin. When a lethal dose of cisplatin was used (IC50 = 32 μM), CAPE (10 μM) increased cell viability. The neurotrophic effect of CAPE is not dependent on NGF nor is it additive to the effect of NGF, but it might involve the activation of the NGF-high-affinity receptors (trkA). The involvement of other neurotrophin receptors such as trkB and trkC is unlikely. This is the first study to demonstrate the protective potential of CAPE against the neurotoxicity of cisplatin and to suggest the involvement of trkA receptors in the neuroprotective mechanism of CAPE. Based on these findings, the beneficial effect of CAPE on cisplatin-induced peripheral neuropathy should be further investigated.

Venom small peptides that target neurotrophin receptors might be beneficial in neurodegeneration, including Parkinsońs disease (PD). Their small size, ease of synthesis, structural stability and target selectivity make them important tools to overcome the limitations of endogenous neurotrophins as therapeutic agents. Additionally, they might be optimized to improve resistance to enzymatic degradation, bioavailability, potency and, mainly, lipophilicity, important to cross the blood brain barrier (BBB). Here, we evaluated the neuroprotective effects and mechanisms of the synthetic snake-venom-based peptide p-BTX-I (Glu-Val-Trp) in PC12 cells treated with MPP + (1-methyl-4-phenylpyridinium), a dopaminergic neurotoxin that induces Parkinsonism in vivo. The peptide p-BTX-I induced neuritogenesis, which was reduced by (i) k252a, antagonist of the NGF-selective receptor, trkA (tropomyosin receptor kinase A); (ii) LY294002, inhibitor of the PI3 K/AKT pathway and (iii) U0126, inhibitor of the MAPK-ERK pathway. Besides that, p-BTX-I also increased the expression of GAP-43 and synapsin, which are molecular markers of axonal growth and synaptic communication. In addition, the peptide increased the viability and differentiation of cells exposed to MPP + , known to inhibit neuritogenesis. Altogether, our findings suggest that the synthetic peptide p-BTX-I protects PC12 cells from MPP + toxicity by a mechanism that mimics the neurotrophic action of NGF. Therefore, the molecular structure of p-BTX-I might be relevant in the development of drugs aimed at restoring the axonal connectivity in neurodegenerative processes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Diagnosis of McArdle disease is frequently delayed by many years following the first presentation of symptoms to a health professional. The aim of this study was to investigate the importance of misdiagnosis in delaying diagnosis of McArdle disease. The frequency of misdiagnosis, duration of diagnostic delay, categories of misdiagnoses and inappropriate medical interventions were assessed in 50 genetically confirmed patients. The results demonstrated a high frequency of misdiagnosis (90%, n = 45/50) most commonly during childhood years (67%; n = 30/45) compared with teenage years and adulthood (teenage: n = 7/45; adult n = 5/45; not known n = 3/45). The correct diagnosis of McArdle disease was rarely made before adulthood (median age of diagnosis 33 years). Thirty-one patients (62%) reported having received more than one misdiagnosis; the most common were "growing pains" (40%, n = 20) and "laziness/being unfit" (46%, n = 23). A psychiatric/psychological misdiagnosis was significantly more common in females than males (females 6/20; males 1/30; p < 0.01). Of the 45 patients who were misdiagnosed, 21 (47%) received incorrect management. This study shows that most patients with McArdle disease received an incorrect explanation of their symptoms providing evidence that misdiagnosis plays an important part in delaying implementation of appropriate medical advice and management to this group of patients., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Mutations in calpain-3 cause limb girdle muscular dystrophy 2A. Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibres. More recently calpain mutations have been shown in association with eosinophilic myositis, suggesting that calpain mutations may render muscle susceptible to inflammatory change. We present the case of a 33-year old female with mild proximal muscle weakness and high CK levels (6698 IU/L at presentation). Muscle biopsy showed clusters of fibre necrosis associated with very dense macrophage infiltrates and small numbers of lymphocytes, raising the possibility of an inflammatory myopathy. No eosinophils were observed. Immunosuppressive treatment was started without clinical improvement. MRI demonstrated bilateral fatty replacement in posterior thigh and calf muscles. Western blot results prompted Sanger sequencing of the calpain-3 gene revealing compound heterozygous mutations c.643&#95;663del and c.1746-20C>G. Our case widens the myopathological spectrum of calpainopathies to include focal macrophage rich inflammatory change., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Some organophosphorus compounds (OPs) induce a neurodegenerative disorder known as organophosphate-induced delayed neuropathy (OPIDN), which is related to irreversible inhibition of neuropathy target esterase (NTE) and impairment of neurite outgrowth. The present study addresses the effects of trichlorfon, mipafox (neuropathic model) and paraoxon (non-neuropathic model) on neurite outgrowth and neuroplasticity-related proteins in retinoic-acid-stimulated SH-SY5Y cells, a cellular model widely used to study the neurotoxicity of OPs. Mipafox (20μM) decreased cellular differentiation and the expression of neurofilament 200 (NF-200), growth associated- (GAP-43) and synaptic proteins (synapsin I and synaptophysin); whereas paraoxon (300μM) induced no effect on cellular differentiation, but significant decrease of NF-200, GAP-43, synapsin I and synaptophysin as compared to controls. However, the effects of paraoxon on these proteins were significantly lower than the effects of mipafox. In conclusion, axonal cytoskeletal proteins, as well as axonal plasticity-related proteins are more effectively affected by neuropathic (mipafox) than by non-neuropathic (paraoxon) OPs, suggesting that they might play a role in the mechanism of OPIDN. At high concentration (1mM), trichlorfon induced effects similar to those of the neuropathic OP, mipafox (20μM), but also caused high inhibition of AChE. Therefore, these effects are unlikely to occur in humans at non-lethal doses of trichlorfon., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation. Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors. We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF. Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells. Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

BACKGROUND Miyoshi myopathy (MM) is an autosomal-recessive muscle disorder caused by mutations in the DYSF gene. Clinical features and histopathological changes in dysferlinopathies may mimic inflammatory myopathies and a high degree of clinical suspicion is required to guide the genetic investigation. CASE REPORT We report the case of a 16-year-old male who presented with severe bilateral calf pain and elevated CK levels (15 000 IU/l) who was on prolonged steroid therapy prompted by the clinical suspicion of inflammatory myopathy. Three years into his illness, he was referred for neuromuscular evaluation presenting with untreatable muscle pain and progressive weakness. The diagnosis of "refractory polymyositis" was revisited. Targeted exome sequencing revealed homozygous pathogenic mutations in the DYSF gene, confirming a diagnosis of Miyoshi myopathy. CONCLUSIONS Our case illustrates that severe muscle pain may be the initial feature of Miyoshi myopathy and should be considered in the differential diagnosis of inflammatory myopathies. Although the described patient reported partial clinical improvement in muscle pain, steroid treatment is not an effective therapy for dysferlinopathy patients and it did not prevent disease progression. In addition, we confirm the utility of next-generation sequencing approaches to myopathies, particularly in complex or unusual cases when muscle biopsy is not available., Competing Interests: Conflicts of Interest: None declared

BACKGROUND McArdle disease is a glycogen storage disorder mainly characterized by exercise intolerance. Prolonged muscle contracture is also a feature of this condition and may lead to rhabdomyolysis (RM), which is a serious event characterized by acute skeletal muscle damage.  CASE REPORT A 44-year-old female patient presented with an acute contracture of the posterior neck muscles, causing severe nuchal rigidity. The contracture was induced during a dental extraction as she held her mouth open for a prolonged period, with her neck in a rigid position. She presented with severe pain in her ear and head, as well as fever, vomiting, and confusion. Based on her symptoms, she was initially misdiagnosed with bacterial meningitis and experienced an acute allergic reaction to the systemic penicillin she was subsequently administered. Lumbar puncture results were normal. High serum creatine kinase (CK) levels, recurrent exercise-related muscle symptoms, and a previous history of recurrent myoglobinuria raised the suspicion of an underlying neuromuscular condition. McArdle disease was confirmed by muscle biopsy and a genetic test, which revealed that the patient was homozygous for the R50X mutation in the PYGM gene. CONCLUSIONS This case illustrates that even seemingly innocuous movements, if rapid isotonic or prolonged isometric in nature, can elicit a muscle contracture in McArdle disease patients. Here, we highlight the need for careful management in this patient population even during routine healthcare procedures. The allergic reaction to antibiotics emphasises that misdiagnoses may result in iatrogenic harm., Competing Interests: Conflicts of Interest: None declared Competing interests None declared.

Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo.

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed.

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)