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Copyright of Česká a Slovenská Neurologie a Neurochirurgie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The therapy of spinal muscular atrophy (SMA) with a link to 5q chromosome is nowadays a very hot area. A previously casually not treatable disease, it has been in the US since 2016, and in Europe since 2017. It is newly treatable, and nowadays there are three causal drugs. Two of them, nusinersen (Spinraza) and risdiplam (Ervysdi) increase the synthesis of the SMN protein by modulation of the RNA transcription of the SMN2 gene. These drugs have to be taken regularly, and are lifelong. The third drug, onasemnogene abeparvovec (Zolgensma) is able to substitute the missing SMN1 gene by a syntetic SMN1 gene delivered by viral vector AAV9. It is the first systemic gene therapy in medicine. Until now, this drug was taken only once. There are 4.5 years of data proving its sustaining effect. The first causal therapy was the drug Nusinersen. It has the huge advantage of 10 years’ experience with a high number of treated patients, more than 10,000. This drug does not go through the cerebro-spinal barrier, due to it having to be applied intrathecaly. Nusinersen is in CZ reimbursed for all types and ages of SMA patients. Recently, in August 2020, the drug risdiplam was registered in the US. Its advantage is per oral application; its disadvantage is the short experiences and limited acces in CZ. Risdiplam is not yet registered in the EU, due to this it is available only through the early access program for SMA patients type 1 and 2. The third causal therapy, and second registered drug in the EU, is onasemnogene abeparvovec. Due to the systemic delivery this therapy is limited only for children before the age of 3 years and weighing less than 13.5 kg. Besides, the already registered therapies there are many clinical trials with experimental drugs ongoing – many neuroprotective drugs and muscle strength-enhancing compounds. The actual therapy cannot help with all the symptoms of the disease, it can only mildly improve the motor function and primarily slow down the progression. Due to this, there is still a need for multidisciplinary symptomatic care that should be provided in Neuromuscular Centres. [ABSTRACT FROM AUTHOR]

Copyright of Česká a Slovenská Neurologie a Neurochirurgie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Česká a Slovenská Neurologie a Neurochirurgie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Česká a Slovenská Neurologie a Neurochirurgie is the property of Czech Medical Association of JE Purkyne and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

There are potential renal risks in Duchenne (DMD) and Becker (BMD) muscular dystrophies in childhood, mainly a chronic exposure to myoglobin and, in some cases, genetic predispositions, if the dystrophin isoforms Dp140 and Dp 71 are lacking. We aimed to describe the renal parameters in boys with DMD and BMD, to identify early markers of renal damage. In a cross-sectional study, the levels of cystatin C, estimate of glomerular filtration according to Grubb (eGFRG), myoglobin, the presence of proteinuria, hemoglobin-/myoglobinuria (both from urinary chemical examination), creatinine, and protein excretion was noted together with blood pressure (BP), and height. We recorded historical urinary findings and myoglobin levels. We used descriptive statistics and tested hypotheses by linear regression, the Fisher exact test, and the unpaired T-test. In 51 boys with dystrophinopathy aged 4-15 years, the average eGFRG was 1,8 ± 0,4 ml/s/1,74m2. Surprisingly, eGFRG was lower than 1,5 ml/s/1,74m2 in 12/51 boys. A history of proteinuria and hemoglobin-/myoglobinuria was noted in 12/51 and 7/51 boys, respectively. Those with eGFR below 1,5 ml/s/1,74m2 had a higher incidence of proteinuria in their history (p=0,02). In those with a history of hematuria/myoglobinuria, the eGFRG was higher (2,06 vs. 1,78 ml/s/1,74m2, p = 0,04). The absence of Dp140 was associated with a higher incidence of hematuria/myoglobinuria (p = 0,01), but not proteinuria (p = 0,09). 18/51 boys BP above the 95th percentile, with no association with the studied markers. The renal function might be altered in boys with dystrophinopathy. Atypical finding in routine urine examination should trigger the evaluation of GFR from cystatin C, acid-base balance, and possibly the excretion of protein in 24-hour urine collection. The cause of the observed decreased eGFRG is not clear. Corticotherapy might increase the level of cystatin C and thus, in theory, lead to a falsly decreased eGFR. This study was supported by Charles University, project GA UK No: 586120, and Institutional Support of the Czech Ministry of Health, Project Nr. 6005. The authors are members of the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD]. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), a rare neurodegenerative disorder with an estimated incidence of 1 in 6,000 to 10,000 live births, is the leading genetic cause of mortality in infants and children. Since the approval of new disease modifying treatments (DMTs; Spinraza in 2017, Zolgensma in 2020, and Evrysdi in 2021), studies have reported modified disease trajectories compared to the known SMA natural history. To describe the natural history of SMA and its progression during the use of DMTs in real-world settings, a retrospective cohort study was designed. Feasibility assessment identified six appropriate SMA registries to take part, comprising data from nine European countries (3 clinician-based registries: Belgium, Czech Republic & Slovakia, Sweden and 3 patient-based registries: Germany & Austria, Spain, UK & Ireland) between April 2008 and May 2023 federated in the TREAT-NMD network. Among 2,188 SMA patients with genetically confirmed 5q SMA, more patients had SMA type 2 (41.8%) than type 3 (35.6%) and type 1 (19.7%); 1,321 (60.3% overall) were treated with Spinraza (75,9%), Evrysdi (30.5%) or Zolgensma (7.6%), and 847 (38.7%) never received treatment. Functional status and motor milestones were rarely reported in never treated patients. Among treated patients, best functional status for SMA types 1, 2, and 3 was "sitter" for 36.6%, 60.9%, and 5.3%, and "walker" for 12.0%, 24.6%, and 87.8% respectively. Best motor milestone for types 1 and 2 was "sit without support" for 27.2% and 38.0%, and "roll onto side" for 18.5% and 2.0% respectively. For type 3, 63.4% reported "climb stairs" and 19.3% reported "walk 10 meters without assistance". Functional status and motor milestones were well captured after treatment but rarely reported before, limiting evaluation of treatment related changes. Areas of improvement for registry data quality have been identified to reduce data missingness, increase standardization, and enhance their utility to inform regulatory decision making. Disclaimer: "This study was funded by the European Medicines Agency and registered in EU PAS (EUPAS50476). The views expressed in this abstract are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the authors are employed/affiliated." [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a disease-modifying therapy approved for the treatment of spinal muscular atrophy (SMA). The efficacy of risdiplam has been demonstrated in clinical trials that included adult patients, but the real-world effectiveness of risdiplam in adults has not yet been extensively investigated. Natural history studies have shown a slow, progressive decline in motor function in adult patients with SMA. It remains unclear how treatment with risdiplam may influence this trajectory in a real-world clinical setting. As such, this study aims to describe adult patients with SMA treated with risdiplam in terms of their demographic and clinical characteristics, treatment patterns and motor function outcomes, and explore, if possible, the comparison of these outcomes with untreated patients. This non-interventional, retrospective cohort study will use data from six registries (clinician and patient reported) from within the TREAT-NMD network (Australia, Belgium, Canada, Czech Republic & Slovakia, Germany & Austria, and the UK & Ireland) to identify adult patients with SMA treated with risdiplam and where feasible, compare with an untreated patient population. Appropriate adjustment methods will be explored to account for potential confounders where possible, and appropriate statistical models will be used to perform comparisons with untreated patients. As of the submission of this abstract, the analysis is ongoing. Available data will be presented with descriptive statistics. In sum, this study will add to the growing real-world evidence for risdiplam in adults. This study will help to contextualise the effect of risdiplam in this patient population and that of untreated patients. [ABSTRACT FROM AUTHOR]

Background and Objective: Patients with spinal muscular atrophy (SMA) treated with a disease-modifying therapy (DMT) are often classified as responders or non-responders based on the attainment of a specific improvement threshold on validated functional scales. This categorization may significantly impact treatment reimbursement in some countries. The aim of this research is to evaluate the perception of treatments and their benefit by patients considered as responders or non-responders. Methods: In this non-commercial multicenter study, 99 post-symptomatically treated SMA type I-III patients with a median age of 11.2 (0.39-57.4) years at treatment initiation were stratified into three groups based on their treatment outcomes, i.e., those exhibiting clinically significant improvement (N = 41), those with non-clinically significant improvement (N = 18), or those showing no improvement (N = 40). Fifteen months after treatment, the initiation patients or patients' caregivers were assessed using a patient-rated scoring system based on the Patient Global Impression of Change (PGIC) scale, comprising 22 questions targeting important aspects and tasks in the daily life of patients with SMA. Results: We found no statistical difference in the patient perception of treatment benefits in 17 out of 22 domains across patient groups. Conclusions: Our results suggest that functional motor scales do not recapitulate patients' and patients' caregivers' experience of the effect of nusinersen treatment in SMA.

Dominant missense variants in MYBPC1 encoding slow Myosin Binding Protein-C (sMyBP-C) have been increasingly linked to arthrogryposis syndromes and congenital myopathy with tremor. Herein, we describe novel compound heterozygous variants - NM_002465.4:[c.2486_2492del];[c.2663A > G] - present in fibronectin-III (Fn-III) C7 and immunoglobulin (Ig) C8 domains, respectively, manifesting as severe, early-onset distal arthrogryposis type-1, with the carrier requiring intensive care and several surgical interventions at an early age. Computational modeling predicts that the c.2486_2492del p.(Lys829IlefsTer7) variant destabilizes the structure of the Fn-III C7 domain, while the c.2663A > G p.(Asp888Gly) variant causes minimal structural alterations in the Ig C8 domain. Although the parents of the proband are heterozygous carriers for a single variant, they exhibit no musculoskeletal defects, suggesting a complex interplay between the two mutant alleles underlying this disorder. As emerging novel variants in MYBPC1 are shown to be causatively associated with musculoskeletal disease, it becomes clear that MYBPC1 should be included in relevant genetic screenings., 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 © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone)., Methods: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2., Results: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups., Discussion: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone., Trial Registration Information: ClinicalTrials.gov Identifier: NCT03439670., Classification of Evidence: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

In this prospective study involving 37 Duchenne muscular dystrophy (DMD) patients aged 8-18 years and older, we examined the impact of neurological and cardiac factors on quality of life (QoL). Our findings revealed a negative correlation between upper limb movement and overall mobility, self-service, and usual activities. Ambulatory and non-ambulatory DMD patients showed significant differences in mobility-related parameters. Cardiac evaluations demonstrated associations between mitral annular plane systolic excursion (MAPSE) and mobility-related aspects. The PEDSQL 3.0 neuromuscular model questionnaire further highlighted age-related and movement-related correlations with QoL. The loss of ambulatory status and reduced upper limb movement were negatively associated with QoL, while upper limb movement positively correlated with septal MAPSE. However, no significant associations were found between MAPSE and anxiety/depression. These findings underscore the multifaceted impact of DMD on QoL and emphasize the importance of considering both neurological and cardiac factors in comprehensive patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Juříková, Masárová, Panovský, Pešl, Revendová, Volný, Feitová, Holeček, Kincl, Danhofer, Voháňka, Haberlová and Podolská.)

Limb girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of muscular dystrophies. The study presents an overview of molecular characteristics of a large cohort of LGMD patients who are representative of the Czech LGMD population. We present 226 LGMD probands in which 433 mutant alleles carrying 157 different variants with a supposed pathogenic effect were identified. Fifty-four variants have been described only in the Czech LGMD population so far. LGMD R1 caplain3-related is the most frequent subtype of LGMD involving 53.1% of patients with genetically confirmed LGMD, followed by LGMD R9 FKRP-related (11.1%), and LGMD R12 anoctamin5-related (7.1%). If we consider identified variants, then all but five were small-scale variants. One large gene deletion was identified in the LAMA2 gene and two deletions in each of CAPN3 and SGCG. We performed comparison our result with other published studies. The results obtained in the Czech LGMD population clearly differ from the outcome of other LGMD populations in two aspects-we have a more significant proportion of patients with LGMD R1 calpain3-related and a smaller proportion of LGMD R2 dysferlin-related., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment., Objectives: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic., Methods: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases)., Results: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform., Conclusions: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Background and Objectives: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally., Methods: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations., Results: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research., Conclusions: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings., Competing Interests: Competing interests: MES has received consulting fees or honoraria from Inflectis Bioscience, Passage Biosci and Mitochondria in Motion, Temple University and Albert Einstein Medical College, and is the Chair of the CMT and Related Disorders (CMTR) Consortium of the Peripheral Nerve Society. SR has been employed at the Janssen Pharmaceutical Companies of Johnson & Johnson since January 2021 and has restricted stock options. Her contributions to the paper were made prior to her current employment. IM is a board member of the CMTR Consortium of the Peripheral Nerve Society. CES is a voluntary advisory board member of the CMT Association. EMY, PB, JBa, SKB, NB, KdV, TE, MAF, RSF, JH, RAK, GAN, MaMR, KR, SWY, MPM, MoMR and JBu report no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)