Journal of Neuromuscular Diseases - Volume 10, issue 6

Authors: Fortunato, Fernanda | Ferlini, Alessandra

Article Type: Review Article

Abstract:  Duchenne muscular dystrophy is a severe, X-linked disease characterized by decreased muscle mass and function in children. Genetic and biochemical research over the years has led to the characterization of the cause and the pathophysiology of the disease. Moreover, the elucidation of genetic mechanisms underlining Duchenne muscular dystrophy has allowed for the design of innovative personalized therapies. The identification of specific, accurate, and sensitive biomarkers is becoming crucial for evaluating muscle disease progression and response to therapies, disease monitoring, and the acceleration of drug development and related regulatory processes. This review illustrated the up-to-date progress in the development …of candidate biomarkers in DMD at the level of proteins, metabolites, micro-RNAs (miRNAs) and genetic modifiers also highlighting the complexity of translating research results to clinical practice. We highlighted the challenges encountered in translating biomarkers into the clinical context and the existing bottlenecks hampering the adoption of biomarkers as surrogate endpoints. These challenges could be overcome by national and international collaborative efforts, multicenter data sharing, definition of public biobanks and patients’ registries, and creation of large cohorts of patients. Novel statistical tools/ models suitable to analyze small patient numbers are also required. Finally, collaborations with pharmaceutical companies would greatly benefit biomarker discovery and their translation in clinical trials. Show more

Keywords: Duchenne muscular dystrophy, biomarkers, proteins, miRNAs, single nucleotide polymorphisms

DOI: 10.3233/JND-221666

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 987-1002, 2023

Authors: Donen, Graham | Milad, Nadia | Bernatchez, Pascal

Article Type: Review Article

Abstract: Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy (MD) that is characterized by early muscle wasting and lethal cardiorespiratory failure. While the mdx mouse is the most common model of DMD, it fails to replicate the severe loss of muscle mass and other complications observed in patients, in part due to the multiple rescue pathways found in mice. This led to several attempts at improving DMD animal models by interfering with these rescue pathways through double transgenic approaches, resulting in more severe phenotypes with mixed relevance to the human pathology. As a growing body of literature …depicts DMD as a multi-system metabolic disease, improvements in mdx -based modeling of DMD may be achieved by modulating whole-body metabolism instead of muscle homeostasis. This review provides an overview of the established dual-transgenic approaches that exacerbate the mild mdx phenotype by primarily interfering with muscle homeostasis and highlights how advances in DMD modeling coincide with inducing whole-body metabolic changes. We focus on the DBA2/J strain-based D2.mdx mouse with heightened transforming growth factor (TGF)-β signaling and the dyslipidemic mdx /apolipoprotein E (mdx /ApoE) knock-out (KO) mouse, and summarize how these novel models emulate the metabolic changes observed in DMD. Show more

Keywords: Duchenne, metabolism, transforming growth factor, cholesterol

DOI: 10.3233/JND-230126

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1003-1012, 2023

Authors: Grounds, Miranda D. | Lloyd, Erin M.

Article Type: Article Commentary

Abstract: This commentary provides an independent consideration of data related to the drug vamorolone (VBP15) as an alternative steroid proposed for treatment of Duchenne muscular dystrophy (DMD). Glucocorticoids such as prednisone and deflazacort have powerful anti-inflammatory benefits and are the standard of care for DMD, but their long-term use can result in severe adverse side effects; thus, vamorolone was designed as a unique dissociative steroidal anti-inflammatory drug, to retain efficacy and minimise these adverse effects. Extensive clinical trials (ongoing) have investigated the use of vamorolone for DMD, with two trials also for limb-girdle muscular dystrophies including dysferlinopathy (current), plus a variety …of pre-clinical trials published. Vamorolone looks very promising, with similar efficacy and some reduced adverse effects (e.g., related to height) compared with other glucocorticoids, specifically prednisone/prednisolone, although it has not yet been directly compared with deflazacort. Of particular interest to clarify is the optimal clinical dose and other aspects of vamorolone that are proposed to provide additional benefits for membranes of dystrophic muscle: to stabilise and protect the sarcolemma from damage and enhance repair. The use of vamorolone (and other glucocorticoids) needs to be evaluated in terms of overall long-term efficacy and cost, and also in comparison with many candidate non-steroidal drugs with anti-inflammatory and other benefits for DMD. Show more

Keywords: Vamorolone, VBP15, glucocorticoids, muscular dystrophies, DMD, dysferlinopathy, dystropathology, muscle necrosis, clinical trials, pre-clinical studies

DOI: 10.3233/JND-230161

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1013-1030, 2023

Authors: Campbell, Amy E. | Arjomand, Jamshid | King, Oliver D. | Tawil, Rabi | Jagannathan, Sujatha

Article Type: Research Article

Abstract: Background: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy caused by misexpression of the double homeobox 4 (DUX4) embryonic transcription factor in skeletal muscle. Identifying quantitative and minimally invasive FSHD biomarkers to report on DUX4 activity will significantly accelerate therapeutic development. Objective: The goal of this study was to analyze secreted proteins known to be induced by DUX4 using the commercially available Olink Proteomics platform in order to identify potential blood-based molecular FSHD biomarkers. Methods: We used high-throughput, multiplex immunoassays from Olink Proteomics to measure the levels of several known DUX4-induced genes in a cellular myoblast …model of FSHD, in FSHD patient-derived myotube cell cultures, and in serum from individuals with FSHD. Levels of other proteins on the Olink Proteomics panels containing these DUX4 targets were also examined in secondary exploratory analysis. Results: Placental alkaline phosphatase (ALPP) levels correlated with DUX4 expression in both cell-based FSHD systems but did not distinguish FSHD patient serum from unaffected controls. Conclusions: ALPP, as measured with the Olink Proteomics platform, is not a promising FSHD serum biomarker candidate but could be utilized to evaluate DUX4 activity in discovery research efforts. Show more

Keywords: DUX4, facioscapulohumeral muscular dystrophy, FSHD, biomarkers, proteomics

DOI: 10.3233/JND-221636

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1031-1040, 2023

Authors: Aoussim, Amira | Légaré, Cécilia | Roussel, Marie-Pier | Madore, Anne-Marie | Morissette, Mathieu C. | Laprise, Catherine | Duchesne, Elise

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. In DM1 patients, skeletal muscle is severely impaired, even atrophied and patients experience a progressive decrease in maximum strength. Strength training for these individuals can improve their muscle function and mass, however, the biological processes involved in these improvements remain unknown. Objective: This exploratory study aims at identifying the proteomic biomarkers and variables associated with the muscle proteome changes induced by training in DM1 individuals. Methods: An ion library was developed from liquid chromatography-tandem mass spectrometry proteomic analyses of Vastus Lateralis …muscle biopsies collected in 11 individuals with DM1 pre-and post-training. Results: The proteomic analysis showed that the levels of 44 proteins were significantly modulated. A literature review (PubMed, UniProt, PANTHER, REACTOME) classified these proteins into biological sub-classes linked to training-induced response, including immunity, energy metabolism, apoptosis, insulin signaling, myogenesis and muscle contraction. Linear models identified key variables explaining the proteome modulation, including atrophy and hypertrophy factors. Finally, six proteins of interest involved in myogenesis, muscle contraction and insulin signaling were identified: calpain-3 (CAN3; Muscle development, positive regulation of satellite cell activation), 14-3-3 protein epsilon (1433E; Insulin/Insulin-like growth factor, PI3K/Akt signaling), myosin-binding protein H (MYBPH; Regulation of striated muscle contraction), four and a half LIM domains protein 3 (FHL3; Muscle organ development), filamin-C (FLNC; Muscle fiber development) and Cysteine and glycine-rich protein 3 (CSRP3). Conclusion: These findings may lead to the identification for DM1 individuals of novel muscle biomarkers for clinical improvement induced by rehabilitation, which could eventually be used in combination with a targeted pharmaceutical approach to improving muscle function, but further studies are needed to confirm those results. Show more

Keywords: Myotonic dystrophy, strength training, proteomics

DOI: 10.3233/JND-221645

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1041-1053, 2023

Authors: Bouman, Karlijn | Groothuis, Jan T. | Doorduin, Jonne | van Alfen, Nens | Udink ten Cate, Floris E.A. | van den Heuvel, Frederik M.A. | Nijveldt, Robin | Kamsteeg, Erik-Jan | Dittrich, Anne T.M. | Draaisma, Jos M.T. | Janssen, Mirian C.H. | van Engelen, Baziel G.M. | Erasmus, Corrie E. | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. Objective: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. Methods: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, …questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. Results: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3–42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. Conclusions: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression. Show more

Keywords: Muscular diseases, cardiomyopathies, respiratory insufficiency, bone density, Vitamin D, calcium, fatigue, pain

DOI: 10.3233/JND-221673

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1055-1074, 2023

Authors: Mayer, Oscar Henry | Amin, Reshma | Sawnani, Hemant | Shell, Richard | Katz, Sherri Lynne

Article Type: Research Article

Abstract: Chronic respiratory failure is a common endpoint in the loss of respiratory muscle function in patients with progressive neuromuscular disease (NMD). Identifying the onset of hypoventilation is critical to allow for the timely introduction of ventilator support and effectively manage respiratory failure [1–3 ]. While there are accepted criteria governing the diagnosis of hypoventilation during polysomnography (PSG) [4 ], there is concern that criteria are insufficient for identifying hypoventilation in the earlier stages of respiratory insufficiency related to NMD. The purpose of this project was to identify more sensitive criteria for identifying hypoventilation. Methods: Fifteen pediatric pulmonologists with broad …experience in managing patients with NMD, 10 of whom were board certified in and practice sleep medicine, were assembled and performed a review of the pertinent literature and a two-round Delphi process with 6 domains (Table 1 ). Results: Within the 6 domains there were three pertinent items per domain (Table 2 ). There was clear agreement on findings on history (morning headaches) and pulmonary function testing (FVC < 50% or awake TcCO2 > 45 mmHg) indicating a high concern for nocturnal hypoventilation. There was close agreement on the definitions for nocturnal hypercapnia and hypoxemia. PSG criteria were identified that indicate a patient is likely in the transitional phase from adequate ventilation to hypoventilation. Discussion: We identified a set of clinical criteria that may allow for more sensitive diagnosis of hypoventilation in NMD and earlier initiation of non-invasive ventilation leading to a reduction in the respiratory morbidity in progressive NMD. These criteria need to be further and more broadly validated prospectively to confirm their utility. Show more

DOI: 10.3233/JND-230053

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1075-1082, 2023

Authors: Fujino, Haruo | Suwazono, Shugo | Ueda, Yukihiko | Kobayashi, Michio | Nakayama, Takahiro | Imura, Osamu | Matsumura, Tsuyoshi | Takahashi, Masanori P.

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy that causes various symptoms, including those of the central nervous system. Some studies have reported cognitive decline in patients with DM1, although the available evidence is limited. Objective: This study aimed to describe longitudinal differences in neuropsychological function in patients with DM1. Methods: A total of 66 Japanese adult patients with DM1 were investigated using a neuropsychological battery to assess several cognitive domains, including memory, processing speed, and executive function. The patients underwent neuropsychological evaluation approximately five years after baseline (Times 1 and 2). …Results: Thirty-eight patients underwent a second neuropsychological evaluation. The participants in the Time 2 evaluation were younger than those who did not participate in Time 2. Patients showed a decline in the Mini-Mental State Examination, Trail Making Test (TMT), Block Design, and Symbol Digit Modalities Test at Time 2 (P  < 0.05). Age at Time 1 was associated with a decline in TMT-A and TMT-B scores (rho = 0.57 and 0.45, respectively). Conclusion: These results suggest a cognitive decline in patients with DM1 and warrant further investigation into the possible effects of age-related changes. Show more

Keywords: Myotonic dystrophy, cognitive impairment, aging, neuropsychological assessment, longitudinal

DOI: 10.3233/JND-230083

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1083-1092, 2023

Authors: Staunton, Hannah | Cleanthous, Sophie | Teodoro, Vanda | Barrett, Louise | Braid, Jessica | Ewens, Bethany | Cano, Stefan | Baranello, Giovanni | Kirschner, Janbernd | Belter, Lisa | Mayhew, Anna

Article Type: Research Article

Abstract: Background: Limited qualitative data exist on the symptoms and impacts of spinal muscular atrophy (SMA) experienced by ambulant individuals. An ambulant module of the SMA Independence Scale (SMAIS) was developed to quantify the assistance required to perform everyday mobility-related activities. Objective: The objective of this study was to develop a patient-centered module that provides key insights into what constitutes independence for ambulant and near-ambulant individuals with SMA. Methods: A stepwise, mixed-method approach was used. Semi-structured interviews were conducted in three waves with individuals with SMA and caregivers of children with SMA who were ambulant or near-ambulant …(can walk ≥5 steps with support). Wave 1 interviews (n  = 20) focused on concept elicitation. Wave 2 and 3 interviews (n  = 15, both) involved completion and cognitive debriefing of items generated based on Wave 1 interviews. Therapeutic area experts were consulted throughout all key steps of the study. In particular, feedback was provided for item refinement and response option decisions. A macro-level preliminary, exploratory analysis, using Rasch Measurement Theory (RMT), provided insight on measurement properties. Results: Wave 1 resulted in 42 mobility and 11 instrumental activity of daily living (iADL) items. During Wave 2, participants defined independence as completing a task with supportive aids but without help from another person, leading to item refinement and modifications to the response scale. Lack of conceptual relevance and ceiling effects led to the removal of all iADL items after Wave 2, and 41 mobility items were tested in Wave 3. Final exploratory RMT and item refinement to reduce overlap led to a 27-item set related to mobility tasks. Conclusions: Our study provides preliminary support for using the 27-item SMAIS–Ambulatory Module for ambulant or near-ambulant individuals with SMA. Larger-scale analyses to further assess the psychometric properties of the scale are warranted. Show more

Keywords: Spinal muscular atrophy, patient-reported outcome measures, psychometrics, activities of daily living

DOI: 10.3233/JND-230096

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1093-1109, 2023

Authors: Di Leo, Valeria | Lawless, Conor | Roussel, Marie-Pier | Gomes, Tiago B. | Gorman, Gráinne S. | Russell, Oliver M. | Tuppen, Helen A.L. | Duchesne, Elise | Vincent, Amy E.

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is a dominant autosomal neuromuscular disorder caused by the inheritance of a CTG triplet repeat expansion in the Dystrophia Myotonica Protein Kinase (DMPK ) gene. At present, no cure currently exists for DM1 disease. Objective: This study investigates the effects of 12-week resistance exercise training on mitochondrial oxidative phosphorylation in skeletal muscle in a cohort of DM1 patients (n  = 11, men) in comparison to control muscle with normal oxidative phosphorylation. Methods: Immunofluorescence was used to assess protein levels of key respiratory chain subunits of complex I (CI) …and complex IV (CIV), and markers of mitochondrial mass and cell membrane in individual myofibres sampled from muscle biopsies. Using control’s skeletal muscle fibers population, we classified each patient’s fibers as having normal, low or high levels of CI and CIV and compared the proportions of fibers before and after exercise training. The significance of changes observed between pre- and post-exercise within patients was estimated using a permutation test. Results: At baseline, DM1 patients present with significantly decreased mitochondrial mass, and isolated or combined CI and CIV deficiency. After resistance exercise training, in most patients a significant increase in mitochondrial mass was observed, and all patients showed a significant increase in CI and/or CIV protein levels. Moreover, improvements in mitochondrial mass were correlated with the one-repetition maximum strength evaluation. Conclusions: Remarkably, 12-week resistance exercise training is sufficient to partially rescue mitochondrial dysfunction in DM1 patients, suggesting that the response to exercise is in part be due to changes in mitochondria. Show more

Keywords: Myotonic dystrophy type 1, skeletal muscle, mitochondrial dysfunction, oxidative phosphorylation deficiency, resistance exercise training, strength training, myotonic dystrophy type 1 therapy

DOI: 10.3233/JND-230099

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1111-1126, 2023

Authors: McCann, Emily P. | Grima, Natalie | Fifita, Jennifer A. | Chan Moi Fat, Sandrine | Lehnert, Klaus | Henden, Lyndal | Blair, Ian P. | Williams, Kelly L.

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported. Objective: To examine the pathogenic potential of genetic variation in ALS, we sought to characterise variant- and gene-level attributes of previously reported ALS-implicated variants. …Methods: A list of 1,087 genetic variants reported in ALS to March 2021 was compiled through comprehensive literature review. Individual variants were annotated using in silico tools and databases across variant features including pathogenicity scores, localisation to protein domains, evolutionary conservation, and minor allele frequencies. Gene level attributes of genic tolerance, gene expression in ALS-relevant tissues and gene ontology terms were assessed for 33 ALS genes. Statistical analysis was performed for each characteristic, and we compared the most penetrant variants found in familial cases with risk alleles exclusive to sporadic cases, to explore genetic variant features that associate with disease penetrance. Results: We provide spreadsheet (hg19 and GRCh38) and variant call format (GRCh38) resources for all 1,087 reported ALS-implicated variants, including detailed summaries for each attribute. We demonstrate that the characteristics of variants found exclusively in sporadic ALS cases are less severe than those observed in familial ALS. Conclusions: We provide a comprehensive, literature-derived catalogue of genetic variation in ALS thus far and reveal crucial attributes that contribute to ALS pathogenicity. Our variant- and gene-level observations highlight the complexity of genetic variation in ALS, and we discuss important implications and considerations for novel variant interpretation. Show more

Keywords: Amyotrophic lateral sclerosis, motor neuron disease, genetic variant, pathogenicity assessment

DOI: 10.3233/JND-230148

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1127-1141, 2023

Authors: Henderson, A. | Harley, G. | Horrocks, I. | Joseph, S. | Dunne, J. | Pysden, K. | Mushtaq, T. | Wong, S.C. | Childs, A.M.

Article Type: Research Article

DOI: 10.3233/JND-230144

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1143-1144, 2023

Authors: de Lima Silva, Elis Vanessa | Donis, Karina Carvalho | Machado, Fabiana Rita Camara | Simão Medeiros, Leonardo | Aschoff, Carlos Alberto de Moura | de Souza, Carolina Fischinger Moura | Poswar, Fabiano de Oliveira | Saute, Jonas Alex Morales

Article Type: Case Report

Abstract: RYR1 -related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. …The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms. Show more

Keywords: Rhabdomyolysis, Myalgia, Malignant Hyperthermia, Dantrolene, RYR1

DOI: 10.3233/JND-230007

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 6, pp. 1145-1149, 2023