Journal of Neuromuscular Diseases - Volume 11, issue 2

Authors: Mackels, Laurane | Servais, Laurent

Article Type: Review Article

Abstract: There has been tremendous progress in treatment of neuromuscular diseases over the last 20 years, which has transformed the natural history of these severely debilitating conditions. Although the factors that determine the response to therapy are many and in some instance remain to be fully elucidated, early treatment clearly has a major impact on patient outcomes across a number of inherited neuromuscular conditions. To improve patient care and outcomes, clinicians should be aware of neuromuscular conditions that require prompt treatment initiation. This review describes data that underscore the importance of early treatment of children with inherited neuromuscular conditions with an …emphasis on data resulting from newborn screening efforts. Show more

Keywords: Inherited neuromuscular conditions, children, timely treatment, early treatment, newborn screening

DOI: 10.3233/JND-230189

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 253-274, 2024

Authors: Lu, Qi L. | Holbrook, Molly C. | Cataldi, Marcela P. | Blaeser, Anthony

Article Type: Review Article

Abstract: Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes. By reviewing clinical reports in conjunction with analysis of clinically relevant mouse models, we identify likely causes for the confusion. Nearly all missense FKRP mutations retain variable, but sufficient function for the synthesis …of matriglycan during the later stage of muscle development and periods of muscle regeneration. These factors lead to a highly heterogenous pattern of matriglycan expression in diseased muscles, depending on age and stages of muscle regeneration. The limited size in clinical biopsy samples from different parts of even a single muscle tissue at different time points of disease progression may well mis-represent the residual function (base-levels) of the mutated FKRPs and phenotypes. We propose to use a simple Multi Point tool from ImageJ to more accurately measure the signal intensity of matriglycan expression on fiber membrane for assessing mutant FKRP function and therapeutic efficacy. A robust and sensitive immunohistochemical protocol would further improve reliability and comparability for the detection of matriglycan. Show more

Keywords: Matriglycan, dystroglycanopathy, FKRP, LGMDR9, measurement, therapy

DOI: 10.3233/JND-230205

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 275-284, 2024

Authors: Bello, Luca | Sabbatini, Daniele | Fusto, Aurora | Gorgoglione, Domenico | Borin, Giovanni Umberto | Penzo, Martina | Riguzzi, Pietro | Villa, Matteo | Vianello, Sara | Calore, Chiara | Melacini, Paola | Vio, Riccardo | Barp, Andrea | D’Angelo, Grazia | Gandossini, Sandra | Politano, Luisa | Berardinelli, Angela | Messina, Sonia | Vita, Gian Luca | Pedemonte, Marina | Bruno, Claudio | Albamonte, Emilio | Sansone, Valeria | Baranello, Giovanni | Masson, Riccardo | Astrea, Guja | D’Amico, Adele | Bertini, Enrico | Pane, Marika | Lucibello, Simona | Mercuri, Eugenio | Spurney, Christopher | Clemens, Paula | Morgenroth, Lauren | Gordish-Dressman, Heather | McDonald, Craig M. | Hoffman, Eric P. | Pegoraro, Elena

Article Type: Research Article

Abstract: Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group …Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01 mL/m2 , p  = 0.03) while for dp116 were correlated with decreased EF (–4.14%, p  = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p  = 0.002, and –10.62 mL/m2 , p  = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD. Show more

Keywords: Duchenne muscular dystrophy, dilated cardiomyopathy, genetic modifiers, LTBP4, glucocorticoid treatment

DOI: 10.3233/JND-230129

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 285-297, 2024

Authors: Yavas, Alper | van Putten, Maaike | Aartsma-Rus, Annemieke

Article Type: Research Article

Abstract: Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts. Here, we investigated the feasibility of enhancing IGF-1 signaling by downregulation of IGF-binding proteins. We observed that out of frame exon skipping of Igfbp1 and Igfbp3 downregulated their protein expression, which …increased Akt phosphorylation on the downstream IGF-1 signaling in vitro . 3’RNA sequencing analysis revealed the related transcriptome in C2C12 cells in response to IGFBP3 downregulation. The AONs did however not induce any exon skipping or protein knockdown in mdx mice after 6 weeks of systemic treatment. We conclude that IGFBP downregulation could be a good strategy to increase IGF-1 signaling but alternative tools are needed for efficient delivery and knockdown in vivo . Show more

Keywords: Insulin-like growth factor-1, Duchenne muscular dystrophy, antisense oligonucleotides, exon skipping, IGF-binding proteins

DOI: 10.3233/JND-230118

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 299-314, 2024

Authors: Mázala, Davi A.G. | Chen, Dapeng | Chin, Eva R.

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+ ) levels and heightened endoplasmic reticulum (ER) stress. Objective: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice. Methods: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), …SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios. Results: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice. Conclusions: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress. Show more

Keywords: Amyotrophic lateral sclerosis, SOD1, calcium, SERCA1, ER stress

DOI: 10.3233/JND-230123

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 315-326, 2024

Authors: Greco, Anna | Mul, Karlien | Jaeger, Martin H. | dos Santos, Jéssica C. | Koenen, Hans | de Jong, Leon | Mann, Ritse | Fütterer, Jurgen | Netea, Mihai G. | Pruijn, Ger J.M. | van Engelen, Baziel G.M. | Joosten, Leo A.B.

Article Type: Research Article

Abstract: Background: FSHD is a highly prevalent inherited myopathy with a still poorly understood pathology. Objective: To investigate whether proinflammatory cytokines are associated with FSHD and which specific innate immune cells are involved in its pathology. Methods: First, we measured circulating cytokines in serum samples: IL-6 (FSHD, n  = 150; HC, n  = 98); TNF (FSHD, n  = 150; HC, n  = 59); IL-1α (FSHD, n  = 150; HC, n  = 66); IL-1β (FSHD, n  = 150; HC, n  = 98); MCP-1 (FSHD, n  = 14; HC, n  = 14); VEGF-A (FSHD, n  = 14; HC, n  = 14). Second, we tested trained immunity in monocytes (FSHD, n  = 15; …HC, n  = 15) and NK cells (FSHD, n  = 11; HC, n  = 11). Next, we explored the cytokine production capacity of NK cells in response to different stimuli (FSHD, n  = 39; HC, n  = 22). Lastly, we evaluated the cytokine production of ex vivo stimulated MRI guided inflamed (TIRM+) and paired MRI guided non inflamed (TIRM–) muscle biopsies of 21 patients and of 8 HC muscle biopsies. Results: We included a total of 190 FSHD patients (N = 190, 48±14 years, 49% men) and of 135 HC (N = 135, 44±15 years, 47% men). We found that FSHD patients had higher concentrations of IL-6 and TNF measured (a) in the circulation, (b) after ex-vivo stimulation of NK cells, and (c) in muscle specimens. Besides, IL-6 circulating concentrations, as well as its production by NK cells and IL-6 content of FSHD muscle specimens, showed a mild correlation with disease duration, disease severity, and muscle weakness. Conclusion: These results show that IL-6 and TNF may contribute to FSHD pathology and suggest novel therapeutic targets. Additionally, the activation of NK cells in FSHD may be a novel pathway contributing to FSHD pathology. Show more

Keywords: Facioscapulohumeral muscular dystrophy, cytokines, inflammation

DOI: 10.3233/JND-230063

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 327-347, 2024

Authors: Ip, Hoi Ning Hayley | Yu, Michael Kwan Leung | Wong, Wilfred Hing Sang | Liu, Amanda | Kwan, Kenny Yat Hong | Chan, Sophelia Hoi Shan

Article Type: Research Article

Abstract: Background: Nusinersen treatment has demonstrated efficacy in improving clinical outcomes for spinal muscular atrophy (SMA), yet its impact on scoliosis progression remains unclear. Objective: This study aimed to assess the progression of scoliosis in pediatric patients with SMA undergoing nusinersen treatment. Methods: In this prospective study, data were systematically collected from Hong Kong pediatric SMA patients receiving nusinersen between 2018 and 2023. All patients had longitudinal radiographic studies pre-nusinersen, and at half-yearly or yearly intervals during treatment based on the scoliosis severity. Motor function evaluations were conducted pre-nusinersen, and after starting treatment at 6- and 12-month …intervals. Results: Twenty-three patients ((SMA type 1 (SMA1) = 8, SMA type 2 (SMA2) = 7, SMA type 3 (SMA3) = 8)) with a median age of 5.8 years (range: 0.4–17.5 years) at nusinersen initiation, and median follow-up duration of 3.4 years (range: 1.1–5.2 years) were included. During the study period, motor scores remained stable or improved in 83% of patients. However, scoliosis progressed across all subtypes, with mean annual progression rates of 5.2, 11.9, and 3.6 degrees in SMA1, SMA2, and SMA3 respectively. Patients initiating nusinersen between ages 5 and 11 years exhibited the most rapid progression, with rates of 11.8, 16.5, and 7.3 degrees per year in SMA1, SMA2, and SMA3 respectively. Positive correlations were observed between the difference in CHOP-INTEND score post-nusinersen and scoliosis progression in SMA1 (rs = 0.741, p  = 0.041). Conversely, negative correlations were found between the difference in HFMSE score post-nusinersen and scoliosis progression in SMA2 (rs =−0.890, p  = 0.012) and SMA3 (rs =−0.777, p  = 0.028). Conclusions: This study reveals that nusinersen treatment in symptomatic pediatric SMA patients with motor improvement is linked to increased scoliosis progression in SMA1, whereas it is associated with decreased progression in SMA2 and SMA3. Age, baseline Cobb angle, and motor milestone improvement are influential factors in scoliosis progression. Show more

Keywords: Spinal muscular atrophy, Paediatric, symptomatic, scoliosis, nusinersen

DOI: 10.3233/JND-230077

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 349-359, 2024

Authors: Cornell, Nikki | Childs, Anne-Marie | Wraige, Elizabeth | Munot, Pinki | Ambegaonkar, Gautam | Chow, Gabriel | Hughes, Imelda | Illingworth, Marjorie | Majumdar, Anirban | Marini-Bettolo, Chiara | Parasuraman, Deepak | Spinty, Stefan | Willis, Tracey | Scoto, Mariacristina | Baranello, Giovanni

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1 ) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2 -splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021. Objective: To describe the …largest paediatric European real-world set of data on patients’ characteristics and short-term safety for risdiplam in Great Britain through EAMS. Methods: We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events. Results: Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0–17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients. Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified. Conclusions: This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam’s role in addressing patients’ needs into the future. Show more

Keywords: Spinal muscular atrophy, risdiplam, treatment, adverse events, safety

DOI: 10.3233/JND-230162

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 361-368, 2024

Authors: Boentert, Matthias | Campana, Emmanuelle Salort | Attarian, Shahram | Diaz-Manera, Jordi | Dimachkie, Mazen M. | Periquet, Magali | Thibault, Nathan | Miossec, Patrick | Zhou, Tianyue | Berger, Kenneth I.

Article Type: Short Communication

Abstract: In the COMET trial of patients with late-onset Pompe disease, greater improvement in upright forced vital capacity (FVC) % predicted was observed with avalglucosidase alfa (AVA) vs alglucosidase alfa (ALGLU) (estimated treatment difference: 2.43%). The pre-specified mixed model repeated measures (MMRM) analysis demonstrated non-inferiority of AVA (P  = 0.0074) and narrowly missed superiority (P  = 0.063; 95% CI: –0.13–4.99). We report superiority of AVA in two post-hoc analyses that account for an extreme outlier participant with low FVC and severe chronic obstructive pulmonary disease at baseline: MMRM excluding the outlier (P  = 0.013) and non-parametric analysis of all data with repeated measures analysis …of covariance (P  = 0.019). Show more

Keywords: Late-onset Pompe disease, acid α-glucosidase deficiency, avalglucosidase alfa, alglucosidase alfa, statistical methods

DOI: 10.3233/JND-230175

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 369-374, 2024

Authors: Ricci, Giulia | Govoni, Alessandra | Torri, Francesca | Astrea, Guja | Buchignani, Bianca | Marinella, Gemma | Battini, Roberta | Manca, Maria Laura | Castiglione, Vincenzo | Giannoni, Alberto | Emdin, Michele | Siciliano, Gabriele

Article Type: Research Article

Abstract: Background: Becker muscular dystrophy (BMD) is a dystrophinopathy due to in-frame mutations in the dystrophin gene (DMD) which determines a reduction of dystrophin at muscle level. BMD has a wide spectrum of clinical variability with different degrees of disability. Studies of natural history are needed also in view of up-coming clinical trials. Objectives: From an initial cohort of 32 BMD adult subjects, we present a detailed phenotypic characterization of 28 patients, then providing a description of their clinical natural history over the course of 12 months for 18 and 24 months for 13 of them. Methods: …Each patient has been genetically characterized. Baseline, and 1-year and 2 years assessments included North Star Ambulatory Assessment (NSAA), timed function tests (time to climb and descend four stairs), 6-minute walk test (6MWT), Walton and Gardner-Medwin Scale and Medical Research Council (MRC) scale. Muscle magnetic resonance imaging (MRI) was acquired at baseline and in a subgroup of 9 patients after 24 months. Data on cardiac function (electrocardiogram, echocardiogram, and cardiac MRI) were also collected. Results and conclusions: Among the clinical heterogeneity, a more severe involvement is often observed in patients with 45-X del, with a disease progression over two years. The 6MWT appears sensitive to detect modification from baseline during follow up while no variation was observed by MRC testing. Muscle MRI of the lower limbs correlates with clinical parameters. Our study further highlights how the phenotypic variability of BMD adult patients makes it difficult to describe an uniform course and substantiates the need to identify predictive parameters and biomarkers to stratify patients. Show more

DOI: 10.3233/JND-221513

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 375-387, 2024