Journal of Neuromuscular Diseases - Volume 10, issue 4

Authors: Lim, Wooi Fang | Rinaldi, Carlo

Article Type: Review Article

Abstract: Three decades since the Human Genome Project began, scientists have now identified more then 25,000 protein coding genes in the human genome. The vast majority of the protein coding genes (> 90%) are multi-exonic, with the coding DNA being interrupted by intronic sequences, which are removed from the pre-mRNA transcripts before being translated into proteins, a process called splicing maturation. Variations in this process, i.e. by exon skipping, intron retention, alternative 5’ splice site (5’ss), 3’ splice site (3’ss), or polyadenylation usage, lead to remarkable transcriptome and proteome diversity in human tissues. Given its critical biological importance, alternative splicing is …tightly regulated in a tissue- and developmental stage-specific manner. The central nervous system and skeletal muscle are amongst the tissues with the highest number of differentially expressed alternative exons, revealing a remarkable degree of transcriptome complexity. It is therefore not surprising that splicing mis-regulation is causally associated with a myriad of neuromuscular diseases, including but not limited to amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), and myotonic dystrophy type 1 and 2 (DM1, DM2). A gene’s transcript diversity has since become an integral and an important consideration for drug design, development and therapy. In this review, we will discuss transcript diversity in the context of neuromuscular diseases and current approaches to address splicing mis-regulation. Show more

Keywords: Alternative splicing, isoform, splicing modulation

DOI: 10.3233/JND-221601

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 473-482, 2023

Authors: Camelo, Clara Gontijo | Artilheiro, Mariana Cunha | Martins Moreno, Cristiane Araújo | Ferraciolli, Suely Fazio | Serafim Silva, André Macedo | Fernandes, Tatiana Ribeiro | Lucato, Leandro Tavares | Rocha, Antônio José | Reed, Umbertina Conti | Zanoteli, Edmar

Article Type: Research Article

Abstract: Background: LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability. Objective: Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function. Methods: This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and …compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains. Results: 44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α 2 LG-domain and the presence of brain malformation (P  = 0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs* 4). Conclusion: Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α 2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain. Show more

Keywords: LAMA2-RD, muscular dystrophy, congenital muscular dystrophy, merosin, LAMA2, brain malformation, epilepsy, intellectual disability, LG-domain

DOI: 10.3233/JND-221638

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 483-492, 2023

Authors: Mugisha, Nancy | Oliveira-Carneiro, Andrea | Behlim, Tarannum | Oskoui, Maryam

Article Type: Review Article

Abstract: Background: 5q Spinal Muscular Atrophy (SMA) is a prototypical lower motor neuron disorder. However, the characteristic early motor impairment raises the question on the scope of brain involvement with implications for further investigations on the brain as a potential therapeutic target. Objective: To review changes across the SMA clinical spectrum reported on brain magnetic resonance imaging (MRI). Methods: We conducted a scoping review of existing literature on PubMed and EMBASE. Two reviewers searched and retrieved relevant articles on magnetic resonance brain imaging in individuals with SMA censoring to April 2022. Full-text articles published in peer-reviewed journals …or abstracts accepted to conferences in English and French were included. Results: Twelve articles were identified describing a total of 39 patients [age range: 11 days to 41 years old, type 0 (n  = 5), type 1 (n  = 4), type 2 (n  = 2), type 3 (n  = 22), type 4 (n  = 6)]. All reported structural changes and did not explore other MRI modalities. In individuals with infantile onset SMA, cortical and subcortical brain abnormalities in white matter, basal ganglia, thalamus, hippocampus, and high intensity areas around lateral ventricles and thalami were reported over time. In individuals with later-onset SMA, reduced cerebellar and lobular volume were observed as well as increased grey matter density in motor areas. Conclusions: Limited data on brain imaging in SMA highlights both cortical and subcortical involvement in SMA, supporting the hypothesis that changes are not restricted to lower motor neuron pathways. Further studies are needed to determine the extent and prevalence of structural and functional brain changes across SMA types. Show more

Keywords: Spinal muscular atrophy, MRI, survival motor neuron

DOI: 10.3233/JND-221567

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 493-503, 2023

Authors: Sun, Zeren | Wang, Xindi | White, Zoe | Dormuth, Colin | Morales, Fernando | Bernatchez, Pascal

Article Type: Systematic Review

Abstract: Background: Muscular dystrophies (MDs) are characterized by chronic muscle wasting but also poorly understood metabolic co-morbidities. We have recently shown that Duchenne MD (DMD) patients, dogs and asymptomatic carriers are affected by a new form of dyslipidemia that may exacerbate muscle damage. Objective: We aimed to perform a systematic review and meta-analysis for evidence that other types of MDs are associated with dyslipidemia compared to healthy controls. Methods: Search was conducted using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials for reports that compare plasma/serum lipids from MD patients and controls, and meta-analysis of cross-sectional studies …quantifying total cholesterol, high-density lipoprotein, low density lipoprotein and triglycerides was performed. Results: Out of 749 studies, 17 met our inclusion criteria for meta-analysis. 14 of the 17 studies (82%) included investigated myotonic dystrophy (DM); other studies were on pseudohypertrophic MD (PMD) or DMD. As a whole, MD individuals had significantly higher levels of circulating total cholesterol (Hedges’ g with 95% confidence interval [CI], 0.80 [0.03 – 1.56]; p  = 0.04) and triglycerides (Hedges’ g with 95% confidence interval [CI], 2.28[0.63 – 3.92]; p  = 0.01) compared to controls. Meta-regression analysis showed the percentage of male gender was significantly associated with the difference in total cholesterol (beta = 0.05; 95% CI, – 0.02 to 0.11; p  = 0.043) and high-density lipoprotein (beta = – 9.38; 95% CI, – 16.26 to – 2.50; p  = 0.028). Conclusions: MD is associated with significantly higher circulating levels of total cholesterol and triglycerides. However, caution on the interpretation of these findings is warranted and future longitudinal research is required to better understand this relationship. Show more

Keywords: Muscular dystrophy, cholesterol, lipoprotein, triglycerides, dyslipidemia

DOI: 10.3233/JND-230064

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 505-516, 2023

Authors: Volpato, Eleonora | Pierucci, Paola | De Candia, Maria Luisa | Casparrini, Massimo | Volpi, Valeria | Pagnini, Francesco | Carpagnano, Giovanna Elisiana | Banfi, Paolo

Article Type: Research Article

Abstract: Background: The management of tracheotomy at home can be very complex, affecting the patient’s quality of life. Objectives: This case series study aimed to explore the experiences of patients affected by neuromuscular diseases (NMD) concerning tracheostomy and Invasive Mechanical Ventilation (IMV) management at home during the COVID-19 health emergency in Italy. Methods: Semi-structured interviews and the following instruments were used: Connor and Davidson Resilience Scale (CD-RISC-25); Acceptance and Action Questionnaire-II (AAQ-II); State-Trait Anxiety Inventory (STAI); Langer Mindfulness Scale (LMS). Descriptive analyses, correlations, and qualitative analyses were carried out. Results: 22 patients [50% female, mean …age = 50.2 (SD = 21.2)] participated in the study. Participants who showed high levels of dispositional mindfulness in terms of novelty-seeking (r  = 0.736, p  = 0.013) and novelty production (r  = 0.644, p  = 0.033) were those with higher resilience. The main emotion that emerged was the fear of contagion (19 patients, 86.36%), due to the previous fragile condition, leading to a significant sense of abandonment. The tracheostomy’s perception is seen in extremes as a lifesaver or a condemnation. The relationship with the health professionals moves from satisfaction to a feeling of abandonment with a lack of preparation. Conclusions: The relationship between resilience, flexibility, state anxiety and dispositional mindfulness offers ways to reinforce tracheostomy management at home, even in critical periods when going to the hospital may be difficult. Show more

Keywords: Neuromuscular disease, chronic respiratory failure, tracheostomy, invasive mechanical ventilation experiences, COVID-19

DOI: 10.3233/JND-221597

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 517-529, 2023

Authors: McGrattan, Katlyn E. | Shell, Richard D. | Hurst-Davis, Rebecca | Young, Sally Dunaway | O’Brien, Eamonn | Lavrov, Arseniy | Wallach, Shiri | LaMarca, Nicole | Reyna, Sandra P. | Darras, Basil T.

Article Type: Research Article

Abstract: Background: Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. Objective: A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. Methods: We defined bulbar function as the ability to meet nutritional needs while maintaining airway …protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. Results: Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. Conclusions: In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation. Show more

Keywords: Airway protection, aspiration, bulbar function, verbal communication, dysphagia, gene therapy, onasemnogene abeparvovec, pneumonia, spinal muscular atrophy, swallowing

DOI: 10.3233/JND-221531

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 531-540, 2023

Authors: van den Bersselaar, Luuk R. | van Alfen, Nens | Kruijt, Nick | Kamsteeg, Erik-Jan | Fernandez-Garcia, Miguel A. | Treves, Susan | Riazi, Sheila | Yang, Chu-Ya | Malagon, Ignacio | van Eijk, Lucas T. | van Engelen, Baziel G.M. | Scheffer, Gert-Jan | Jungbluth, Heinz | Snoeck, Marc M.J. | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: Variants in RYR1 , the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1 -related malignant hyperthermia (MH) susceptibility. Objective: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. Methods: We performed a prospective cross-sectional observational muscle ultrasound …study in patients with a history of RYR1 -related MH susceptibility (n  = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. Results: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P  = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P  < 0.001), biceps femoris (z = 0.43; P  = 0.002), deltoid (z = 0.31; P  = 0.009), trapezius (z = 0.38; P  = 0.010) and the sum of all muscles (z = 0.40; P  < 0.001) were significantly higher compared to 0, indicating hypertrophy. Conclusions: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity. Show more

Keywords: Anesthesia, exertional rhabdomyolysis, malignant hyperthermia, muscle ultrasound, myopathy, RYR1, ryanodine receptor-1

DOI: 10.3233/JND-230018

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 541-554, 2023

Authors: Suzuki, Naoki | Mori-Yoshimura, Madoka | Katsuno, Masahisa | Takahashi, Masanori P. | Yamashita, Satoshi | Oya, Yasushi | Hashizume, Atsushi | Yamada, Shinichiro | Nakamori, Masayuki | Izumi, Rumiko | Kato, Masaaki | Warita, Hitoshi | Tateyama, Maki | Kuroda, Hiroshi | Asada, Ryuta | Yamaguchi, Takuhiro | Nishino, Ichizo | Aoki, Masashi

Article Type: Research Article

Abstract: Background: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. Objective: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. Methods: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was …set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. Results: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was –0.1 kg (–2.1 to 2.0) in the SA-ER group and –5.1 kg (–10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (–0.3 to 9.9; P  = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P  = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. Conclusions: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan. Show more

Keywords: GNE myopathy, clinical trial, Phase II/III, aceneuramic acid

DOI: 10.3233/JND-230029

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 555-566, 2023

Authors: Pane, Marika | Coratti, Giorgia | Brogna, Claudia | Bovis, Francesca | D’Amico, Adele | Pegoraro, Elena | Bello, Luca | Sansone, Valeria | Albamonte, Emilio | Ferraroli, Elisabetta | Mazzone, Elena Stacy | Fanelli, Lavinia | Messina, Sonia | Catteruccia, Michela | Cicala, Gianpaolo | Ricci, Martina | Frosini, Silvia | De Luca, Giacomo | Rolle, Enrica | De Sanctis, Roberto | Forcina, Nicola | Norcia, Giulia | Passamano, Luigia | Gardani, Alice | Pini, Antonella | Monaco, Giulia | D’Angelo, Maria Grazia | Capasso, Anna | Leone, Daniela | Zanin, Riccardo | Vita, Gian Luca | Panicucci, Chiara | Bruno, Claudio | Mongini, Tiziana | Ricci, Federica | Berardinelli, Angela | Battini, Roberta | Masson, Riccardo | Baranello, Giovanni | Dosi, Claudia | Bertini, Enrico | Politano, Luisa | Mercuri, Eugenio

Article Type: Research Article

Abstract: Background: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. Methods: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250–350, ≤250 meters. Non ambulant patients were subdivided according to …the time since they lost ambulation: <1, 1-2, 2–5 or >5 years. Results: At 12 months, the mean PUL 2.0 change on all the paired assessments was –1.30 (–1.51––1.05) for the total score, –0.5 (–0.66––0.39) for the shoulder domain, –0.6 (–0.74––0.5) for the elbow domain and –0.1 (–0.20––0.06) for the distal domain. At 24 months, the mean PUL 2.0 change on all the paired assessments was –2.9 (–3.29––2.60) for the total score, –1.30 (–1.47––1.09) for the shoulder domain, –1.30 (–1.45––1.11) for the elbow domain and –0.4 (–1.48––1.29) for the distal domain. Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p  < 0.001). Conclusion: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials. Show more

Keywords: Duchenne muscular dystrophy, performance of upper limb, functional abilities, ambulatory status, PUL 2.0

DOI: 10.3233/JND-221556

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 567-574, 2023

Authors: Dietz, Julienne | Jacobsen, Frank | Zhuge, Heidi | Daya, Nassam | Bigot, Anne | Zhang, Wenli | Ehrhardt, Anja | Vorgerd, Matthias | Ehrke-Schulz, Eric

Article Type: Research Article

Abstract: Background: Depending on the therapy approach and disease background, the heterogeneity of muscular tissues complicates the development of targeted gene therapy, where either expression in all muscle types or restriction to only one muscle type is warranted. Muscle specificity can be achieved using promotors mediating tissue specific and sustained physiological expression in the desired muscle types but limited activity in non-targeted tissue. Several muscle specific promotors have been described, but direct comparisons between them are lacking. Objective: Here we present a direct comparison of muscle specific Desmin-, MHCK7, microRNA206- and Calpain3 promotor. Methods: To directly compare …these muscle specific promotors we utilized transfection of reporter plasmids using an in vitro model based on electrical pulse stimulation (EPS) to provoke sarcomere formation in 2D cell culture for quantification of promotor activities in far differentiated mouse and human myotubes. Results: We found that Desmin- and MHCK7 promotors showed stronger reporter gene expression levels in proliferating and differentiated myogenic cell lines than miR206 and CAPN3 promotor. However, Desmin and MHCK7 promotor promoted gene expression also cardiac cells whereas miR206 and CAPN3 promotor expression was restricted to skeletal muscle. Conclusions: Our results provides direct comparison of muscle specific promotors with regard to expression strengths and specificity as this is important feature to avoid undesired transgene expression in non-target muscle cells for a desired therapy approach. Show more

Keywords: Muscle, promotor, gene therapy, targeted expression

DOI: 10.3233/JND-221574

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 575-592, 2023