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

Authors: Fischer, Ryan | Porter, Katherine | Donovan, Joanne M. | Scavina, Mena T. | Armstrong, Niki | Denger, Brian | Hasham, Shabir | Peay, Holly

Article Type: Research Article

Abstract: Background: Corticosteroids are recommended to all people with Duchenne as standard of care; patient experience data is important to guide corticosteroid decision making and as a comparator for new treatment options. Objective: This study assesses patient and caregiver-reported benefits and side effects from corticosteroids to treat Duchenne muscular dystrophy, their importance, and satisfaction. Methods: Using one-on-one interviews (n  = 28) and an online survey (n  = 236), parents and adults with Duchenne reported corticosteroid benefits and side effects rated as both experienced and important. Results: Benefits to breathing, heart function, arm strength, slowing progression of weakness, …and getting around were rated as particularly important, regardless of ambulatory status. Important side effects included increased fracture risk, unwanted weight gain, and diabetes/prediabetes. Parents rated behavior issues and adults rated delayed puberty as having high importance. Being ambulatory was independently associated with reporting more net benefit (p  = 0.02). For side effects, parent scores were significantly higher than adult score (p  = 0.02). Corticosteroid type was not significant. Participants were, overall, satisfied with corticosteroids (means ranging from 6.2 to 7.7 on a scale of 0–10), with no significant differences based on corticosteroid type. Conclusions: Overall, most participants were satisfied with the use of corticosteroids. While a range of side effects were rated as important and relatively common, individuals using corticosteroids and their caregivers indicate that benefits outweigh the side effects. Qualitative data indicate that high acceptability is influenced by lack of treatment alternatives. Patient experience data on use of corticosteroids in Duchenne may be relevant to drug development, regulatory assessment of new treatments, and to families making decisions about corticosteroid use. Show more

Keywords: Steroids, corticosteroids, Duchenne, satisfaction, standard of care, side effects

DOI: 10.3233/JND-221617

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 593-613, 2023

Authors: Unnikrishnan, Gopikrishnan | Polavarapu, Kiran | Bardhan, Mainak | Nashi, Saraswati | Vengalil, Seena | Preethish-Kumar, Veeramani | Valasani, Ravi Kiran | Huddar, Akshata | Nishadham, Vikas | Nandeesh, Bevinahalli Nanjegowda | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background: The phenotypic spectrum of Fukutin-related protein (FKRP ) mutations is highly variable and comprises of limb girdle muscular dystrophy (LGMD) R9 (previously LGMD 2I) and FKRP related congenital muscular dystrophies. Objective: To identify the distinct genotype phenotype pattern in Indian patients with FKRP gene mutations. Methods: We retrospectively reviewed the case files of patients with muscular dystrophy having a genetically confirmed FKRP mutation. All patients had undergone genetic testing using next-generation sequencing. Results: Our patients included five males and four females presenting between 1.5 years and seven years of age …(median age - 3 years). The initial symptom was a delayed acquisition of gross motor developmental milestones in seven patients and recurrent falls and poor sucking in one patient each. Two patients had a language delay, with both having abnormalities on the brain MRI. Macroglossia, scapular winging, and facial weakness were noted in one, three and four patients respectively. Calf muscle hypertrophy was seen in eight patients and ankle contractures in six. At the last follow-up, three patients had lost ambulation (median age - 7 years; range 6.5–9 years) and three patients had not attained independent ambulation. Creatine kinase levels ranged between 2793 and 32,396 U/L (mean 12,120 U/L). A common mutation - c.1343C>T was noted in 5 patients in our cohort. Additionally, four novel mutations were identified. Overall, six patients had an LGMD R9 phenotype, and three had a congenital muscular dystrophy phenotype. Conclusion: Patients with FKRP mutations can have varied presentations. A Duchenne-like phenotype was the most commonly encountered pattern in our cohort, with c.1343C>T being the most common mutation Show more

Keywords: FKRP, muscular dystrophy, LGMD, congenital muscular dystrophies

DOI: 10.3233/JND-221618

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 615-626, 2023

Authors: Sarasate, Mikel | González, Nuria | Córdoba-Izquierdo, Ana | Prats, Enric | Gonzalez-Moro, Jose Miguel Rodriguez | Martí, Sergi | Lujan, Manel | Calle, Myriam | Antón, Antonio | Povedano, Mónica | Farrero, Eva

Article Type: Research Article

Abstract: Background and objective: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation. Methods: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% …threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy. Trial registration number ClinicalTrials.gov: NCT01641965. Results: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87–5.50] vs. 3.33 [1.34–4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p  = 0.267). Conclusions: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%. Show more

Keywords: ALS, Early NIV, survival, respiratory insufficiency, respiratory complications

DOI: 10.3233/JND-221658

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 627-637, 2023

Authors: Dunaway Young, Sally | McGrattan, Katlyn | Johnson, Emily | van der Heul, Marise | Duong, Tina | Bakke, Merete | Werlauff, Ulla | Pasternak, Amy | Cattaneo, Camilla | Hoffman, Katie | Fanelli, Lavinia | Breaks, Anne | Allison, Kristen | Baranello, Giovanni | Finkel, Richard | Coratti, Giorgia | Lofra, Robert Muni

Article Type: Research Article

Abstract: Background: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. Objective: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. Methods: Fifty-six international clinicians experienced in SMA were invited and engaged using …the Delphi method over multiple rounds of web-based surveys to establish consensus. Results: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n  = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. Conclusions: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals. Show more

Keywords: Spinal muscular atrophy, bulbar function, outcome measures, deglutition, voice, speech, swallowing

DOI: 10.3233/JND-221672

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 639-652, 2023

Authors: Trifunov, Selena | Natera-de Benito, Daniel | Carrera-García, Laura | Codina, Anna | Expósito-Escudero, Jesica | Ortez, Carlos | Medina, Julita | Torres Alcala, Soraya | Bernal, Sara | Alias, Laura | Badosa, Carmen | Balsells, Sol | Alcolea, Daniel | Nascimento, Andres | Jimenez-Mallebrera, Cecilia

Article Type: Research Article

Abstract: Background: Three therapeutic strategies have radically changed the therapeutic scenario for spinal muscular atrophy (SMA). However, therapeutic response differs between individuals. There is a need to identify biomarkers to further assess therapeutic response and to better understand which variables determine the extent of response. Methods: We conducted a study using an optimized digital droplet PCR-based method for the ultra-sensitive detection of SMN transcript in serum EVs from SMA 2 individuals treated with nusinersen over 14 months. In parallel, we investigated levels of serum and CSF neurofilament heavy chain (pNF-H) in the same cohort. Results: Expression of …flSMN transcript in EVs of SMA 2 individuals prior to nusinersen was lower than in controls (0.40 vs 2.79 copies/ul; p  < 0.05) and increased after 14 months of nusinersen (0.40 vs 1.11 copies/ul; p  < 0.05). The increase in flSMN with nusinersen was significantly higher in younger individuals (p  < 0.05). Serum pNF-h was higher in non-treated individuals with SMA 2 than in controls (230.72 vs 22.88 pg/ml; p  < 0.05) and decreased with nusinersen (45.72 pg/ml at 6 months, 39.02 pg/ml at 14 months). CSF pNF-h in SMA 2 individuals also decreased with nusinersen (248.04 pg/ml prior to treatment, 197.10 pg/dl at 2 months, 104.43 pg/dl at 6 months, 131.03 pg/dl at 14 months). Conclusions: We identified an increase of flSMN transcript in serum EVs of SMA 2 individuals treated with nusinersen that was more pronounced in the younger individuals. Our results indicate that flSMN transcript expression in serum EVs is a possible biomarker in SMA to predict or monitor the response to treatment. Show more

Keywords: Biomarkers, cerebrospinal fluid, nusinersen, response predictors, serum, spinal muscular atrophy

DOI: 10.3233/JND-230012

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 653-665, 2023

Authors: Chen, Pin-Shiuan | Chao, Chi-Chao | Tsai, Li-Kai | Huang, Hsin-Yi | Chien, Yin-Hsiu | Huang, Pei-Hsin | Hwu, Wuh-Liang | Hsieh, Sung-Tsang | Lee, Ni-Chung | Hsueh, Hsueh-Wen | Yang, Chih-Chao

Article Type: Research Article

Abstract: Background: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular disorders. To achieve an accurate diagnosis, physicians should interpret the genetic report carefully along with clinical information and examinations. We described our experience with (1) clinical validation in patients with variants found using WES and (2) a diagnostic approach for those with negative findings from WES. Methods: WES was performed on patients with the clinical impression of hereditary neuromuscular disorders. Information on clinical manifestations, neurological examination, electrodiagnostic studies, histopathology of muscle and nerve, and laboratory tests were collected. Results: Forty-one patients (Male/Female: 18/23, age of onset: …34.5±15.9) accepted WES and were categorized into four scenarios: (1) patients with a positive WES result, (2) patients with an inconclusive WES result but supporting clinical data, (3) negative findings from WES, but a final diagnosis after further work-up, and (4) undetermined etiology from WES and in further work-ups. The yield rate of the initial WES was 63.4% (26/41). Among these, seventeen patients had positive WES result, while the other nine patients had inconclusive WES result but supporting clinical data. Notably, in the fifteen patients with negative findings from WES, four patients (26.7%) achieved a diagnosis after further workup: tumor-induced osteomalacia, metabolic myopathy with pathogenic variants in mitochondrial DNA, microsatellite expansion disease, and vasculitis-related neuropathy. The etiologies remained undetermined in eleven patients (myopathy: 7, neuropathy: 4) after WES and further workup. Conclusions: It is essential to design genotype-guided molecular studies to correlate the identified variants with their clinical features. For patients who had negative findings from WES, acquired diseases, mitochondrial DNA disorders and microsatellite expansion diseases should be considered. Show more

Keywords: Whole-exome sequencing, neuromuscular disorders, myopathy, neuropathy, motor neuron disease

DOI: 10.3233/JND-230013

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 667-684, 2023

Authors: Connolly, Anne M. | Zaidman, Craig M. | Brandsema, John F. | Phan, Han C. | Tian, Cuixia | Zhang, Xueping | Li, Jack | Eisner, Mark D. | Carrier, Ewa

Article Type: Research Article

Abstract: BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change …from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was –4.2 (0.7) (95% CI –5.5, –2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results. Show more

Keywords: Clinical trial, connective tissue growth factor, Duchenne muscular dystrophy, percent predicted forced vital capacity, grip strength, monoclonal antibody, pamrevlumab

DOI: 10.3233/JND-230019

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 685-699, 2023

Authors: Joosten, Isis B.T. | Fuchs, Cas J. | Beelen, Milou | Plasqui, Guy | van Loon, Luc J.C. | Faber, Catharina G.

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) patients are at risk for metabolic abnormalities and commonly experience overweight and obesity. Possibly, weight issues result from lowered resting energy expenditure (EE) and impaired muscle oxidative metabolism. Objectives: This study aims to assess EE, body composition, and muscle oxidative capacity in patients with DM1 compared to age-, sex- and BMI-matched controls. Methods: A prospective case control study was conducted including 15 DM1 patients and 15 matched controls. Participants underwent state-of-the-art methodologies including 24 h whole room calorimetry, doubly labeled water and accelerometer analysis under 15-days of free-living conditions, muscle biopsy, …full body magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DEXA), computed tomography (CT) upper leg, and cardiopulmonary exercise testing. Results: Fat ratio determined by full body MRI was significantly higher in DM1 patients (56 [49–62] %) compared to healthy controls (44 [37–52] % ; p  = 0.027). Resting EE did not differ between groups (1948 [1742–2146] vs (2001 [1853–2425>] kcal/24 h, respectively; p  = 0.466). In contrast, total EE was 23% lower in DM1 patients (2162 [1794–2494] vs 2814 [2424–3310] kcal/24 h; p  = 0.027). Also, DM1 patients had 63% less steps (3090 [2263–5063] vs 8283 [6855–11485] steps/24 h; p  = 0.003) and a significantly lower VO2 peak (22 [17–24] vs 33 [26–39] mL/min/kg; p  = 0.003) compared to the healthy controls. Muscle biopsy citrate synthase activity did not differ between groups (15.4 [13.3–20.0] vs 20.1 [16.6–25.8] μM/g/min, respectively; p  = 0.449). Conclusions: Resting EE does not differ between DM1 patients and healthy, matched controls when assessed under standardized circumstances. However, under free living conditions, total EE is substantially reduced in DM1 patients due to a lower physical activity level. The sedentary lifestyle of DM1 patients seems responsible for the undesirable changes in body composition and aerobic capacity. Show more

Keywords: Myotonic dystrophy, energy expenditure, body composition, physical activity

DOI: 10.3233/JND-230036

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 701-712, 2023

Authors: Wennberg, Alexandra | Lenzoni, Sabrina | Turcano, Pierpaolo | Casagrande, Elena | Caumo, Luca | Sorarú, Gianni | Pegoraro, Elena | Semenza, Carlo

Article Type: Short Communication

Abstract: Sleep quality and its association with cognition has been widely studied in some neurodegenerative diseases, but less is known about this association in spinal muscular atrophy (SMA). In adult SMA (n  = 21) patients and age-matched controls (n  = 23), we assessed subjectively measured sleep quality and daytime somnolence. Cognition was assessed with a multi-domain neuropsychological battery. Further, we investigated the association between clinical functional scores and sleep questionnaire scores. Among SMA patients, better motor and limb function was associated with better subjective sleep quality (p ’s< 0.05). Clinicians should consider sleep quality in patient care and future studies are needed to better …understand these relationships. Show more

Keywords: Spinal muscular atrophy, neuromuscular disease, sleep quality, cognition

DOI: 10.3233/JND-221627

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 713-717, 2023

Authors: Machetanz, Gerrit | Grziwotz, Marc | Semmler, Luisa | Maier, Mathias | Maegerlein, Christian | Deschauer, Marcus

Article Type: Case Report

Abstract:  In patients with spinal muscular atrophy (SMA) headache after intrathecal administration of nusinersen is usually attributed to post-lumbar puncture syndrome. However, lumbar puncture opening pressure (LOP) has also been reported to be increased in children with SMA, both before and after treatment with nusinersen, although symptoms associated with increased LOP were not observed. We report to our knowledge the first case of symptomatic intracranial hypertension in an adult SMA patient. This 21-year-old man suffered from headache and vomiting followed by visual disturbances after the 12th injection of nusinersen. Bilateral papilledema was recognized ophthalmologically. MRI of the head showed signs of …intracranial hypertension and additionally arachnoid cysts but not hydrocephalus. Symptoms resolved after 8 weeks of treatment with repeated lumbar punctures and acetazolamide. This case raises the possibility of intracranial hypertension as a complication of nusinersen therapy although arachnoid cysts represent another risk factor for intracranial hypertension. We recommend that patients suffering from headache after nusinersen injections should not only be questioned and examined for symptoms suggestive of post-lumbar puncture syndrome, but also intracranial hypertension. Show more

Keywords: Spinal muscular atrophy, nusinersen, antisense oligonucleotides, intracranial hypertension, arachnoid cysts

DOI: 10.3233/JND-230032

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 719-725, 2023

Authors: Baskar, Dipti | Vengalil, Seena | Nashi, Saraswati | Bardhan, Mainak | Srivastava, Kosha | Sanka, Sai Bhargava | Polavarapu, Kiran | Menon, Deepak | Preethish-Kumar, Veeramani | Padmanabha, Hansashree | Arunachal, Gautham | Nalini, Atchayaram

Article Type: Case Report

Abstract: Chronic progressive external ophthalmoplegia (CPEO) is symptom complex with progressive ptosis and restricted ocular motility without diplopia. MYH2 myopathy is rare disorder presenting with CPEO and muscle weakness. We report two Indian patients of MYH2 myopathy with unique features. Patient-1 presented with early adult-onset esophageal reflux followed by, proximal lower limb weakness, proptosis, CPEO without ptosis. He had elevated creatine kinase along with characteristic muscle MRI findings of prominent semitendinosus and medial gastrocnemius involvement. Patient -2 presented with early adult onset CPEO without limb weakness. His creatine kinase was normal. Both the patients had novel MYH2 mutations: …a homozygous 5’splice variation in intron 4 (c.348 + 2dup) in patient 1 and homozygous single base pair deletion in exon 32 (p. Ala1480ProfsTer11) in patient 2. Unique features noted include adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities. MYH2 myopathy has to be considered in adult patients with CPEO. Show more

Keywords: MYH2 myopathy, chronic progressive external ophthalmoplegia CPEO, India

DOI: 10.3233/JND-230017

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 727-730, 2023