Journal of Neuromuscular Diseases - Volume 10, issue 5

Authors: Pugliese, Alessia | Holland, Stephen H. | Rodolico, Carmelo | Lochmüller, Hanns | Spendiff, Sally

Article Type: Review Article

Abstract: Presynaptic congenital myasthenic syndromes (CMS) are a group of genetic disorders affecting the presynaptic side of the neuromuscular junctions (NMJ). They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft. Other proteins involved in presynaptic endplate development and maintenance can also be impaired. Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis. However, milder phenotypes with proximal muscle weakness and good response to treatment have been described. Finally, many presynaptic …genes are expressed in the brain, justifying the presence of additional central nervous system symptoms. Several animal models have been developed to study CMS, providing the opportunity to identify disease mechanisms and test treatment options. In this review, we describe presynaptic CMS phenotypes with a focus on in vivo models, to better understand CMS pathophysiology and define new causative genes. Show more

Keywords: Congenital myasthenic syndromes, neuromuscular junction, animal models, gene mutations

DOI: 10.3233/JND-221646

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 731-759, 2023

Authors: Caron, Leslie | Testa, Stefano | Magdinier, Frédérique

Article Type: Review Article

Abstract: Neuromuscular disorders (NMDs) are a large group of diseases associated with either alterations of skeletal muscle fibers, motor neurons or neuromuscular junctions. Most of these diseases is characterized with muscle weakness or wasting and greatly alter the life of patients. Animal models do not always recapitulate the phenotype of patients. The development of innovative and representative human preclinical models is thus strongly needed for modeling the wide diversity of NMDs, characterization of disease-associated variants, investigation of novel genes function, or the development of therapies. Over the last decade, the use of patient’s derived induced pluripotent stem cells (hiPSC) has resulted …in tremendous progress in biomedical research, including for NMDs. Skeletal muscle is a complex tissue with multinucleated muscle fibers supported by a dense extracellular matrix and multiple cell types including motor neurons required for the contractile activity. Major challenges need now to be tackled by the scientific community to increase maturation of muscle fibers in vitro , in particular for modeling adult-onset diseases affecting this tissue (neuromuscular disorders, cachexia, sarcopenia) and the evaluation of therapeutic strategies. In the near future, rapidly evolving bioengineering approaches applied to hiPSC will undoubtedly become highly instrumental for investigating muscle pathophysiology and the development of therapeutic strategies. Show more

Keywords: Induced pluripotent stem cells, neuromuscular disorders, satellite cells, myoblasts, myotubes, motor neurons, neuromuscular junctions, 3D culture, therapy

DOI: 10.3233/JND-230076

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 761-776, 2023

Authors: Middelink, Marloes | Voermans, Nicol C. | van Engelen, Baziel G.M. | Janssen, Mirian C.H. | Groothuis, Jan T. | Knuijt, Simone | Zweers-van Essen, Heidi

Article Type: Systematic Review

Abstract: Background: Eating an adequate diet and maintaining a healthy body weight can be challenging for patients with muscular disorders (MD). Starting tube feeding can have a positive impact on nutritional status, functioning and quality of life. Guidelines on when to start tube feeding in adults with MD are lacking. Objective: We aim to review the scientific literature on indications to start tube feeding in adults with facioscapulohumeral dystrophy (FSHD), inclusion body myositis (IBM), muscular dystrophy type 1 (DM1), oculopharyngeal muscular dystrophy (OPMD) and congenital myopathies. Methods: This scoping review was conducted according to the Preferred Reporting …Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines. Relevant studies were identified in Pubmed, Embase and Cinahl (April 2022). The medical subject headings (MeSH) and text words used were related to FSHD, IBM, DM1, OPMD or congenital myopathies and dysphagia, enteral nutrition or malnutrition. Results: Of 1046 unique articles, 9 case reports and 2 retrospective case series were included. Indications to start tube feeding were dysphagia, malnutrition/weight loss and respiratory infections (due to aspiration). Percutaneous endoscopic gastrostomy (PEG) tubes were used most often and complications were respiratory failure, problems with the tube itself, accidental tube removal, cutaneous symptoms, digestive symptoms, and peritonitis. Conclusion: Data on tube feeding in MD is scarce. Indications to start tube feeding were similar across the various MD. We call for more research in this field and suggest to include screening for dysphagia, aspiration and malnutrition in for the treatment of various MD. Show more

Keywords: Enteral nutrition, dysphagia, pneumonia, aspiration, malnutrition, weight loss, muscular dystrophies, myositis, inclusion body, myopathies, structural, congenital

DOI: 10.3233/JND-230014

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 777-785, 2023

Authors: Markvardsen, Lars K. | Sindrup, Søren H. | Christiansen, Ingelise | Sheikh, Aisha M. | Holbech, Jakob V. | Andersen, Henning

Article Type: Research Article

Abstract: Background: Attempting discontinuation of treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is recommended. However, there is no evidence based regimen for tapering off subcutaneous immunoglobulin (SCIG). This trial investigated stepwise tapering off SCIG to detect remission and the lowest effective dosage. During tapering off, frequent vs less frequent clinical evaluation was compared. Methods: Patients with CIDP receiving a stable SCIG dosage followed a standardized tapering off regimen: 90%, 75%, 50%, 25% and 0% of the initial dose every 12th week, pending no deterioration occurred. In case of relapse during tapering off, the lowest effective dose was …identified. Treatment with SCIG was registered for two years after participation. Disability score and grip strength were primary parameters. Participants were randomized to clinical evaluation every 6th week (frequent) or 12th week (less frequent). Results: Fifty-five patients were included of which thirty-five relapsed. Twenty patients (36%) were able to discontinue treatment without relapse. In relapsing patients, median dosage could be reduced by 10% (range, 0–75). After two years, 18 of 20 patients were still in remission without treatment. Frequent clinical evaluation did not detect deterioration more frequently than less frequent evaluation; RR 0.5 (95% CI, 0.2–1.2) (p  = 0.17). Conclusion: In stable CIDP patients, SCIG could be completely tapered off in 36% of the patients and only in 10% of these patients relapse occurred during the following two years. More frequent evaluation was not superior to detect deterioration. Show more

Keywords: Inflammatory neuropathy, immunoglobulin

DOI: 10.3233/JND-221615

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 787-796, 2023

Authors: Zygmunt, Deborah A. | Lam, Patricia | Ashbrook, Anna | Koczwara, Katherine | Lek, Angela | Lek, Monkol | Martin, Paul T.

Article Type: Research Article

Abstract: Background: GNE myopathy (GNEM) is a severe muscle disease caused by mutations in the UDP-GlcNAc-2-epimerase/ManNAc-6-kinase (GNE ) gene, which encodes a bifunctional enzyme required for sialic acid (Sia) biosynthesis. Objective: To develop assays to demonstrate the potency of AAV gene therapy vectors in making Sia and to define the dose required for replacement of endogenous mouse Gne gene expression with human GNE in skeletal muscles. Methods: A MyoD -inducible Gne -deficient cell line, Lec3MyoDI , and a GNE- deficient human muscle cell line, were made and tested to define the potency of various AAV …vectors to increase binding of Sia-specific lectins, including MAA and SNA. qPCR and qRT-PCR methods were used to quantify AAV biodistribution and GNE gene expression after intravenous delivery of AAV vectors designed with different promoters in wild-type mice. Results: Lec3 cells showed a strong deficit in MAA binding, while GNE –/– MB135 cells did not. Overexpressing GNE in Lec3 and Lec3MyoDI cells by AAV infection stimulated MAA binding in a dose-dependent manner. Use of a constitutive promoter, CMV, showed higher induction of MAA binding than use of muscle-specific promoters (MCK, MHCK7). rAAVrh74.CMV.GNE stimulated human GNE expression in muscles at levels equivalent to endogenous mouse Gne at a dose of 1×1013 vg/kg, while AAVs with muscle-specific promoters required higher doses. AAV biodistribution in skeletal muscles trended higher when CMV was used as the promoter, and this correlated with increased sialylation of its viral capsid. Conclusions: Lec3 and Lec3MyoDI cells work well to assay the potency of AAV vectors in making Sia. Systemic delivery of rAAVrh74.CMV.GNE can deliver GNE gene replacement to skeletal muscles at doses that do not overwhelm non-muscle tissues, suggesting that AAV vectors that drive constitutive organ expression could be used to treat GNEM. Show more

Keywords: GNE myopathy, gene therapy, sialic acid, AAV, muscular dystrophy

DOI: 10.3233/JND-221596

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 797-812, 2023

Authors: Finkel, Richard S. | Day, John W. | Pascual Pascual, Samuel Ignacio | Ryan, Monique M. | Mercuri, Eugenio | De Vivo, Darryl C. | Montes, Jacqueline | Gurgel-Giannetti, Juliana | Monine, Michael | Gambino, Giulia | Makepeace, Corinne | Foster, Richard | Berger, Zdenek

Article Type: Research Article

Abstract: Background: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. Objective: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. Methods: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to …higher doses. Results: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1–12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. Conclusions: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen. Show more

Keywords: Spinal muscular atrophy, nusinersen, safety, pharmacokinetics

DOI: 10.3233/JND-221667

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 813-823, 2023

Authors: van Kleef, Esmee S.B. | Langer, Daniel | van Engelen, Baziel G.M. | Ottenheijm, Coen A.C. | Voermans, Nicol C. | Doorduin, Jonne

Article Type: Research Article

Abstract: Background: Respiratory muscle weakness is a common feature in nemaline myopathy. Inspiratory muscle training (IMT) is an intervention that aims to improve inspiratory muscle strength. Objective: The aim of this controlled before-and-after pilot study was to investigate if IMT improves respiratory muscle strength in patients with nemaline myopathy. Methods: Nine patients (7 females; 2 males, age 36.6±20.5 years) with respiratory muscle weakness and different clinical phenotypes and genotypes were included. Patients performed eight weeks of sham IMT followed by eight weeks of active threshold IMT. The patients trained twice a day five days a week for …15 minutes at home. The intensity was constant during the training after a gradual increase to 30% of maximal inspiratory pressure (MIP). Results: Active IMT significantly improved MIP from 43±15.9 to 47±16.6 cmH2 O (p  = 0.019). The effect size was 1.22. There was no significant effect of sham IMT. Sniff nasal inspiratory pressure, maximal expiratory pressure, spirometry, and diaphragm thickness and thickening showed no significant improvements. Conclusions: This pilot study shows that threshold IMT is feasible in patients with nemaline myopathy and improves inspiratory muscle strength. Our findings provide valuable preliminary data for the design of a larger, more comprehensive trial. Show more

Keywords: Respiratory muscle weakness, nemaline myopathy, inspiratory muscle training, diaphragm

DOI: 10.3233/JND-221665

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 825-834, 2023

Authors: Kleinle, Stephanie | Scholz, Veronika | Benet-Pagés, Anna | Wohlfrom, Tobias | Gehling, Stefanie | Scharf, Florentine | Rost, Simone | Prott, Eva-Christina | Grinzinger, Susanne | Hotter, Anna | Haug, Verena | Niemeier, Sabine | Wiethoff-Ubrig, Lucia | Hagenacker, Tim | Goldhahn, Klaus | von Moers, Arpad | Walter, Maggie C. | Reilich, Peter | Eggermann, Katja | Kraft, Florian | Kurth, Ingo | Erdmann, Hannes | Holinski-Feder, Elke | Neuhann, Teresa | Abicht, Angela

Article Type: Research Article

Abstract: Background: The importance of early diagnosis of 5q-Spinal muscular atrophy (5q-SMA) has heightened as early intervention can significantly improve clinical outcomes. In 96% of cases, 5q-SMA is caused by a homozygous deletion of SMN1 . Around 4 % of patients carry a SMN1 deletion and a single-nucleotide variant (SNV) on the other allele. Traditionally, diagnosis is based on multiplex ligation probe amplification (MLPA) to detect homozygous or heterozygous exon 7 deletions in SMN1 . Due to high homologies within the SMN1/SMN2 locus, sequence analysis to identify SNVs of the SMN1 gene is unreliable by standard Sanger or …short-read next-generation sequencing (srNGS) methods. Objective: The objective was to overcome the limitations in high-throughput srNGS with the aim of providing SMA patients with a fast and reliable diagnosis to enable their timely therapy. Methods: A bioinformatics workflow to detect homozygous SMN1 deletions and SMN1 SNVs on srNGS analysis was applied to diagnostic whole exome and panel testing for suggested neuromuscular disorders (1684 patients) and to fetal samples in prenatal diagnostics (260 patients). SNVs were detected by aligning sequencing reads from SMN1 and SMN2 to an SMN1 reference sequence. Homozygous SMN1 deletions were identified by filtering sequence reads for the ,, gene-determining variant“ (GDV). Results: 10 patients were diagnosed with 5q-SMA based on (i) SMN1 deletion and hemizygous SNV (2 patients), (ii) homozygous SMN1 deletion (6 patients), and (iii) compound heterozygous SNVs in SMN1 (2 patients). Conclusions: Applying our workflow in srNGS-based panel and whole exome sequencing (WES) is crucial in a clinical laboratory, as otherwise patients with an atypical clinical presentation initially not suspected to suffer from SMA remain undiagnosed. Show more

Keywords: 5q-SMA, spinal muscular atrophy, clinical genetics, neuromuscular disorders, bioninformatics, dark genes

DOI: 10.3233/JND-221668

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 835-846, 2023

Authors: Sun, Jianli | Harrington, Melissa A. | Porter, Ben

Article Type: Research Article

Abstract: Background: Sex is a significant risk factor in many neurodegenerative disorders. A better understanding of the molecular mechanisms behind sex differences could help develop more targeted therapies that would lead to better outcomes. Untreated spinal muscular atrophy (SMA) is the leading genetic motor disorder causing infant mortality. SMA has a broad spectrum of severity ranging from prenatal death to infant mortality to normal lifespan with some disability. Scattered evidence points to a sex-specific vulnerability in SMA. However, the role of sex as a risk factor in SMA pathology and treatment has received limited attention. Objective: Systematically investigate sex …differences in the incidence, symptom severity, motor function of patients with different types of SMA, and in the development of SMA1 patients. Methods: Aggregated data of SMA patients were obtained from the TREAT-NMD Global SMA Registry and the Cure SMA membership database by data enquiries. Data were analyzed and compared with publicly available standard data and data from published literature. Results: The analysis of the aggregated results from the TREAT-NMD dataset revealed that the male/female ratio was correlated to the incidence and prevalence of SMA from different countries; and for SMA patients, more of their male family members were affected by SMA. However, there was no significant difference of sex ratio in the Cure SMA membership dataset. As quantified by the clinician severity scores, symptoms were more severe in males than females in SMA types 2 and 3b. Motor function scores measured higher in females than males in SMA types 1, 3a and 3b. The head circumference was more strongly affected in male SMA type 1 patients. Conclusions: The data in certain registry datasets suggest that males may be more vulnerable to SMA than females. The variability observed indicates that more investigation is necessary to fully understand the role of sex differences in SMA epidemiology, and to guide development of more targeted treatments. Show more

Keywords: Spinal muscular atrophy, sex difference, male/female ratio, severity, motor function, development

DOI: 10.3233/JND-230011

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 847-867, 2023

Authors: Keene, Kevin R. | Notting, Irene C. | Verschuuren, Jan J.G.M. | Voermans, N. | de Keizer, Ronald. O.B. | Beenakker, Jan-Willem M. | Tannemaat, Martijn R. | Kan, Hermien E.

Article Type: Research Article

Abstract: Introduction: MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves’ ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Methods: Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze …deviations were assessed by synoptophore and Hess-charting. Results: Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p  < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3 , p  < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3 , p  < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p  < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. Interpretation: We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery. Show more

Keywords: Myasthenia gravis, quantitative MRI, eye muscles, extra-ocular muscles, chronic progressive external ophthalmoplegia (CPEO), diplopia, ptosis, oculopharyngeal muscular dystrophy (OPMD) and Graves’ orbitopathy

DOI: 10.3233/JND-230023

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 869-883, 2023