Journal of Neuromuscular Diseases - Volume 11, issue 3

Authors: Rasing, Nathaniël B. | van de Geest-Buit, Willianne A. | Chan, On Ying A. | Mul, Karlien | Lanser, Anke | van Engelen, Baziel G.M. | Erasmus, Corrie E. | Fischer, Agneta H. | Ingels, Koen J.A.O. | Post, Bart | Siemann, Ietske | Groothuis, Jan T. | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: Facial weakness is a key feature of facioscapulohumeral muscular dystrophy (FSHD) and may lead to altered facial expression and subsequent psychosocial impairment. There is no cure and supportive treatments focus on optimizing physical fitness and compensation of functional disabilities. Objective: We hypothesize that symptomatic treatment options and psychosocial interventions for other neurological diseases with altered facial expression could be applicable to FSHD. Therefore, the aim of this review is to collect symptomatic treatment approaches that target facial muscle function and psychosocial interventions in various neurological diseases with altered facial expression in order to discuss the applicability to …FSHD. Methods: A systematic search was performed. Selected studies had to include FSHD, Bell’s palsy, Moebius syndrome, myotonic dystrophy type 1, or Parkinson’s disease and treatment options which target altered facial expression. Data was extracted for study and patients’ characteristics, outcome assessment tools, treatment, outcome of facial expression and or psychosocial functioning. Results: Forty studies met the inclusion criteria, of which only three studies included FSHD patients exclusively. Most, twenty-one, studies were performed in patients with Bell’s palsy. Studies included twelve different therapy categories and results were assessed with different outcomes measures. Conclusions: Five therapy categories were considered applicable to FSHD: training of (non-verbal) communication compensation strategies, speech training, physical therapy, conference attendance, and smile restoration surgery. Further research is needed to establish the effect of these therapies in FSHD. We recommend to include outcome measures in these studies that cover at least cosmetic, functional, communication, and quality of life domains. Show more

Keywords: (MeSH terms): Muscular dystrophy, facioscapulohumeral, bell palsy, Parkinson’s disease, myotonic dystrophy, mobius syndrome, facial expression, therapeutics, psychosocial functioning

DOI: 10.3233/JND-230213

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 535-565, 2024

Authors: Voet, Nicoline | Pater, Ronne | Garmendia, Joana | Sistiaga, Andone | Labayru, Garazi | Gallais, Benjamin | de Groot, Ingrid | Muslemani, Samar | Gagnon, Cynthia | Graham, Christopher

Article Type: Review Article

Abstract:  Patient-reported outcome measures (PROMs) are valuable in comprehensively understanding patients’ health experiences and informing healthcare decisions in research and clinical care without clinicians’ input. Until now, no central resource containing information on all PROMS in neuromuscular diseases (NMD) is available, hindering the comparison and choice of PROMs used to monitor NMDs and appropriately reflect the patient’s voice. This scoping review aimed to present a comprehensive assessment of the existing literature on using PROMs in children and adults with NMD. A scoping methodology was followed using Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and COnsensus-based …Standards for the selection of health Measurement INstruments (COSMIN) guidelines to assess the literature on PROMs in NMDs. Eligibility criteria encompassed articles describing psychometric development or evaluation of generic or disease-specific PROM-based instruments for adults and children with specific NMDs. The data charting process involved extracting measurement properties of included PROMs, comprising validity, reliability, responsiveness, and interpretability information. The review identified 190 PROMs evaluated across 247 studies in individuals with NMDs. The majority of PROMs were disease specific. The physical functioning domain was most assessed. Validity was the most frequently investigated measurement property, with a limited number of PROMs sufficiently evaluated for a range of psychometric characteristics. There is a strong need for further research on the responsiveness and interpretability of PROMs and the development of PROMs on social functioning in NMD. Show more

Keywords: Neuromuscular diseases, patient-reported outcome measures, health-related quality of life, validation of measurement instruments, scoping review, measurement properties

DOI: 10.3233/JND-240003

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 567-577, 2024

Authors: Landfeldt, E. | Alemán, A. | Abner, S. | Zhang, R. | Werner, C. | Tomazos, I. | Ferizovic, N. | Lochmüller, H. | Kirschner, J.

Article Type: Systematic Review

Abstract: Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD). Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included “Duchenne muscular dystrophy” as a Medical Subject Heading or free text term, in combination with variations of the term “predictor”. Risk of bias was assessed using the Newcastle–Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids …(vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model. Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40–0.48]) (n  = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. ≥350 metres and <330 vs. ≥330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n  = 5 studies). Deletion of exons 3–7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49–50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n  = 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n  = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n  = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n  = 2 studies) and eteplirsen (n  = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n  = 6 studies). In total, 33% of studies exhibited some risk of bias. Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population. Show more

Keywords: Motor function, 6MWT, Neuromuscular Disease, treatment, guidelines, NOS

DOI: 10.3233/JND-230220

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 579-612, 2024

Authors: Diogenes, Larissa | Dellavance, Alessandra | Baldo, Danielle Cristiane | Gozzi-Silva, Sarah Cristina | Gomes, Kethellen | Prado, Monica Simon | Andrade, Luis Eduardo C. | Keppeke, Gerson Dierley

Article Type: Research Article

Abstract: Background/Objective: Myasthenia Gravis (MG) is an autoimmune disorder characterized by pathogenic autoantibodies (AAbs) targeting nicotinic acetylcholine receptors (AChR), disrupting neuromuscular communication. RadioImmunoPrecipitation Assay (RIPA) is recommended to detect AChR AAbs, but its complexity and radioactive requirements limit widespread use. We compare non-RIPA anti-AChR immunoassays, including Cell-Based Assay (CBA) and two ELISA kits, against the gold standard RIPA. Methods/Results: 145 samples were included with medical indication for anti-AChR testing. By the RIPA method, 63 were negative (RIPA-Neg < 0.02 nmol/L), 18 were classified as Borderline (≥0.02 –1 nmol/L), and 64 were positive (RIPA-Pos > 1 nmol/L). The competitive ELISA showed poor …agreement with RIPA (Kappa = 0.216). The indirect ELISA demonstrated substantial agreement with RIPA (Kappa = 0.652), with ∼76% sensitivity and ∼94% specificity for MG diagnostic. The CBA, where fixed cells expressing clustered AChR were used as substrate, exhibited almost perfect agreement with RIPA (Kappa = 0.984), yielding ∼98% sensitivity and 96% specificity for MG. In addition, a semiquantitative analysis showed a strong correlation between CBA titration, indirect ELISA, and RIPA levels (r  = 0.793 and r  = 0.789, respectively). Conclusions: The CBA displayed excellent analytical performance for MG diagnostic when compared to RIPA, making it a potential replacement for RIPA in clinical laboratories. Some solid-phase assays (such as the indirect ELISA applied here), as well as CBA titration, offer reliable options to estimate anti-AChR AAb levels after confirming positivity by the CBA.∥ Show more

Keywords: Myasthenia gravis, nicotinic acetylcholine receptor, Autoantibodies, radioimmunoprecipitation, cell-based assay, enzyme-linked immunosorbent assay

DOI: 10.3233/JND-230210

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 613-623, 2024

Authors: Della Marina, Adela | Hentschel, Andreas | Czech, Artur | Schara-Schmidt, Ulrike | Preusse, Corinna | Laner, Andreas | Abicht, Angela | Ruck, Tobias | Weis, Joachim | Choueiri, Catherine | Lochmüller, Hanns | Kölbel, Heike | Roos, Andreas

Article Type: Research Article

Abstract: Background: NEFL encodes for the neurofilament light chain protein. Pathogenic variants in NEFL cause demyelinating, axonal and intermediate forms of Charcot-Marie-Tooth disease (CMT) which present with a varying degree of severity and somatic mutations have not been described yet. Currently, 34 different CMT-causing pathogenic variants in NEFL in 174 patients have been reported. Muscular involvement was also described in CMT2E patients mostly as a secondary effect. Also, there are a few descriptions of a primary muscle vulnerability upon pathogenic NEFL variants. Objectives: To expand the current knowledge on the genetic landscape, clinical presentation and …muscle involvement in NEFL-related neurological diseases by retrospective case study and literature review. Methods: We applied in-depth phenotyping of new and already reported cases, molecular genetic testing, light-, electron- and Coherent Anti-Stokes Raman Scattering-microscopic studies and proteomic profiling in addition to in silico modelling of NEFL-variants. Results: We report on a boy with a muscular phenotype (weakness, myalgia and cramps, Z-band alterations and mini-cores in some myofibers) associated with the heterozygous p.(Phe104Val) NEFL -variant, which was previously described in a neuropathy case. Skeletal muscle proteomics findings indicated affection of cytoskeletal proteins. Moreover, we report on two further neuropathic patients (16 years old girl and her father) both carrying the heterozygous p.(Pro8Ser) variant, which has been identified as 15% somatic mosaic in the father. While the daughter presented with altered neurophysiology,neurogenic clump feet and gait disturbances, the father showed clinically only feet deformities. As missense variants affecting proline at amino acid position 8 are leading to neuropathic manifestations of different severities, in silico modelling of these different amino acid substitutions indicated variable pathogenic impact correlating with disease onset. Conclusions: Our findings provide new morphological and biochemical insights into the vulnerability of denervated muscle (upon NEFL-associated neuropathy) as well as novel genetic findings expanding the current knowledge on NEFL-related neuromuscular phenotypes and their clinical manifestations. Along this line, our data show that even subtle expression of somatic NEFL variants can lead to neuromuscular symptoms. Show more

Keywords: Neurofilament light chain, protein accumulation, muscle proteomics, somatic mutation, CARS microscopy muscle

DOI: 10.3233/JND-230230

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 625-645, 2024

Authors: Estévez-Arias, Berta | Matalonga, Leslie | Martorell, Loreto | Codina, Anna | Ortez, Carlos | Carrera-García, Laura | Expósito-Escudero, Jessica | Yubero, Delia | Hoenicka, Janet | Jou, Cristina | Palau, Francesc | Beltran, Sergi | Lochmüller, Hanns | Töpf, Ana | Nascimento, Andrés | Natera-de Benito, Daniel

Article Type: Research Article

Abstract: Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1 -CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant …might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism. Show more

Keywords: Congenital myopathy,, RYR1, mosaicism, genome sequencing

DOI: 10.3233/JND-230216

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 647-653, 2024

Authors: van Bruggen, H. Willemijn | Wijngaarde, Camiel A. | Asselman, Faylynn | Stam, Marloes | Creugers, Nico H.J. | Wadman, Renske I. | van der Pol, W. Ludo | Kalaykova, Stanimira I.

Article Type: Research Article

Abstract: Background: Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. Objective: In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3. Methods: We included 44 patients with SMA types 2 and 3 (mean age was 33.6 (95% CI 28.4;38.9) and re-examined them after on average 4 …years. None were treated with SMN- modulating treatments before or during the course of this study. Longitudinal assessments included a questionnaire on mandibular and bulbar function, the Mandibular Function Impairment Questionnaire (MFIQ), and a clinical examination of masticatory performance, maximum voluntary bite force, and mandibular movements including the active maximal mouth opening. Results: We found significant higher MFIQ scores and a significant decrease of all mandibular movements in patients with SMA type 2 (p  < 0.001), but not in SMA type 3. Masticatory performance and maximum voluntary bite force did not change significantly. Mean reduction of active maximal mouth opening at follow-up was 3.5 mm in SMA type 2 (95% CI: 2.3; 4.7, p  < 0.001). SMA type 2 was an independent predictor for a more severe reduction of the mouth opening (β= –2.0 mm (95% CI: –3.8; –0.1, p  = 0.043)). Conclusions: Bulbar functions such as mandibular mobility and active maximum mouth opening decrease significantly over the course of four years in patients with SMA type 2. Show more

Keywords: Spinal muscular atrophy, bulbar function, dysphagia

DOI: 10.3233/JND-240007

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 655-664, 2024

Authors: Wolfe, Amy | Stimpson, Georgia | Ramsey, Danielle | Coratti, Giorgia | Dunaway Young, Sally | Mayhew, Anna | Pane, Marika | Rohwer, Annemarie | Muni Lofra, Robert | Duong, Tina | O’Reilly, Emer | Milev, Evelin | Civitello, Matthew | Sansone, Valeria A. | D’Amico, Adele | Bertini, Enrico | Messina, Sonia | Bruno, Claudio | Albamonte, Emilio | Mazzone, Elena | Main, Marion | Montes, Jacqueline | Glanzman, Allan M. | Zolkipli-Cunningham, Zarazuela | Pasternak, Amy | Marini-Bettolo, Chiara | Day, John W. | Darras, Basil T. | De Vivo, Darryl C. | Baranello, Giovanni | Scoto, Mariacristina | Finkel, Richard S. | Mercuri, Eugenio | Muntoni, Francesco

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had …undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a’s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes. Show more

Keywords: Spinal muscular atrophy, scoliosis, outcome measure, physical therapists

DOI: 10.3233/JND-230211

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 665-677, 2024

Authors: Nicolau, Stefan | Malhotra, Jyoti | Kaler, Maryann | Magistrado-Coxen, Pamela | Iammarino, Megan A. | Reash, Natalie F. | Frair, Emma C. | Wijeratne, Saranga | Kelly, Benjamin J. | White, Peter | Lowes, Linda P. | Waldrop, Megan A. | Flanigan, Kevin M.

Article Type: Short Communication

Abstract: Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive …fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications. Show more

Keywords: Muscular dystrophy, duchenne, dystrophin, oligonucleotides, antisense, clinical trial

DOI: 10.3233/JND-230107

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 679-685, 2024

Authors: Zaidman, Craig M. | Goedeker, Natalie L. | Aqul, Amal A. | Butterfield, Russell J. | Connolly, Anne M. | Crystal, Ronald G. | Godwin, Kara E. | Hor, Kan N. | Mathews, Katherine D. | Proud, Crystal M. | Kula Smyth, Elizabeth | Veerapandiyan, Aravindhan | Watkins, Paul B. | Mendell, Jerry R.

Article Type: Research Article

Abstract: BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. …OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider’s judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis. Show more

Keywords: Duchenne muscular dystrophy, gene therapy, dystrophin, liver injury, myocarditis, myositis, vomiting

DOI: 10.3233/JND-230185

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 3, pp. 687-699, 2024