Journal of Neuromuscular Diseases - Volume 10, issue 3

Authors: Ribault, Shams | Rippert, Pascal | Jain, Minal | Le Goff, Laure | Genod, Dominique Vincent | Barriere, Aurélie | Berruyer, Anne | Garde, Camille | Tinat, Marie | Pons, Christelle | Vuillerot, Carole

Article Type: Systematic Review

Abstract: Background: Recent pharmaceutical breakthroughs in neuromuscular diseases may considerably change the prognosis and natural history these diseases. The ability to measure clinically relevant outcomes such as motor function is critical for the assessment of therapeutics and the follow up of individuals. The Motor Function Measure (MFM) is a quantitative scale designed to measure motor function in adult and children with neuromuscular disease (NMD). Objective: The objective of this study is to assess the quality and level of evidence of the MFM’s published measurement properties by completing a systematic review of the validation and responsiveness studies of the MFM20 …(a 20-item version of MFM adapted for children 2 to 6 years of age) and the MFM32 (the original 32 item version), in all NMDs and in specific diseases. Methods: A search for MFM responsiveness and MFM validation studies was completed in February 2023 in EMBASE, MEDLINE, SCOPUS and Web of Science databases. The PRISMA guidelines and the COSMIN manual for systematic reviews were followed for databases searches, articles screening and selection, study quality and measurement properties evaluation. Results: 49 studies were included in analysis. In studies including individuals with all NMDs, MFM’s internal consistency, reliability, convergent validity, construct validity and responsiveness were rated as sufficient with a high quality of evidence. Structural validity was rated sufficient with a moderate quality of evidence In SMA in particular, MFM’s reliability, internal consistency, convergent validity, discriminant validity and responsiveness are sufficient with a high quality of evidence. More studies would be required to assess specific measurement properties in different diseases. MFM32’s minimal clinically relevant difference has been defined between 2 and 6%. Conclusion: MFM’s structural validity, internal consistency, reliability, construct validity, convergent validity and responsiveness have been verified with moderate to high level of evidence. Show more

Keywords: Outcome assessment, validation study, natural history, neuromuscular diseases, systematic review

DOI: 10.3233/JND-230001

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 301-314, 2023

Authors: Aartsma-Rus, Annemieke | De Waele, Liesbeth | Houwen-Opstal, Saskia | Kirschner, Janbernd | Krom, Yvonne D. | Mercuri, Eugenio | Niks, Erik H. | Straub, Volker | van Duyvenvoorde, Hermine A. | Vroom, Elizabeth

Article Type: Article Commentary

Abstract: Antisense oligonucleotide (ASO) mediated exon skipping aims to reframe dystrophin transcripts for patients with Duchenne muscular dystrophy (DMD). Currently 4 ASOs have been approved by the Food and Drug Administration targeting exon 45, 51 and 53 based on low level dystrophin restoration. Additional studies to confirm functional effects are ongoing. Furthermore, efforts are ongoing to increase muscle specific delivery of ASOs. Consequently, there are 5 clinical trials ongoing or planned for exon 51 skipping ASOs in Europe. While exon 51 skipping applies to the largest group of patients, DMD expert centers do not have sufficient numbers of patients or capacity …to run all these trials in parallel. Even at a national level numbers may be too scarce. At the same time, some families now face the choice between participation in different clinical trials of exon 51 skipping, sometimes in addition to the choice of participating in a micro-dystrophin gene therapy trial. In this opinion paper, we outline the challenges, compare the different exon 51 skipping trials, and outline how different European centers and countries try to cope with running multiple trials in parallel for a small group of eligible patients. Show more

Keywords: Duchenne muscular dystrophy, dystrophin, exon 51 skipping, antisense oligonucleotide, clinical trial

DOI: 10.3233/JND-221648

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 315-325, 2023

Authors: Lek, Angela | Atas, Evrim | Hesterlee, Sharon E. | Byrne, Barry J. | Bönnemann, Carsten G.

Article Type: Meeting Report

Abstract: Muscular Dystrophy Association (MDA) has invested over $125M in the development of gene therapy for neuromuscular disorders (NMD) over the past 20 years. As a lead initiator of progress in this important field of medicine and to help ensure continued progress towards therapies for patients, MDA organized a dedicated summit in January 2022 to address emerging challenges in safely delivering adeno-associated virus (AAV) mediated gene therapies with a focus on their application in NMD. In this meeting, chaired by Carsten Bönnemann (NINDS, NIH) and Barry Byrne (University of Florida), academic and industry experts and stakeholders convened to openly discuss adverse …events linked to clinical trials, as well as other challenges emerging in preclinical studies associated with difficulties in the translation of AAV-mediated gene therapies. Show more

DOI: 10.3233/JND-221639

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 327-336, 2023

Authors: Krosschell, Kristin J. | Brown, Laurey | Hoffman, Katie | Zumpf, Katelyn B. | Munson, Hannah | Bidwell, Jessa | Schulte, Duncan P. | Schwaede, Abigail N. | Buehner, Amber N. | DiDonato, Christine J. | Kuntz, Nancy L. | Rao, Vamshi K.

Article Type: Research Article

Abstract: Background: Ambulatory individuals with spinal muscular atrophy experience weakness and impairments of speed and endurance. This leads to decreased motor skill performance required for daily living including transitioning from floor to stand, climbing stairs, and traversing short and community distances. Motor function improvements have been reported in individuals receiving nusinersen, but changes in timed functional tests (TFTs) which assess shorter distance walking and transitions have not been well documented. Objective: To evaluate changes in TFT performance over the course of nusinersen treatment in ambulatory individuals with SMA and identify potential factors [age, SMN2 copy number, BMI, Hammersmith …Functional Motor Scale Expanded (HFMSE score), Peroneal Compound Motor Action Potential (CMAP) amplitude] associated with TFT performance. Methods: Nineteen ambulatory participants receiving nusinersen were followed from 2017 through 2019 (range: 0–900 days, mean 624.7 days, median 780 days); thirteen of 19 (mean age = 11.5 years) completed TFTs. The 10-meter walk/run test, time-to-rise from supine, time-to-rise from sitting, 4-stair climb, 6-minute walk test (6MWT), Hammersmith Expanded and peroneal CMAP were assessed at each visit. Linear mixed-effects models were used to evaluate unadjusted and adjusted changes in these outcomes over time. Results: Apart from time to rise from sitting and from supine, all TFTs were found to improve over the course of treatment after adjusting for baseline age and BMI. Conclusions: Improvement in TFTs over time in patients with SMA treated with nusinersen suggests that shorter TFTs may have value to assess individuals with SMA who have or later gain ambulatory function during treatment. Show more

Keywords: Spinal muscular atrophy (SMA), Nusinersen, 10-meter walk/run test (10MWRT), Timed function tests (TFT), 6-minute walk test (6MWT), Time to climb 4 stairs (TTC-4 stairs), Time to rise from supine (TTR-supine), Time to rise from bench (TTR-bench), Hammersmith Functional Motor Scale Expanded (HFMSE), Compound motor action potential (CMAP)

DOI: 10.3233/JND-221519

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 337-348, 2023

Authors: Fang, Yuan | McDonald, Craig M. | Clemens, Paula R. | Gordish, Heather-Dressman | Illei, Kate | Hoffman, Eric P. | Dang, Utkarsh J.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of drug effects in clinical trials. Objective: We hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression. Methods: Data on boys with DMD (ages 4–<10 years), both treated with steroidal anti-inflammatories and untreated, were obtained from CINRG Duchenne Natural History Study (n  = 209) and vamorolone VBP15-002/003/LTE (n  = 46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 …stairs) were simultaneously modeled in a longitudinal latent class analysis. Results: Three classes of differentially progressing early age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in required sample size as compared to using summaries from all participants. Gene mutations were also investigated in post-hoc analyses, with mutations near the beginning of the DMD gene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class. Conclusions: This study provides insight into the variation in DMD progression through a latent class analysis. Our findings show class-related trajectories of motor outcomes and pharmacological response to corticosteroids, and suggest that enrichment strategies and/or subgroup analyses could be considered further in design of therapeutic interventions in DMD. Show more

Keywords: Duchenne muscular dystrophy, longitudinal trajectories, heterogeneity in progression, early age outcomes, cluster analysis

DOI: 10.3233/JND-221527

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 349-364, 2023

Authors: Kilroy, Elisabeth A | Burris, Rachael | Javelosa, Edritz | Waits, Jessica | Lek, Angela | Rodgers, Rayne | Opgenorth, Hayley | Hesterlee, Sharon

Article Type: Research Article

Abstract: Background: Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant clinical data shortage for these rare diseases. To maximize the development and impact of new therapies, the Muscular Dystrophy Association (MDA) created the neuroMuscular ObserVational Research Data Hub (MOVR) as an observational research study that collects disease-specific measures from individuals living with NMDs in the United States. Objective: This manuscript provides a description of MOVR, participants enrolled in MOVR, and longitudinal data availability. Methods: MOVR collects longitudinal data from individuals diagnosed …with ALS, BMD, DMD, FSHD, LGMD, Pompe disease, or SMA, and who are seen for care at a participating MDA Care Center. Data are entered from medical records into standardized electronic case report forms (eCRFs). These eCRFs capture participants’ demographics, diagnostic journeys, clinical visits, and discontinuation from the study. Results: From January 2019 to May 2022, MOVR collected data from 50 participating care centers and 1,957 participants. Data from 1,923 participants who participated in MDA’s pilot registry were migrated into MOVR, creating a total of 3,880 participants in MOVR. Initial analysis of aggregated data demonstrated that 91% of eCRFs were complete. Forty-three percent of participants had 3 or more encounters and 50% of all encounters were 5 months or less from the previous encounter. Discussion: As a centralized data hub for multiple NMDs, MOVR serves as a platform that can be used to inform disease understanding, guide clinical trial design, and accelerate drug development for NMDs. Show more

Keywords: Neuromuscular diseases, registries, muscular dystrophies, amyotrophic lateral sclerosis, spinal muscular atrophy, Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, limb girdle muscular dystrophy, Pompe disease, Becker muscular dystrophy

DOI: 10.3233/JND-221551

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 365-380, 2023

Authors: Lake, Nicole J. | Phua, Joel | Liu, Wei | Moors, Tristen | Axon, Steven | Lek, Monkol

Article Type: Research Article

Abstract: Background: Recessive pathogenic variants in LAMA2 resulting in complete or partial loss of laminin α2 protein cause congenital muscular dystrophy (LAMA2 CMD). The prevalence of LAMA2 CMD has been estimated by epidemiological studies to lie between 1.36–20 cases per million. However, prevalence estimates from epidemiological studies are vulnerable to inaccuracies owing to challenges with studying rare diseases. Population genetic databases offer an alternative method for estimating prevalence. Objective: We aim to use population allele frequency data for reported and predicted pathogenic variants to estimate the birth prevalence of LAMA2 CMD. Methods: A …list of reported pathogenic LAMA2 variants was compiled from public databases, and supplemented with predicted loss of function (LoF) variants in the Genome Aggregation Database (gnomAD). gnomAD allele frequencies for 273 reported pathogenic and predicted LoF LAMA2 variants were used to calculate disease prevalence using a Bayesian methodology. Results: The world-wide birth prevalence of LAMA2 CMD was estimated to be 8.3 per million (95% confidence interval (CI) 6.27 –10.5 per million). The prevalence estimates for each population in gnomAD varied, ranging from 1.79 per million in East Asians (95% CI 0.63 –3.36) to 10.1 per million in Europeans (95% CI 6.74 –13.9). These estimates were generally consistent with those from epidemiological studies, where available. Conclusions: We provide robust world-wide and population-specific birth prevalence estimates for LAMA2 CMD, including for non-European populations in which LAMA2 CMD prevalence hadn’t been studied. This work will inform the design and prioritization of clinical trials for promising LAMA2 CMD treatments. Show more

Keywords: LAMA2 , congenital muscular dystrophy, prevalence, population allele frequencies

DOI: 10.3233/JND-221552

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 381-387, 2023

Authors: Finkel, Richard S. | Darras, Basil T. | Mendell, Jerry R. | Day, John W. | Kuntz, Nancy L. | Connolly, Anne M. | Zaidman, Craig M. | Crawford, Thomas O. | Butterfield, Russell J. | Shieh, Perry B. | Tennekoon, Gihan | Brandsema, John F. | Iannaccone, Susan T. | Shoffner, John | Kavanagh, Sarah | Macek, Thomas A. | Tauscher-Wisniewski, Sitra

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1 ) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. Objective: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. Methods: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6–<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one …of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6–<24 months) and older (24–<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. Results: Thirty-two patients were enrolled and completed the study (medium dose, n  = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P  < 0.01). Conclusions: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history. Show more

Keywords: Adeno-associated virus, clinical trial, gene therapy, Hammersmith Functional Motor Scale Expanded, intrathecal administration, motor milestones, neurodegenerative disorders, onasemnogene abeparvovec, spinal muscular atrophy, vector genomes

DOI: 10.3233/JND-221560

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 389-404, 2023

Authors: Youn, Clover E. | Lu, Christine | Cauchi, Jonathan | MacGowan, Daniel | Morgenstern, Rachelle | Scelsa, Stephen

Article Type: Research Article

Abstract: Introduction: Though eye movements are relatively spared in motor neuron disease (MND), recent literature suggests patients may exhibit oculomotor dysfunction (OD). Frontal lobe involvement has been postulated based on oculomotor pathway anatomy and clinical overlap of amyotrophic lateral sclerosis (ALS) with frontotemporal dementia. We examined oculomotor characteristics in patients with MND presenting to an ALS Center, hypothesizing that patients with prominent upper motor neuron involvement or pseudobulbar affect (PBA) may demonstrate greater OD. Methods: This was a single-center prospective observational study. Patients with diagnosis of MND were examined at bedside. Center for Neurologic Study-Liability Scale (CNS-LS) was administered …to screen for pseudobulbar affect. Primary outcome was OD and the secondary outcome was the association between presence of OD in patients with MND experiencing symptoms of PBA or upper motor neuron dysfunction. Wilcoxon rank-sum scores and Fisher’s exact tests were used to perform statistical analyses. Results: 53 patients with MND underwent the clinical ophthalmic evaluation. On bedside examination, 34 patients (64.2%) presented with OD. There were no significant associations between locations of MND at presentation and the presence or type of OD. OD was associated with increased disease severity as measured by reduced FVC (p  = 0.02). There was no significant association between OD and CNS-LS (p  = 0.2). Discussion: Though our study did not find a significant association between OD and upper versus lower MND at presentation, OD may be useful as an additional clinical marker for advanced disease. Show more

Keywords: Motor neuron disease, amyotrophic lateral sclerosis, eye movement data analysis, ophthalmoplegia

DOI: 10.3233/JND-221579

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 405-410, 2023

Authors: Padberg, G.W. | van Engelen, B.G.M. | Voermans, N.C.

Article Type: Research Article

Abstract:  Facioscapulohumeral muscular dystrophy (FSHD) is an exclusively human neuromuscular disease. In the last decades the cause of FSHD was identified: the loss of epigenetic repression of the D4Z4 repeat on chromosome 4q35 resulting in inappropriate transcription of DUX4. This is a consequence of a reduction of the array below 11 units (FSHD1) or of a mutation in methylating enzymes (FSHD2). Both require the presence of a 4qA allele and a specific centromeric SSLP haplotype. Muscles become involved in a rostro-caudally order with an extremely variable progression rate. Mild disease and non-penetrance in families with affected individuals is common. Furthermore, 2% …of the Caucasian population carries the pathological haplotype without clinical features of FSHD. In order to explain the various features of FSHD we applied Ockham’s Razor to all possible scenarios and removed unnecessary complexities. We postulate that early in embryogenesis a few cells escape epigenetic silencing of the D4Z4 repeat. Their number is assumed to be roughly inversely related to the residual D4Z4 repeat size. By asymmetric cell division, they produce a rostro-caudal and medio-lateral decreasing gradient of weakly D4Z4-repressed mesenchymal stem cells. The gradient tapers towards an end as each cell-division allows renewed epigenetic silencing. Over time, this spatial gradient translates into a temporal gradient based on a decreasing number of weakly silenced stem cells. These cells contribute to a mildly abnormal myofibrillar structure of the fetal muscles. They also form a downward tapering gradient of epigenetically weakly repressed satellite cells. When activated by mechanical trauma, these satellite cells de-differentiate and express DUX4. When fused to myofibrils they contribute to muscle cell death in various ways. Over time and dependent on how far the gradient reaches the FSHD phenotype becomes progressively manifest. We thus hypothesize FSHD to be a myodevelopmental disease with a lifelong attempt to restore DUX4 repression. Show more

Keywords: FSHD, facioscapulohumeral disease, embryogenesis, mesenchymal cells, satellite cells

DOI: 10.3233/JND-221624

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 3, pp. 411-425, 2023