Journal of Neuromuscular Diseases - Volume 11, issue 2

Authors: Allen, Jodi | Stone-Ghariani, Aoife | Quezada, Gabriella | Banks, Donna | Rose, Frank | Knight, William | Newman, Jill | Newman, William | Anderson, Philip | Smith, Christina

Article Type: Research Article

Abstract: Background: Dysphagia is common in adults living with neuromuscular disease (NMD). Increased life expectancy, secondary to improvements in standards of care, requires the recognition and treatment of dysphagia with an increased priority. Evidence to support the establishment of healthcare pathways is, however, lacking. The experiences of people living with NMD (pplwNMD) and their caregivers are valuable to guide targeted, value-based healthcare. Objective: To generate preliminary considerations for neuromuscular dysphagia care and future research in the United Kingdom, based on the experiences of those living with, or caring for, people with NMD. Methods: Two surveys (one for …adults living with NMD and dysphagia, and a second for caregivers) were co-designed with an advisory group of people living with NMD. Surveys were electronically distributed to adults living with NMD and their caregivers between 18th May and 26th July 2020. Distribution was through UK disease registries, charity websites, newsletters, and social media. Results: Adults living with NMD receive little information or education that they are likely to develop swallowing difficulties. Most respondents report wanting this information prior to developing these difficulties. Difficulties with swallowing food and medication are common in this group, and instrumental assessment is considered a helpful assessment tool. Both adults living with NMD and caregivers want earlier access to neuromuscular swallowing specialists and training in how best to manage their difficulties. Conclusions: Improvement is needed in the dysphagia healthcare pathway for adults living with NMD to help mitigate any profound physical and psychological consequences that may be caused by dysphagia. Education about swallowing difficulties and early referral to a neuromuscular swallowing specialist are important to pplwNMD and their caregivers. Further research is required to better understand the experiences of pplwNMD and their caregivers to inform the development of dysphagia healthcare pathways. Show more

Keywords: Swallowing, myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA), advisory group

DOI: 10.3233/JND-230002

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 389-410, 2024

Authors: Lidonnici, Dario | Brambilla, Pietro | Ravasio, Roberto | Zozulya-Weidenfeller, Alla | Beiderbeck, Annette | van Aswegen, Mariska | Oliveira, Rosa | Sansone, Valeria A.

Article Type: Research Article

Abstract: Background: Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented. Objective: Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic. Methods: A panel of 8 Italian neurologists took part in a two-round Delphi panel between …June and October 2022, analyzing the current use of mexiletine in Italian clinical practice. Results: The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400–600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100–600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic. Conclusions: Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations. Show more

Keywords: Delphi, mexiletine, myotonic disorders, myotonia, myotonic dystrophy, myotonia symptoms, neurologists

DOI: 10.3233/JND-230115

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 411-423, 2024

Authors: Servais, Laurent | Day, John W. | De Vivo, Darryl C. | Kirschner, Janbernd | Mercuri, Eugenio | Muntoni, Francesco | Proud, Crystal M. | Shieh, Perry B. | Tizzano, Eduardo F. | Quijano-Roy, Susana | Desguerre, Isabelle | Saito, Kayoko | Faulkner, Eric | Benguerba, Kamal M. | Raju, Dheeraj | LaMarca, Nicole | Sun, Rui | Anderson, Frederick A. | Finkel, Richard S.

Article Type: Research Article

Abstract: Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. …Median (IQR) age at initial SMA diagnosis was 1 (0–6) month and at onasemnogene abeparvovec infusion was 3 (1–10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2 , and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0 ] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0 ] points). All patients maintained/achieved motor milestones. 48.5% (n  = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec. Show more

Keywords: AAV9 vector-based gene replacement therapy, long-term follow-up, motor neuron disease, newborn screening, onasemnogene abeparvovec, outcomes, rare disease, real-world evidence, RESTORE registry, spinal muscular atrophy

DOI: 10.3233/JND-230122

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 425-442, 2024

Authors: Rudolfsen, Jan Håkon | Vissing, John | Werlauff, Ulla | Olesen, Charlotte | Illum, Niels | Olsen, Jens | Poulsen, Peter Bo | Strand, Mette | Born, Alfred Peter

Article Type: Research Article

Abstract: Background: Duchenne Muscular Dystrophy (DMD) is a progressive genetic disease with a prevalence of 1 per 3,600–6,000 male births. Individuals with DMD are typically diagnosed at age 4–7 years; median survival is 30 years. They require multidisciplinary care, personal assistance, and often special education. Objective: The aim was to assess the burden of disease in DMD in Denmark. This includes incidence, prevalence, use of healthcare services, labour market participation, educational outcomes, and overall attributable costs due to DMD. Impact on the closest relatives (siblings and parents) was also investigated. Methods: The comprehensive Danish national health and …administrative registers were used to assess the burden of disease following individuals with DMD and closest relatives from five years before, and up to 20 years after DMD diagnosis. Individuals with DMD (and relatives) from 1994–2021 were included. All outcomes were compared to matched control groups without the disease drawn from the Danish population. Results: 213 unique individuals with DMD were identified. They had lower grades in school, required more special education and more healthcare and home care compared to their control group. The extra costs of special education summed to EUR 180,900 over the course of 11 years elementary school. They had an annual average productivity loss of EUR 20,200 between the age of 18 to 30. The extra healthcare costs of DMD in the 20 years after diagnosis were estimated to EUR 1,524,000. If an individual with DMD lives to be 30, total extra costs sum to EUR 2,365,800. Conclusions: Using national register data this study presented detailed results on the burden of disease of DMD, including impact on closest relatives. With 60 additional hospital admissions and 200 extra outpatient contacts in 20 years healthcare costs, but also costs of home care and special education, increases as disease progresses. Show more

Keywords: Muscular dystrophy, duchenne, incidence, prevalence, cost of illness, siblings, education, parents, productivity, cost, registers, population

DOI: 10.3233/JND-230133

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 443-457, 2024

Authors: McNiff, Megan M. | Hawkins, Sheila | Haase, Bine | Bullivant, Joanne | McIver, Tammy | Mitelman, Olga | Emery, Nicholas | Tasca, Giorgio | Voermans, Nicol | Diaz-Manera, Jordi

Article Type: Research Article

Abstract: Background: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness leading to permanent disability. There are no curative treatments, however, there are several upcoming clinical trials testing new therapies in FSHD. Objective: This study aimed to explore the disease burden and patient preferences of people with FSHD to ensure that clinical trials can be designed to include outcome measures that are relevant and important to patients. Methods: A survey was developed with a steering committee clinicians and physiotherapists with relevant experience in the disease, patient representatives, a registry expert and industry consultants. …Themes of the survey included; participant demographics, disease progression and impact on function, factors encouraging or discouraging clinical trial participation, and positive outcomes of a clinical trial. Results: 1147 participants responded to the online survey, representing 26 countries across Europe and a range of disease severities. The study highlighted the key symptoms causing concern for FSHD patients - muscle weakness and mobility issues - reflecting what participants want targeted for future therapies. The need for clear information and communication throughout clinical trials was emphasised. Factors most encouraging trial participation included access to new investigational therapies, access to trial results and benefits for the FSHD community. Factors most discouraging trial participation included travel related issues and fear of side effects. Conclusions: The results from this study identify the patient reported burden of FSHD and should provide researchers and industry with areas of therapeutic research that would be meaningful to patients, as well as supporting the development of patient centric outcome measures in clinical trials. Show more

Keywords: Facioscapulohumeral muscular dystrophy (FSHD), patient preferences, patient reported outcomes, decision-making, clinical trials, therapies

DOI: 10.3233/JND-230171

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 459-472, 2024

Authors: Zang, Jana | Witt, Stefanie | Johannsen, Jessika | Weiss, Deike | Denecke, Jonas | Dumitrascu, Charlotte | Nießen, Almut | Quitmann, Julia Hannah | Pflug, Christina | Flügel, Till

Article Type: Research Article

Abstract: Background: The manifestation of bulbar symptoms, especially swallowing, is important for evaluating disease-modifying therapies for spinal muscular atrophy (SMA). Due to the lack of instruments, the topic is still underrepresented in research. Objective: This study aimed to develop a tool to monitor swallowing development in children aged 0 to 24 months with SMA. Methods: The method was guided by the COSMIN guidelines and followed a multi-stage Delphi process. The first step was a rapid review of swallowing outcomes in children with SMA younger than 24 months. In the second step, online group interviews …with experts (n  = 7) on dysphagia in infants were conducted, followed by an anonymous online survey among experts in infants with SMA (n  = 19). A predefined consensus threshold for nominal scaled voting was set at≥75 % and for 5-point Likert scale voting at 1.25 of the interquartile range. The third step was the pilot test of the instrument, performed with three groups (healthy controls n  = 8; pre-symptomatic n  = 6, symptomatic n  = 6). Results: Based on the multi-level interprofessional consensus, the DySMA comprises two parts (history and examination), ten categories, with 36 items. Implementation and scoring are clearly articulated and easy to implement. The pilot test showed that swallowing development could be recorded in all groups. Conclusion: The DySMA is well suited for monitoring swallowing development in pre-symptomatic and symptomatic treated infants with SMA. It can be performed in a time-efficient and interprofessional manner. The resulting score is comparable to results from other instruments measuring other domains, e.g., motor function. Show more

Keywords: Spinal muscular atrophy, deglutition, bulbar function, dysphagia, feeding

DOI: 10.3233/JND-230177

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 473-483, 2024

Authors: Gangfuß, Andrea | Rating, Philipp | Ferreira, Tomas | Hentschel, Andreas | Marina, Adela Della | Kölbel, Heike | Sickmann, Albert | Abicht, Angela | Kraft, Florian | Ruck, Tobias | Böhm, Johann | Schänzer, Anne | Schara-Schmidt, Ulrike | Neuhann, Teresa M. | Horvath, Rita | Roos, Andreas

Article Type: Research Article

Abstract: Background: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6 ) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS). Objective: Here, we identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability. Methods: To address the pathogenicity of the variant, biochemical …studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed. Results: The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum. Conclusions: Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6 -associated phenotypes. Show more

Keywords: Charcot-Marie-Tooth disease, axonal neuropathy, NDUFS6, white blood cell proteomics

DOI: 10.3233/JND-230181

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 485-491, 2024

Authors: Eisenkölbl, Astrid | Pühringer, Manuel

Article Type: Case Report

Abstract: Adeno-associated viruses (AAV) are well-suited to serve as gene transfer vectors. Onasemnogene abeparvovec uses AAV9 as virus vector. Previous exposure to wild-type AAVs or placental transfer of maternal AAV antibodies, however, can trigger an immune response to the vector virus which may limit the therapeutic effectiveness of gene transfer and impact safety. We present the case of a female patient with spinal muscular atrophy (SMA) and three survival motor neuron 2 (SMN2 ) gene copies. The infant had elevated titers of AAV9 antibodies at diagnosis at 9 days of age. Being presymptomatic at diagnosis, it was decided to retest the …patient’s AAV9 antibody titer at two-weekly intervals. Six weeks after initial diagnosis, a titer of 1:12.5 allowed treatment with onasemnogene abeparvovec. The presented case demonstrates that, provided the number of SMN2 gene copies and the absence of symptoms allow, onasemnogene abeparvovec therapy is feasible in patients with initially exclusionary AAV9 antibody titers of >1:50. Show more

Keywords: Spinal muscular atrophy, gene transfer therapy, AAV9 antibody titer, onasemnogene abeparvovec, floppy infant

DOI: 10.3233/JND-221659

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 493-498, 2024

Authors: McDonald, Craig | Camino, Eric | Escandon, Rafael | Finkel, Richard S. | Fischer, Ryan | Flanigan, Kevin | Furlong, Pat | Juhasz, Rose | Martin, Ann S. | Villa, Chet | Sweeney, H. Lee

Article Type: Meeting Report

Abstract: Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene …therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy’s prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD. Show more

Keywords: Patient-Focused Drug Development (PFDD), Duchenne Muscular Dystrophy (DMD), Dystrophinopathies, Natural History of DMD, Genetic Testing and Diagnosis, Outcome Measures, Cardiomyopathy In DMD, Gene Therapy for DMD, Patient Experience and Engagement, Regulatory Guidance and Considerations

DOI: 10.3233/JND-230219

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 499-523, 2024

Authors: Armstrong, Niki | Apkon, Susan | Berggren, Kiera N. | Braun, Catherine | Ciafaloni, Emma | Connolly, Anne | Kennedy, Annie | Kuntz, Nancy | Mathews, Katherine | McGuire, Michelle | Parad, Richard | Scavina, Mena | Scharf, Rebecca J. | Waldrop, Megan

Article Type: Meeting Report

Abstract: Objective: This report summarizes the key discussions from the “Early Care (0–3 years) in Duchenne Muscular Dystrophy” meeting, which aimed to address the challenges and opportunities in the diagnosis and care of Duchenne muscular dystrophy (DMD) and female carriers within the 0–3-year age group. Methods: The meeting brought together experts and healthcare providers who shared insights, discussed advancements in DMD care, and identified research needs. Presentations covered diagnostic challenges, approved therapies, clinical trials, identification of young female carriers, and the importance of clinical care and support for families. Results: The meeting highlighted the importance of timely …diagnosis and the lack of evidence-based guidelines for the care of children with DMD aged 0–3 years. Diagnostic challenges were discussed, including delays in receiving a DMD diagnosis and disparities based on ethnicity. The potential benefits and process of newborn screening were addressed. Approved therapeutic interventions, such as corticosteroids and exon-skipping drugs, were explored, with studies indicating the potential benefits of early initiation of corticosteroid therapy and the safety of exon-skipping drugs in DMD. Clinical trials involving infants and young boys were discussed, focusing on drugs like ataluren, vamorolone, and gene therapies. The meeting emphasized the importance of clinical care and support for families, including comprehensive information provision, early intervention services, and individualized support. The identification and care of young female carriers were also addressed. Conclusion: The meeting provided a platform for experts and healthcare providers to discuss and identify key aspects of early care for children with DMD aged 0–3 years. The meeting emphasized the need for early diagnosis, evidence-based guidelines, and comprehensive care and support for affected children and their families. Further research, collaboration, and the development of consensus guidelines are needed to improve early diagnosis, treatment, and outcomes in this population. Show more

Keywords: Duchenne muscular dystrophy, newborn screening, neurodevelopmental disorders, therapeutics, genetic counseling, genetic testing, neuromuscular diseases –diagnosis, genetic carrier screening, patient care management

DOI: 10.3233/JND-230180

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 2, pp. 525-533, 2024