Journal of Neuromuscular Diseases - Volume 8, issue 4

Authors: Walter, Maggie C. | Chiriboga, Claudia | Duong, Tina | Goemans, Nathalie | Mayhew, Anna | Ouillade, Laëtitia | Oskoui, Maryam | Quinlivan, Ros | Vázquez-Costa, Juan F. | Vissing, John | Servais, Laurent

Article Type: Short Communication

Abstract: While Spinal Muscular Atrophy (SMA) has historically been managed with supportive measures, the emergence of innovative medicines has given those living with SMA hope for improved quality of life and has revolutionized care. Despite these advances, the use of therapies and changes in disease management strategies have focused on pediatric populations, leaving adults living with SMA, and those transitioning into adulthood, relatively neglected. Through a multi-faceted approach that gathered unbiased perspectives from clinical experts, validated insights from individuals with lived experiences, and substantiated findings with evidence from the literature, we have exposed unmet needs that are hindering the field and, …ultimately, impacting care and quality of life for adults living with SMA. Here, we set new aspirations and calls to action to inspire continued research in this field, stimulate dialogue across the SMA community and inform policies that deliver effective management and care throughout an adult’s journey living with SMA. Show more

Keywords: Adults living with SMA, Burden of Disease (BoD), health services, lived experience, Neuromuscular Disease (NMD), Quality of Life (QoL), Spinal Muscular Atrophy (SMA), transition

DOI: 10.3233/JND-200611

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 543-551, 2021

Authors: McMillan, H.J. | Gerber, B. | Cowling, T. | Khuu, W. | Mayer, M. | Wu, J.W. | Maturi, B. | Klein-Panneton, K. | Cabalteja, C. | Lochmüller, H.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a rare neurodegenerative disease characterized by progressive muscular weakness, which occurs in one in 6,000 to 10,000 live births. The burden of SMA on Canadian patients and caregivers is not known. Objective: To characterize the burden of SMA in Canada as reported by patients and caregivers, including disease and treatment impacts, indirect costs, and caregiver burden. Methods: Surveys were distributed by Cure SMA Canada and Muscular Dystrophy Canada to individuals with SMA and their caregivers. The online surveys were anonymous and completed between January 28 and February 21, 2020. …Results: 965 patient and 962 caregiver responses met the eligibility criteria. Patients reported SMA subtypes as: type I (25.0%), type II (41.3%), type III (29.3%). Using the EQ-5D, patients were shown to have impaired quality of life with an average health utility index of 0.49 (SD: 0.26). The median expenditure was $4,500 CAD (IQR: $1,587 – $11,000) for assistive devices; $6,800 CAD (IQR: $3,900–$13,000) on health professional services; and $1,200 CAD (IQR: $600 –$3,100) on SMA-related travel and accommodation in the past 12 months. Caregivers reported needing respite care (45.7%), physiotherapy for an injury from a lift/transfer (45.7%), or other health impacts (63.3%). Caregivers reported changes to personal plans, sleep disturbances, and work adjustments, with a mean Caregiver Strain Index score of 7.5 [SD: 3.3]. Conclusion: SMA in Canada is associated with a significant burden for patients and their caregivers. Show more

Keywords: Muscular atrophy, spinal, spinal muscular atrophies of childhood, quality of life, caregivers economics, medical, cost of illness, chronic disease, neurodegenerative diseases, muscle weakness

DOI: 10.3233/JND-200610

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 553-568, 2021

Authors: Johnson, Nicole B. | Proud, Crystal | Wassel, Christina L. | Dreyfus, Jill | Cochrane, Thos | Paradis, Angela D.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a rare genetic disease characterized by progressive muscular weakness and atrophy resulting from motor neuron degeneration. Limited information is available on disease progression among older SMA patients, particularly adults. Objective: This study sought to characterize the natural history of SMA among adult patients in US hospital settings through the assessment of symptoms, complications, costs, and healthcare resource utilization (HRU) over 3 years before the availability of disease-modifying therapies. Methods: The study population included adult (≥18 years) patients with inpatient and/or hospital-based outpatient discharge records and ≥2 primary or secondary SMA …ICD-9 codes ≥30 days apart in the Premier Healthcare Database during the main study period (2007–2014). Index date was the date of the first SMA ICD-9 code. The frequency of SMA-related symptoms and complications was assessed 1 year preindex through 2 years postindex to characterize disease progression. Costs and HRU were also assessed across the study period. Results: A total of 446 adult patients from 337 US hospitals met inclusion criteria for these analyses. All evaluated SMA-related symptoms and complications increased steadily over time, from 1 year preindex to 2 years postindex both overall and in each age group. Adult patients with SMA had increasing total costs and HRU over the 3-year study period: total costs were $1,759 preindex and $12,308 by 2 years postindex. Conclusions: Findings are consistent with increasing disease burden over time and support the progressive nature of SMA for adult patients with hospital interactions. Show more

Keywords: Spinal muscular atrophy, burden of illness, signs and symptoms, complications, health expenditures

DOI: 10.3233/JND-200624

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 569-578, 2021

Authors: Slayter, Jeremy | Hodgkinson, Victoria | Lounsberry, Josh | Brais, Bernard | Chapman, Kristine | Genge, Angela | Izenberg, Aaron | Johnston, Wendy | Lochmüller, Hanns | O’Ferrall, Erin | Pfeffer, Gerald | Plamondon, Stephanie | Rodrigue, Xavier | Schellenberg, Kerri | Shoesmith, Christen | Stables, Christine | Taillon, Monique | Warman-Chardon, Jodi | Korngut, Lawrence | O’Connell, Colleen

Article Type: Research Article

Abstract: Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics. Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA. Methods: A modified delphi method consisting of 2 …virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada. Results: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently. Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available. Show more

Keywords: Adult spinal muscular atrophy, outcome measures, neuromuscular diseases, consensus, delphi method

DOI: 10.3233/JND-200617

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 579-588, 2021

Authors: Berti, Beatrice | Fanelli, Lavinia | de Sanctis, Roberto | Onesimo, Roberta | Palermo, Concetta | Leone, Daniela | Carnicella, Sara | Norcia, Giulia | Forcina, Nicola | Coratti, Giorgia | Giorgio, Valentina | Cerchiari, Antonella | Lucibello, Simona | Finkel, Richard | Pane, Marika | Mercuri, Eugenio

Article Type: Research Article

Abstract: We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life. The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child’s …ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria. In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3–24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format. When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (p  < 0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties. Show more

Keywords: Spinal muscular atrophy, swallowing, dysphagia, oral motor function, type 1 SMA infants

DOI: 10.3233/JND-200614

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 589-601, 2021

Authors: Grande, Valentina | Hathazi, Denisa | O’Connor, Emily | Marteau, Theo | Schara-Schmidt, Ulrike | Hentschel, Andreas | Gourdon, Genevieve | Nikolenko, Nikoletta | Lochmüller, Hanns | Roos, Andreas

Article Type: Research Article

Abstract: Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3′ -untranslated region of the DM1 protein kinase gene called DMPK . DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3β), a highly conserved and ubiquitous …serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3β-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3βby unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80– 150) and high (2600– 3600) CTG-repeats. Apart from GSK3β increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3β. In silico -based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3β inhibitor treatment responses. Show more

Keywords: GSK3β , fibroblast proteomics, CTPS1, CAPN1, HDAC2, CTNNB1

DOI: 10.3233/JND-200558

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 603-619, 2021

Authors: Rist, Pamela M. | Kupelian, Varant | Petrillo, Marco | Sohn, Jihee | Farwell, Wildon | Sesso, Howard D.

Article Type: Brief Report

Abstract: Little is known about the feasibility of using long-term stored blood samples to measure neurofilament levels and about long-term changes in neurofilament levels among healthy individuals. We performed a pilot study among 26 adult men in preparation for a larger-scale study of the natural history of neurofilament levels. Median change over 14 years in pNf-H was 97.1 pg/mL (IQR: 5.0 to 242.0 pg/mL) and in Nf-L was 2.117 pg/mL (IQR: –2.691 to 3.393 pg/mL). We demonstrated the feasibility of measuring neurofilament concentrations in stored blood samples and found a trend between age and increases in Nf-L levels among adults.

Keywords: Epidemiology, neurofilament, aging

DOI: 10.3233/JND-200623

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 621-624, 2021

Authors: Kassardjian, Charles | Widdifield, Jessica | Paterson, J. Michael | Kopp, Alexander | Nagamuthu, Chenthila | Barnett, Carolina | Tu, Karen | Breiner, Ari

Article Type: Research Article

Abstract: Background: Prednisone is a common treatment for myasthenia gravis (MG), and osteoporosis is a known potential risk of chronic prednisone therapy. Objective: Our aim was to evaluate the risk of serious fractures in a population-based cohort of MG patients. Methods: An inception cohort of patients with MG was identified from administrative health data in Ontario, Canada between April 1, 2002 and December 31, 2015. For each MG patient, we matched 4 general population comparators based on age, sex, and region of residence. Fractures were identified through emergency department and hospitalization data. Crude overall rates and sex-specific …rates of fractures were calculated for the MG and comparator groups, as well as rates of specific fractures. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Results: Among 3,823 incident MG patients (followed for a mean of 5 years), 188 (4.9%) experienced a fracture compared with 741 (4.8%) fractures amongst 15,292 matched comparators. Crude fracture rates were not different between the MG cohort and matched comparators (8.71 vs. 7.98 per 1000 patient years), overall and in men and women separately. After controlling for multiple covariates, MG patients had a significantly lower risk of fracture than comparators (HR 0.74, 95% CI 0.63–0.88). Conclusions: In this large, population-based cohort of incident MG patients, MG patients were at lower risk of a major fracture than comparators. The reasons for this finding are unclear but may highlight the importance osteoporosis prevention. Show more

Keywords: Myasthenia gravis, fractures, osteoporosis, corticosteroids, immunosuppression

DOI: 10.3233/JND-200612

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 625-632, 2021

Authors: Villar-Quiles, Rocío N. | Donkervoort, Sandra | de Becdelièvre, Alix | Gartioux, Corine | Jobic, Valérie | Foley, A. Reghan | McCarty, Riley M. | Hu, Ying | Menassa, Rita | Michel, Laurence | Gousse, Gaelle | Lacour, Arnaud | Petiot, Philippe | Streichenberger, Nathalie | Choumert, Ariane | Declerck, Léa | Urtizberea, J.A. | Sole, Guilhem | Furby, Alain | Cérino, Matthieu | Krahn, Martin | Campana- Salort, Emmanuelle | Ferreiro, Ana | Eymard, Bruno | Bönnemann, Carsten G. | Bharucha-Goebel, Diana | Sumner, Charlotte J. | Connolly, Anne M. | Richard, Pascale | Allamand, Valérie | Métay, Corinne | Stojkovic, Tanya

Article Type: Research Article

Abstract: Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3 ) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging. Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A>G (p.Lys2483Glu). Methods: We report the clinical and molecular …findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3 variant, and four homozygous patients. Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3 variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles. Conclusions: In light of our results, we postulate that the COL6A3 variant c.7447A>G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies. Show more

Keywords: Collagen VI-related myopathies, COL6A3, collagen type VI, neuromuscular disorders, limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), muscular MRI, NGS

DOI: 10.3233/JND-200577

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 633-645, 2021

Authors: Werlauff, Ulla | Hansen, Pernille Diemer | Witting, Nanna | Vissing, John

Article Type: Research Article

Abstract: Background: Clinical characteristics of patients with congenital myopathies (CM) are well known but there is a lack of knowledge about the natural history and course of disease of the different genetic subtypes. In 2010 we assessed the national cohort of Danish patients with CM to decide genetic diagnosing and describe genotype- phenotype relationships. AIM of this follow-up study was to evaluate the course of disease since the initial study and to evaluate the applicability of standard assessment methods to reflect change over time and patients own opinion on the course of disease. Methods: All available genetically diagnosed …patients studied by us in 2010 (n  = 41) were invited to the follow-up study; assessment of motor function (MFM-32), muscle strength (MRC %)and respiratory function (FVC %) and prime assessor were the same as in the initial study. Patients were asked whether the course of disease had progresses, was stable or had improved. Results: 23 patients (15–61 y) accepted the invitation. Mean follow-up time was 7.7 years. Loss of muscle strength was more prominent in patients with mutations in DNM2, RYR1 and TPM2/3 genes and deterioration in FVC % was more evident in patients carrying NEB and ACTA1 gene mutations. MFM-sum score was less sensitive to change compared to MRC-sum score. In general, agreement between the patient’s own opinion of the course of disease and results of assessments was good. Conclusion: The number of patients in the study is too small to be conclusive, but the results indicate that CM can be stable or slowly progressive depending on the genetic subtype. Show more

Keywords: Congenital myopathy, natural history, functional abilities, muscle strength, evaluation

DOI: 10.3233/JND-200574

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 647-655, 2021