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

Authors: Lawal, Tokunbor A. | Patankar, Aneesh | Todd, Joshua J. | Razaqyar, Muslima S. | Chrismer, Irene C. | Zhang, Xuemin | Waite, Melissa R. | Jain, Minal S. | Emile-Backer, Magalie | Witherspoon, Jessica W. | Liu, Chia-Ying | Grunseich, Christopher | Meilleur, Katherine G.

Article Type: Research Article

Abstract: Background: Ryanodine receptor 1-related myopathy (RYR1 -RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI). Objective: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1 -RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity. Methods: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences. A modified ImageJ-based program was used for quantification. IMFI data was analyzed by mode …of inheritance, motor function, and clinical severity. Results: Upper and lower leg IMFI from 36 genetically confirmed and ambulatory RYR1 -RM affected individuals (26 dominant and 10 recessive) were analyzed using Grey-scale quantification. There was no statistically significant difference in IMFI between dominant and recessive cases in upper or lower legs. IMFI in both upper and lower legs was inversely correlated with participant performance on the motor function measure (MFM-32) total score (upper leg: p  < 0.001; lower leg: p  = 0.003) and the six-minute walk test (6MWT) distance (upper leg: p  < 0.001; lower leg: p  = 0.010). There was no significant difference in mean IMFI between participants with mild versus severe clinical phenotypes (p  = 0.257). Conclusion: A modified ImageJ-based algorithm was able to select and quantify fatty infiltration in a cohort of heterogeneously affected individuals with RYR1 -RM. IMFI was not predictive of mode of inheritance but showed strong correlation with motor function and capacity tests including MFM-32 and 6MWT, respectively. Show more

Keywords: Ryanodine receptor 1, skeletal muscle, central core myopathy, muscle disorders, muscle disease manifestations, magnetic resonance imaging, computer-assisted image analysis

DOI: 10.3233/JND-200549

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 657-668, 2021

Authors: Güttsches, Anne-Katrin | Rehmann, Robert | Schreiner, Anja | Rohm, Marlena | Forsting, Johannes | Froeling, Martijn | Tegenthoff, Martin | Vorgerd, Matthias | Schlaffke, Lara

Article Type: Research Article

Abstract: Background: Skeletal muscle biopsy is one of the gold standards in the diagnostic workup of muscle disorders. By histopathologic analysis, characteristic features like inflammatory cellular infiltrations, fat and collagen replacement of muscle tissue or structural defects of the myofibers can be detected. In the past years, novel quantitative MRI (qMRI) techniques have been developed to quantify tissue parameters, thus providing a non-invasive diagnostic tool in several myopathies. Objective: This proof-of-principle study was performed to validate the qMRI-techniques to skeletal muscle biopsy results. Methods: Ten patients who underwent skeletal muscle biopsy for diagnostic purposes were examined by …qMRI. Fat fraction, water T2-time and diffusion parameters were measured in the muscle from which the biopsy was taken. The proportion of fat tissue, the severity of degenerative and inflammatory parameters and the amount of type 1- and type 2- muscle fibers were determined in all biopsy samples. The qMRI-data were then correlated to the histopathological findings. Results: The amount of fat tissue in skeletal muscle biopsy correlated significantly with the fat fraction derived from the Dixon sequence. The water T2-time, a parameter for tissue edema, correlated with the amount of vacuolar changes of myofibers and endomysial macrophages in the histopathologic analysis. No significant correlations were found for diffusion parameters. Conclusion: In this proof-of-principle study, qMRI techniques were related to characteristic histopathologic features in neuromuscular disorders. The study provides the basis for further development of qMRI methods in the follow-up of patients with neuromuscular disorders, especially in the context of emerging treatment strategies. Show more

Keywords: Neuromuscular diseases, magnetic resonance imaging, histology, myositis, muscle tissue

DOI: 10.3233/JND-210641

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 669-678, 2021

Authors: Krøigård, Thomas | Svendsen, Toke K. | Wirenfeldt, Martin | Schrøder, Henrik D. | Qvortrup, Camilla | Pfeiffer, Per | Gaist, David | Sindrup, Søren H.

Article Type: Research Article

Abstract: Background: Oxaliplatin-induced peripheral neuropathy negatively affects the quality of life for patients with gastrointestinal cancers and may cause neuropathic pain. Measures of peripheral nerve structure or function, such as intraepidermal nerve fiber density (IENFD) during treatment could reduce neuropathy severity through individualized dose reduction. Objective: The aim was to evaluate the predictive values of IENFD, quantitative sensory testing (QST), and nerve conduction studies (NCS) for significant neuropathy and neuropathic pain. Methods: Fifty-five patients were examined prospectively before, during, and six months following treatment using skin biopsies, QST and NCS. Clinically significant neuropathy six months after treatment …was defined as reduced Total Neuropathy Score of more than five and neuropathic pain was assessed according to International Association for the Study of Pain criteria. Results: Thirty patients had a clinically significant neuropathy, and 14 had neuropathic pain. Vibration detection threshold (VDT) before treatment was correlated with clinically significant neuropathy six months after treatment (OR 0.54, p  = 0.01) and reductions in cold detection threshold (CDT) after 25% of treatment (OR 1.38, p  = 0.04) and heat pain threshold (HPT) after 50% of treatment (OR 1.91, p  = 0.03) with neuropathic pain. Cut off values of 5 for baseline VDT and changes of more than –0.05 °C and –0.85 °C in CDT and HPT were estimated. Sensitivity and specificity was low to moderate. There was no correlation between changes in IENFD or NCS and significant neuropathy or neuropathic pain. Conclusions: Vibration detection thresholds and thermal detection thresholds may be useful for prediction of clinically significant and painful neuropathy, respectively. However, low to moderate sensitivity and specificity may limit the predictive value in clinical practice. Show more

Keywords: Nerve conduction studies, neuropathic pain, oxaliplatin, peripheral neuropathy, quantitative sensory testing, skin biopsies

DOI: 10.3233/JND-210630

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 679-688, 2021

Authors: Birnbaum, Simone | Bachasson, Damien | Sharshar, Tarek | Porcher, Raphaël | Hogrel, Jean-Yves | Portero, Pierre

Article Type: Research Article

Abstract: Background: Muscle weakness and fatigability, the prominent symptoms of autoimmune myasthenia gravis (MG), negatively impact daily function and quality of life (QoL). It is currently unclear as to what extent symptoms limit activity and whether physical activity (PA) behaviours are associated with reduced QoL. Objectives: This study aimed to describe habitual PA patterns and explore relationships between PA metrics, clinical MG characteristics, and health-related QoL (HRQoL). Methods: PA data from a tri-axial trunk accelerometer worn for seven days, was collected from females with generalized, stable MG and compared to control subjects. MG-specific evaluations, the six-minute walk …test and knee extension strength were assessed in individuals with MG (IwMG). Mann-Whitney tests were used to study between-group differences. Spearman rank correlation coefficient was performed to explore relationships between variables. Results: Thirty-three IwMG (mean (SD) age 45 (11) years) and 66 control subjects were included. IwMG perform less vigorous-intensity PA than control subjects (p  = 0.001), spend more time sedentary (p  = 0.02) and engage in less and shorter durations of moderate-vigorous-intensity PA (MVPA). For IwMG, habitual PA correlated positively with 6 min walking distance (rho = 0.387, p  = 0.029) and negatively with body mass index (rho = –0.407, p  = 0.019). We did not find any association between PA or sedentary behaviour and; HRQoL, symptom severity nor lower limb strength. Conclusions: Individuals with stable MG perform less PA, at lower intensities, and are more inactive than control individuals. Further research is warranted to understand factors influencing PA patterns in MG and whether interventions could be successful in increasing PA quantity and intensity in IwMG. Show more

Keywords: Autoimmune myasthenia gravis, physical activity, sedentary behaviour, quality of life, accelerometry

DOI: 10.3233/JND-210637

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 689-697, 2021

Authors: Nash, Yuval | Sitty, Michal

Article Type: Research Article

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients’ quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.

Keywords: ALS, symptoms, biomarkers, prognosis

DOI: 10.3233/JND-210632

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 699-713, 2021

Authors: Damen, Manon | Schijvenaars, Mascha | Schimmel-Naber, Marlies | Groothuismink, Johanne | Coenen, Marieke | Tieleman, Alide

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 2 (DM2) is caused by a CCTG repeat expansion in intron 1 of the CCHC-Type Zinc Finger Nucleic Acid Binding Protein (CNBP ) gene. Previous studies indicated that this repeat expansion originates from separate founders. Objective: This study was set out to determine whether or not patients with DM2 originating from European and non-European countries carry the previously described European founder haplotypes. Methods: Haplotype analysis was performed in 59 DM2 patients from 29 unrelated families. Twenty-three families were from European descent and 6 families originated from non-European countries (India, Suriname and Morocco). …Seven short tandem repeats (CL3N122, CL3N99, CL3N59, CL3N117, CL3N119, CL3N19 and CL3N23) and 4 single nucleotide polymorphisms (SNP) (rs1871922, rs1384313, rs4303883 and CGAP_886192) in and around the CNBP gene were used to construct patients’ haplotypes. These haplotypes were compared to the known DM2 haplotypes to determine the ancestral origin of the CNBP repeat expansion. Results: Of 41 patients, the haplotype could be assigned to the previously described Caucasian haplotypes. Three patients from Morocco and Portugal had a haplotype identical to the earlier reported Moroccan haplotype. Twelve patients from India and Suriname, however, carried a haplotype that seems distinct from the previously reported haplotypes. Three individuals could not be assigned to a specific haplotype. Conclusion: The ancestral origin of DM2 in India might be distinct from the Caucasian families and the solely described Japanese patient. However, we were unable to establish this firmly due to the limited genetic variation in the region surrounding the CNBP gene. Show more

Keywords: Myotonic dystrophy type 2, haplotypes, India, European continental ancestry group

DOI: 10.3233/JND-210671

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 715-722, 2021

Authors: Chen, Zhiyong | Koh, Jasmine S. | Saini, Monica | Tay, Karine S.S. | Jayne Tan, Yi | Chai, Josiah Y.H. | Fam, Su Rong | Juraidah, A.R. | Lim, Peck Kee | Ng, Adeline S.L. | Prasad, Kalpana | Tan, Chai Beng | Umapathi, T | Verma, Kamal K. | Yong, Ming Hui | Yu, Chen | Ng, Peng Soon

Article Type: Research Article

Abstract: Background and aims: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. Methods: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007–2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. Results: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac …dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). Conclusion: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis. Show more

Keywords: Amyloid neuropathies, familial, amyloidosis, hereditary, transthyretin-related, TTR protein, human

DOI: 10.3233/JND-210656

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 723-733, 2021

Authors: Fatehi, Farzad | Advani, Soroor | Okhovat, Ali Asghar | Ziaadini, Bentolhoda | Shamshiri, Hosein | Nafissi, Shahriar

Article Type: Research Article

Abstract: Background: Muscle MRI protocols have been developed to assess muscle involvement in a wide variety of muscular dystrophies. Different muscular dystrophies can involve muscle groups in characteristic patterns. These patterns can be identified in muscle MRI in the form of fatty infiltration. Objective: This study was conducted to add the existing knowledge of muscle MRI in GNE myopathy and evaluate the correlation of muscular involvement with different gene mutations. Methods: The MRI scans of the 18 GNE patients were analyzed retrospectively. Cluster analysis was done for grouping the muscles and patients. Results: The four …muscles with the highest fat infiltration were adductor magnus, tibialis anterior, semitendinosus, and semimembranosus. Furthermore, three clusters of muscle involvement were found, including cluster 1, typical muscle involvement indicating muscles with the highest infiltration: extensor digitorum longus, gracilis, biceps femoris, soleus, gastrocnemius medial, adductor longus, tibialis anterior, adductor magnus, semimembranosus, semitendinosus; cluster 2, less typical muscle involvement indicating muscles with intermediate fat infiltration, peroneus longus, gastrocnemius lateral, and minimal fat infiltration in most of the patients, i.e., tibialis posterior; and cluster 3, atypical muscle involvement with low-fat infiltration: rectus femoris, sartorius, vastus intermedius, vastus medialis, and vastus lateralis. Conclusions: This study found three clusters of muscle involvement and three groups of patients among GNE patients. Hamstring muscles and the anterior compartment of the lower leg were the muscles with the highest fat infiltration. Moreover, a weak genotype-muscle MRI association was found in which tibialis posterior was more involved in patients with the most frequent mutation, i.e., C.2228T > C (p.M743T) mutation; however, this finding may be related to longer disease duration. Show more

Keywords: Muscle MRI, GNE myopathy, Nonaka myopathy, h-IBM2

DOI: 10.3233/JND-210629

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 735-742, 2021

Authors: Pini, Jonathan | Siciliano, Gabriele | Lahaut, Pauline | Braun, Serge | Segovia-Kueny, Sandrine | Kole, Anna | Hérnando, Ines | Selb, Julij | Schirinzi, Erika | Duong, Tina | Hogrel, Jean-Yves | Olmedo, José Javier Serrano | Vissing, John | Servais, Laurent | Vincent-Genod, Dominique | Vuillerot, Carole | Bannwarth, Sylvie | Eggenspieler, Damien | Vicart, Savine | Diaz-Manera, Jordi | eNMD group | Lochmüller, Hanns | Sacconi, Sabrina

Article Type: Meeting Report

Abstract: By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients’ social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients’ and physicians’ unmet needs. It is vital to improve several aspects of patients’ quality of life …with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients’ data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment. Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients’ states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients’ follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound. In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases. Show more

Keywords: e-Health, eNMD congress, neuromuscular disease, innovation, unmet needs

DOI: 10.3233/JND-210655

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 743-754, 2021

Authors: Vilchez Padilla, Juan Jesús

Article Type: Meeting Report

DOI: 10.3233/JND-209002

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 755-764, 2021