Journal of Neuromuscular Diseases - Volume 8, issue 4

Authors: Norcia, Giulia | Lucibello, Simona | Coratti, Giorgia | Onesimo, Roberta | Pede, Elisa | Ferrantini, Gloria | Brogna, Claudia | Cicala, Graziamaria | Carnicella, Sara | Forcina, Nicola | Fanelli, Lavinia | Pane, Marika | Mercuri, Eugenio

Article Type: Review Article

Abstract: Background: Over the last few years there has been increasing attention to detect early signs of impairment in young Duchenne muscular dystrophy boys but less has been reported on whether the delay may also affect the very early aspects of motor development, such as gross motor milestones. Objective: The aim of this study was to retrospectively assess the age when early motor milestones were achieved in Duchenne muscular dystrophy. Methods: The study is a retrospective analysis of data collected as part of a larger natural history project. Information on past medical history, collected at the time …the boys were seen for the first time, were recorded and re available on clinical notes and on electronic CRF. Results: Data were collected in 134 DMD boys. Sitting was achieved at 7.04 months. The % of DMD boys not achieving sitting by 9.4 months was 10%, ranging from 2% in the boys with mutations before exon 44 to 33% in those beyond exon 63. Walking was achieved at a mean age of 16.35 months. The % of DMD boys not achieving independent walking by 18 months was 17%, ranging from 9% in the boys with mutations between 44 and 51 to 42% in those beyond exon 63. Conclusions: Our results showed that the risk of a delay in sitting and walking was increasingly high in patients with mutations predictive of the involvement of different brain dystrophin isoforms. Show more

Keywords: Duchenne muscular dystrophy, early motor milestones, dystrophin isoforms, gross motor milestones

DOI: 10.3233/JND-210640

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 453-456, 2021

Authors: Welland, Natasha Lervaag | Hæstad, Helge | Fossmo, Hanne Ludt | Giltvedt, Kaja | Ørstavik, Kristin | Nordstrøm, Marianne

Article Type: Review Article

Abstract: Background: Primary periodic paralysis (PPP) are rare inherited neuromuscular disorders including Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP) and Andersen-Tawil syndrome (ATS) characterised by attacks of weakness or paralysis of skeletal muscles. Limited effective pharmacological treatments are available, and avoidance of lifestyle related triggers seems important. Objective: Our aim was to search and assess the scientific literature for information on trigger factors related to nutrition and physical activity in PPP. Methods: We searched Ovid Medline and Embase database for scientific papers published between January 1, 1990, to January 31, 2020. Results: We did …not identify published observation or intervention studies evaluating effect of lifestyle changes on attacks. Current knowledge is based on case-reports, expert opinions, and retrospective case studies with inadequate methods for description of nutrition and physical activity. In HypoPP, high carbohydrate and salt intake, over-eating, alcohol, dehydration, hard physical activity, and rest after exercise are frequently reported triggers. Regarding HyperPP, fasting, intake of potassium, alcohol, cold foods or beverages, physical activity, and rest after exercise are frequently reported triggers. No nutrition related triggers are reported regarding ATS, exercise can however induce ventricular arrhythmias. Conclusions: Our results support that dietary intake and physical activity may play a role in causing paralytic attacks in PPP, although the current scientific evidence is weak. To provide good evidence-based patient care, several lifestyle aspects need to be further assessed and described. Show more

Keywords: Primary periodic paralysis, Hypokalemic periodic paralysis, Hyperkalemic periodic paralysis, Anderson-Tawil syndrome, dietary intake, physical activity

DOI: 10.3233/JND-200604

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 457-468, 2021

Authors: Mendell, Jerry R. | Khan, Navid | Sha, Nanshi | Eliopoulos, Helen | McDonald, Craig M. | Goemans, Nathalie | Mercuri, Eugenio | Lowes, Linda P. | Alfano, Lindsay N. | on behalf of the Eteplirsen Study Group

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51® ) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 …years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p  = 0.015] at Year 3 and 159 m [95%CI (66, 253), p  = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p  = 0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD. Show more

Keywords: Duchenne muscular dystrophy, Duchenne, dystrophin, EXONDYS 51, eteplirsen, 6-minute walk test, loss of ambulation

DOI: 10.3233/JND-200548

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 469-479, 2021

Authors: Vather-Wu, Naomi | Krasowski, Matthew D. | Mathews, Katherine D. | Shibli-Rahhal, Amal

Article Type: Research Article

Abstract: Background: Expert guidelines recommend annual monitoring of 25-hydroxyvitamin D (25-OHD) and maintaining 25-OHD ≥30 ng/ml in patients with dystrophinopathies. Objective: We hypothesized that 25-OHD remains stable and requires less frequent monitoring in patients taking stable maintenance doses of vitamin D. Methods: We performed a retrospective cohort study, using the electronic health record to identify 26 patients with dystrophinopathies with a baseline 25-OHD ≥30 ng/mL and at least one additional 25-OHD measurement. These patients had received a stable dose of vitamin D for ≥3 months prior to their baseline 25-OHD measurement and throughout follow-up. The main outcome measured was …the mean duration time the subjects spent with a 25-OHD ≥30 ng/mL. Results: Only 19% of patients dropped their 25-OHD to < 30 ng/ml, with a mean time to drop of 33 months and a median nadir 25-OHD of 28 ng/mL. Conclusions: These results suggest that measurement of 25-OHD every 2–2.5 years may be sufficient in patients with a baseline 25-OHD ≥30 ng/mL and who are on a stable maintenance dose of vitamin D. Other patients may require more frequent assessments. Show more

Keywords: Dystrophinopathy, vitamin D, Duchenne muscular dystrophy

DOI: 10.3233/JND-200625

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 481-487, 2021

Authors: Cooper-Olson, Grace | Rodino-Klapac, Louise R. | Potter, Rachael A.

Article Type: Short Communication

Abstract: Recombinant micro-dystrophin genes are designed to treat Duchenne muscular dystrophy (DMD) by retaining dystrophin domains believed to play key functional roles while fitting the packaging capacity of adeno-associated virus vectors. Domains R1-3 are important for muscle force generation and for association with the sarcolemma, but the nature of this interaction is not fully understood. We measured lipid-binding affinity of 3 peptides containing different spectrin-like repeat modules (R1-3; R1-2; and R1, 2, 22). Lipid-binding affinity was highest with R1-3, suggesting that the complete R1-R3 region could be beneficial and should be considered for inclusion in micro-dystrophin constructs.

Keywords: Lipid binding, dystrophin, spectrin-like repeats

DOI: 10.3233/JND-200622

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 489-494, 2021

Authors: Stalens, Caroline | Motté, Leslie | Béhin, Anthony | Ben Yaou, Rabah | Leturcq, France | Bassez, Guillaume | Laforêt, Pascal | Fontaine, Bertrand | Ederhy, Stéphane | Masingue, Marion | Saadi, Malika | Louis, Sarah Leonard | Berber, Nawal | Stojkovic, Tanya | Duboc, Denis | Wahbi, Karim

Article Type: Research Article

Abstract: Background: The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%. Objective: To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy. Methods: From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and …≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to <35% in patients who received an ACE-i when LVEF fell below 40% (conventional treatment), versus below 50% (early treatment). Results: From the 183 patients entered in our registry, we identified 85 whose LVEF was between 40 and 49%, 51 of whom received early and 34 received conventional ACE-i treatment. Among patients with early versus conventional treatments, 2 (3.9%) versus 4 (11.8%) were hospitalized for management of HF [hazard ratio (HR) 0.151; 95% confidence interval (CI) 0.028 to 0.822; p  = 0.029], and 9 (17.6%) versus 10 (29.4%) had a decrease in LVEF below 35% (HR 0.290; 95% CI 0.121 to 0.694; p  = 0.005). Conclusions: The long-term cardiac outcome of patients presenting with Becker MD was significantly better when treatment with ACE-i was introduced after a decrease in LVEF below 50%, instead of below 40% as recommended in the current practice guidelines issued by professional societies. Show more

Keywords: Becker muscular dystrophy, non-ischemic cardiomyopathy, inherited myopathy, angiotensin-converting enzyme inhibitor, heart failure

DOI: 10.3233/JND-200620

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 495-502, 2021

Authors: Heutinck, Lotte | van Gameren, Maaike | Verschuuren, Jan J.G.M. | Geurts, Alexander C.H. | Jansen, Merel | de Groot, Imelda J.M.

Article Type: Research Article

Abstract: Background: In order to successfully implement the international clinical care guidelines for Duchenne muscular dystrophy (DMD) in the Netherlands, it is essential to know what barriers are experienced by healthcare practitioners regarding guideline adherence and organization of care. In the Netherlands, academic medical centers provide follow up visits and work together with peripheral hospitals, rehabilitation centers, centers for home ventilation and primary care centers for treatment. Objective: To investigate perceived barriers to international clinical DMD guideline adherence and identify potential areas of improvement for implementation in the Dutch ‘shared care’ organization. Methods: Semi-structured in-depth interviews with …healthcare practitioners of academic medical hospitals and questionnaires for healthcare practitioners of rehabilitation centers, based on the framework of Cabana. Results: The analyses identified 4 barriers for non-adherence to the DMD guideline: (i) lack of familiarity/awareness, (ii) lack of agreement with specific guideline, (iii) lack of outcome expectancy, (iv) external barriers. Conclusions: A heterogeneous set of barriers is present. Therefore, a multifaceted intervention strategy is proposed to overcome these barriers, including a clear division of roles, allowing for local (Dutch) adaptations per specialism by local consensus groups, and the facilitation of easy communication with experts/opinion leaders as well as between care professionals. Show more

Keywords: Duchenne muscular dystrophy, clinical care guidelines, guideline implementation

DOI: 10.3233/JND-200586

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 503-512, 2021

Authors: Ben Larbi, Sabrina | Saclier, Marielle | Fessard, Aurélie | Juban, Gaëtan | Chazaud, Bénédicte

Article Type: Research Article

Abstract: Background: The mdx -C57/B6 mouse model does not show the clinical signs of Duchenne muscular dystrophy (DMD), although muscles exhibit hallmarks of permanent regeneration and alterations in muscle function. The DMDmdx 4Cv strain exhibits very few revertant dystrophin positive myofibers, making that model suitable for studies on gene and cell therapies. Objective: The study appraises the histological evolution of the Tibialis Anterior muscle of WT and DMD mdx 4Cv mutant from 1 to 24 months. Methods: Histological analysis included a series of immunostainings of muscle sections for assessing tissue …features (fibrosis, lipid deposition, necrosis) and cellular characteristics (size of myofibers, number and distribution of myonuclei, number of satellite cells, vessels, macrophages). Results: None of the investigated cell types (satellite cells, endothelial cells, macrophages) showed variations in their density within the tissue in both WT and DMD mdx 4Cv muscle. However, analyzing their number per myofiber showed that in DMD mdx 4Cv , myofiber capillarization was increased from 1 to 6 months as compared with WT muscle, then dropped from 12 months. Macrophage number did not vary in WT muscle and peaked at 6 months in DMD mdx 4Cv muscle. The number of satellite cells per myofiber did not vary in WT muscle while it remained high in DMD mdx 4Cv muscle, starting to decrease from 12 months and being significantly lower at 24 months of age. Myofiber size was not different in DMD mdx 4Cv from WT except at 24 months, when it strongly decreased in DMD mdx 4Cv muscle. Necrosis and lipid deposition were rare in DMD mdx 4Cv muscle. Fibrosis did not increase with age in DMD mdx 4Cv muscle and was higher than in WT at 6 and 12 months of age. Conclusions: As a whole, the results show a strong decrease of the myofiber size at 24 months, and an increased capillarization until 6 months of age in DMD mdx 4Cv as compared with the WT. Thus, DMD mdx 4Cv mice poorly recapitulates histological DMD features, and its use should take into account the age of the animals according to the purpose of the investigation. Show more

Keywords: mdx, aging, histology, duchenne muscular dystrophy

DOI: 10.3233/JND-200562

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 513-524, 2021

Authors: Nagabushana, Divya | Polavarapu, Kiran | Bardhan, Mainak | Arunachal, Gautham | Gunasekaran, Swetha | Preethish-Kumar, Veeramani | Anjanappa, Ram Murthy | Thomas, PriyaTreesa | Sadasivan, Arun | Vengalil, Seena | Nashi, Saraswati | Chawla, Tanushree | Warrier, Manjusha | Keerthipriya, Muddasu | Raju, Sanita | Mohan, Dhaarini | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort. Methods: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy …were collected from the confirmed carriers. Results: Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy. Conclusion: Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo . Show more

Keywords: Duchenne muscular dystrophy, carrier, large deletions, large duplications, small pathogenic variants, India

DOI: 10.3233/JND-210658

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 525-535, 2021

Authors: Hiebeler, Miriam | Abicht, Angela | Reilich, Peter | Walter, Maggie C.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disease leading to ongoing degeneration of anterior horn cells in the spinal cord. Nusinersen is the first approved treatment for the condition, an intrathecally administered antisense oligonucleotide. It modulates pre-RNA splicing of the SMN2 gene and increases full-length SMN protein expression, thereby increasing SMN protein levels. The benefit of Nusinersen for patients with spinal muscular atrophy type 3 (SMA3) has recently been shown in several real-world cohorts. Objective: We aim to elucidate not only the effect of therapy with Nusinersen, but the development of the disease course after discontinuation …of treatment. To our knowledge, there are so far no reports on the effects of Nusinersen discontinuation. Methods: We report on a 45-year-old female patient with genetically confirmed SMA3 and a disease duration of 40 years prior to treatment onset. Results: The patient was non-ambulantory, best motor function at treatment onset was holding arms with support, reflected in MRC of 3/5 in upper limbs. After having received Nusinersen for 11 months without complications, the patient showed improvement in motor functions, as measured by hand grip measurement (HGS), Hammersmith Functional Rating Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Due to worsening of a pre-existing anxiety disorder, treatment was discontinued after six injections. Sixteen months later, progression of the disease became evident with worsening of HFMSE and RULM scores, while hand strength remained stable. Conclusion: Treatment with Nusinersen in SMA3 improves motor function in longstanding disease even in clinically advanced stages; however, after discontinuation of treatment, further progression mirroring the natural history of the disease is anticipated. Show more

Keywords: Spinal muscular atrophy type 3, SMA3, nusinersen, hammersmith functional motor scale, revised upper limb module, outcome measure

DOI: 10.3233/JND-210644

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 537-542, 2021

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