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