Journal of Neuromuscular Diseases - Volume 10, issue 2

Authors: Pascual-Morena, Carlos | Cavero-Redondo, Iván | Martínez-Vizcaíno, Vicente | Sequí-Domínguez, Irene | Fernández-Bravo-Rodrigo, Jaime | Jiménez-López, Estela

Article Type: Review Article

Abstract: Background: Dystrophinopathies are associated with neuropsychiatric disorders due to alterations in dystrophin/DMD expression. Objective: The objective was to estimate the association of developmental disorders, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), depression, anxiety disorders, and obsessive-compulsive disorder with the dystrophin/DMD genotype in population with dystrophinopathies. Methods: Systematic searches of Medline, Scopus, Web of Science, and Cochrane Library were performed from inception to September 2022. We included observational studies in the population with Becker or Duchenne muscular dystrophies (BMD, DMD) that estimated the prevalence of these disorders according to Dp140 and/or Dp71 genotype. …Meta-analysis of the prevalence ratio (PR) of genotype comparisons was conducted for each disorder. Results: Ten studies were included in the systematic review. In BMD, Dp140+ vs. Dp140– and Dp71+ vs. Dp71– were associated with developmental disorders with a PR of 0.11 (0.04, 0.34) and 0.22 (0.07, 0.67), respectively. In DMD, Dp140+/Dp71+ vs. Dp140– /Dp71– had a PR of 0.40 (0.28, 0.57), and Dp71+ vs. Dp71– had a PR of 0.47 (0.36, 0.63) for ADHD. However, there was no association of genotype with ASD, only a trend was observed for Dp71+ vs. Dp71–, with a PR of 0.61 (0.35, 1.06). Moreover, the data showed no association of these isoforms with emotional-related disorders. Conclusions: In BMD, Dp140 and Dp71 could be associated with developmental disorders, while ADHD might be associated with the Dp71 genotype in DMD. Further research is needed regarding Dp140 and Dp71, especially in DMD for ASD. Show more

Keywords: Dystrophin, Duchenne muscular dystrophy, autistic disorder, neurodevelopmental disorders, mood disorders

DOI: 10.3233/JND-221586

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 159-172, 2023

Authors: El-Hassar, Lynda | Amara, Ahmed | Sanson, Benoit | Lacatus, Oana | Amir Belhouchet, Ahmed | Kroneman, Madelon | Claeys, Kristl | Plançon, Jean Philippe | Rodolico, Carmelo | Primiano, Guido | Trojsi, Francesca | Filosto, Massimiliano | Mongini, Tiziana Enrica | Bortolani, Sara | Monforte, Mauro | Carraro, Elena | Maggi, Lorenzo | Ricci, Federica | Silani, Vincenzo | Orsucci, Daniele | Créange, Alain | Péréon, Yann | Stojkovic, Tanya | van der Beek, Nadine Anna Maria Elisabeth | Toscano, Antonio | Pareyson, Davide | Attarian, Shahram | Van den Bergh, Peter Y.K. | Remiche, Gauthier | Hoeijmakers, Janneke G.J. | Badrising, Umesh | Voermans, Nicol C. | Kaindl, Angela M. | Schara-Schmidt, Ulrike | Schoser, Benedikt | Gazzerro, Elisabetta | Haberlová, Jana | Voháňka, Stanislav | Pál, Endre | Molnar, Maria Judit | Leonardis, Lea | Tournev, Ivailo L | Osorio, Andrés Nascimento | Olivé, Montse | Muelas, Nuria | Alonso-Perez, Jorge | Plá, Francesc | de Visser, Marianne | Siciliano, Gabriele | Sacconi, Sabrina

Article Type: Research Article

Abstract: Background: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients’ homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. Objectives: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. …Methods: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). Results: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers’ assistance for accessing the TM platform. Conclusions: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations. Show more

Keywords: Telemedicine, neuromuscular diseases, Covid-19, Europe

DOI: 10.3233/JND-221525

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 173-184, 2023

Authors: Lim, Johan | Walter, Hannah A.W. | de Bruin-Bon, Rianne A.C.M. | Jarings, Myrthe C. | Planken, R. Nils | Kok, Wouter E.M. | Raaphorst, Joost | Pinto, Yigal M. | Amin, Ahmad S. | Boekholdt, S. Matthijs | van der Kooi, Anneke J.

Article Type: Research Article

Abstract: Background: Cardiac involvement in idiopathic inflammatory myopathy (IIM or “myositis”) is associated with an approximate 4% mortality, but standardised screening strategies are lacking. Objective: We explored a multimodality screening on potentially reversible cardiac involvement –i.e. active (peri)myocarditis –in newly diagnosed IIM. Methods: We included adult IIM patients from 2017 to 2020. At time of diagnosis, patients underwent cardiac evaluation including laboratory biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR). Based on 2019 consensus criteria for myocarditis, an adjudication committee made diagnoses of definite, probable, possible or no (peri)myocarditis. We explored diagnostic values of sequentially added …diagnostic modalities by Constructing Classification and Regression Tree (CART) analysis in patients with definite/probable versus no (peri)myocarditis. Results: We included 34 IIM patients, in whom diagnoses of definite (six, 18%), probable (two, 6%), possible (11, 32%), or no (peri)myocarditis (15, 44%) were adjudicated. CART-analysis showed high-sensitivity cardiac troponin T (cut-off value < 2.3 times the upper limit of normal (xULN)) ruled out (peri)myocarditis with a sensitivity of 88%, while high-sensitivity troponin I (cut-off value > 2.9 xULN for females and > 1.8 xULN for males) ruled in (peri)myocarditis with a specificity of 100%. Applying high-sensitivity cardiac troponins with these cut-off values in a diagnostic algorithm without and with a CMR to the total population of 34 patients demonstrated a diagnostic accuracy for a clear diagnosis of probable/definite or no (peri)myocarditis of 59% and 68%, respectively. Conclusions: A diagnostic algorithm for detection of (peri)myocarditis in adult IIM may consist of sequential testing with high-sensitivity cardiac troponins and CMR. Show more

Keywords: Neuromuscular diseases, muscular diseases, myositis, heart diseases

DOI: 10.3233/JND-221582

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 185-197, 2023

Authors: Dunaway Young, Sally | Pasternak, Amy | Duong, Tina | McGrattan, Katlyn E. | Stranberg, Sarah | Maczek, Elizabeth | Dias, Courtney | Tang, Whitney | Parker, Dana | Levine, Alexis | Rohan, Alyssa | Wolford, Connie | Martens, William | McDermott, Michael P. | Darras, Basil T. | Day, John W.

Article Type: Research Article

Abstract: Background: Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA. Objective: To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics. Methods: We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3–73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients …and group comparisons were performed using Wilcoxon rank sum tests. Results: A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2 (77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs  = 0.66). Conclusions: Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments. Show more

Keywords: Spinal muscular atrophy, patient-reported outcome measures, deglutition, swallow, dysphagia, communication, voice, speech

DOI: 10.3233/JND-221573

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 199-209, 2023

Authors: Mansouri, Vahid | Heidari, Morteza | Bemanalizadeh, Maryam | Azizimalamiri, Reza | Nafissi, Shahriar | Akbari, Masood Ghahvechi | Barzegar, Mohammad | Moayedi, Ali Reza | Badv, Reza Shervin | Mohamadi, Mahmood | Tavasoli, Ali Reza | Amirsalari, Susan | Khajeh, Ali | Inaloo, Soroor | Fatehi, Farzad | Hosseinpour, Sareh | Babaei, Meisam | Hosseini, Seyed Ahmad | Mahdi Hosseiny, Seyyed Mohammad | Fayyazi, Afshin | Hosseini, Firoozeh | Toosi, Mehran Beiraghi | Khosroshahi, Nahid | Ghabeli, Homa | Biglari, Habibeh Nejad | Kakhki, Simin Khayatzadeh | Mirlohi, Seyed Hossein | Bidabadi, Elham | Mohammadi, Bahram | Omrani, Abdolmajid | Sedighi, Mostafa | Vafaee-Shahi, Mohammad | Rasulinezhad, Maryam | Hoseini, Seyyed Mohamad | Movahedinia, Mojtaba | Rezaei, Zahra | Karimi, Parviz | Farshadmoghadam, Hossein | Anvari, Saeed | Yaghini, Omid | Nasiri, Jafar | Zamani, Gholamreza | Ashrafi, Mahmoud Reza

Article Type: Research Article

Abstract: Background: Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined. Objective: To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA). Methods: IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project. Results: By October 1, …2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1 , while the frequency of patients with higher copy numbers of SMN2 , was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP ) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease. Conclusions: The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran. Show more

Keywords: Registry, Iran, Spinal muscular atrophy, Neuronal apoptosis inhibitory protein

DOI: 10.3233/JND-221614

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 211-225, 2023

Authors: Inbaraj, Ganagarajan | Arjun, Krishnamurthy | Meghana, Adoor | Preethish-Kumar, Veeramani | John, Anu P | Polavarapu, Kiran | Nashi, Saraswati | Sekar, Deepha | Udupa, Kaviraja | Prathuysha, Parthipulli V. | Prasad, Krishna | Bardhan, Mainak | Raju, Trichur R. | Kramer, Boris W. | Nalini, Atchayaram | Sathyaprabha, Talakad N.

Article Type: Research Article

Abstract: Background and Objective: Duchenne muscular dystrophy (DMD) is a degenerative X-linked muscle disease. Death frequently results from complications in cardiopulmonary systems. Preclinical/early diagnosis of cardiac autonomic abnormalities may aid initiate cardioprotective therapy and enhance prognosis. Methods: A cross sectional, prospective study of 38 DMD boys compared with 37 age-matched healthy controls was conducted. Lead II electrocardiography and beat-to-beat blood pressure were recorded to assess heart rate variability (HRV), blood pressure variability (BPV), and baroreceptor sensitivity (BRS) in a standardized environment. Data were analysed and correlated with disease severity and genotype. Results: In the DMD group, the …median age at assessment was 8 years [IQR 7–9 years], the median age at disease onset was 3 years [IQR, 2–6 years], and the mean duration of illness was 4 years [IQR, 2.5–5]. DNA sequencing showed deletions in 34/38 (89.5 %) and duplications in 4/38 (10.5%) patients. The median heart rate in DMD children was significantly higher [101.19 (Range, 94.71–108.49)] /min compared to controls [81 (Range, 76.2–92.76)] /min (p  < 0.05). All the assessed HRV and BPV parameters were significantly impaired in DMD cases except for the coefficient of variance of systolic blood pressure. Further, BRS parameters were also significantly reduced in DMD, excluding alpha-LF. A positive correlation was found between alpha HF with age at onset and duration of illness. Conclusion: This study demonstrates a distinct early impairment of neuro-cardio-autonomic regulation in DMD. Simple yet effective non-invasive techniques such as HRV, BPV, and BRS may help identify cardiac dysfunction in a pre-clinical state, paving the way for early cardio-protective therapies and limiting disease progression in DMD patients. Show more

Keywords: Duchenne muscular dystrophy, autonomic modulation, heart rate variability, blood pressure variability, baroreflex sensitivity

DOI: 10.3233/JND-221621

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 227-238, 2023

Authors: Slayter, Jeremy | Casey, Lauren | O’Connell, Colleen

Article Type: Research Article

Abstract: BACKGROUND: Spinal Muscular Atrophy (SMA) is a hereditary neuromuscular disease with an estimated prevalence of 1/10 000 births. SMA is increasingly recognized as a multi-system disease with a need to study additional under-recognized health domains such as quality of life, fatigue, bulbar function, respiratory function, and independence. OBJECTIVE: Identify and assess reported evidence from the literature investigating Patient Reported Outcome Measures (PROMs) in adults with SMA. Develop a novel method drawing from network theory to graphically depict the literature, PROMs, and supporting psychometric evidence. METHODS: A scoping review was completed following PRISM-ScR, COSMIN and JBI scoping …review guidelines. Literature investigating PROMs in adult SMA or neuromuscular disease was identified from peer-reviewed and grey databases. A network graph was derived from extracted data. RESULTS: 5292 articles were retrieved, 81 articles met inclusion criteria; corresponding to 31 unique PROMs. Only two PROMs were developed specifically for SMA. Few PROMs covered multiple domains of health. Most PROMs were incompletely validated, focusing on concurrent validity, and few assessed responsiveness or internal consistency. CONCLUSIONS: PROMs are emerging tools for monitoring and assessing adults with SMA. Despite their potential benefits, additional validation studies should be completed prior to their use for clinical decision-making. Network graphics may represent a technique to aid in the visualization of evidence supporting a scoping review. Show more

Keywords: Review, muscular atrophy, spinal, patient reported outcome measures, patient outcome assessment, rehabilitation, neuromuscular disease, reproducibility of results, health status, psychological tests, neurodegenerative diseases

DOI: 10.3233/JND-221595

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 239-250, 2023

Authors: Klein, Eike | Dräger, Bianca | Boentert, Matthias

Article Type: Research Article

Abstract: Objective: This study aimed to validate the single breath count test (SBCT) against volitional measures of respiratory muscle function in healthy subjects and people with neuromuscular disorders (NMD; n  = 100 per group). Methods: Testing comprised upright and supine SBCT, forced vital capacity (FVC), maximum inspiratory pressure (MIP), and sniff nasal inspiratory pressure (SNIP). Predictability of FVC by SBCT was assessed using logarithmic regression analysis. Receiver operating characteristics curves were used to identify SBCT thresholds for lung restriction (FVC < 80% predicted), inspiratory muscle weakness (MIP < 60 cmH2 O), and indication for non-invasive ventilation (NIV) in NMD patients. Results: In …both groups, SBCT showed moderate correlation with FVC. In patients, SBCT values were also correlated with MIP and SNIP. Strength of correlations was similar with supine and upright SBCT which accounted for 23.7% of FVC variance in healthy individuals (44.5% in patients). Predictive thresholds of upright SBCT were < 27 for MIP < 60 cmH2 O (sensitivity 0.61/specificity 0.86), <39 for NIV indication (0.92/0.46), and <41 for FVC < 80% predicted (0.89/0.62). Conclusion: The SBCT is positively correlated with spirometry. It predicts both lung restriction and NIV indication in NMD patients. The SBCT allows for remote monitoring and may substitute for spirometry/manometry if appropriate devices are unavailable. Show more

Keywords: Single breath count test, spirometry, maximum inspiratory pressure, neuromuscular disorders, non-invasive ventilation

DOI: 10.3233/JND-221530

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 251-261, 2023

Authors: Jaxybayeva, Altynshash | Chunkayeva, Dana | Myrzaliyeva, Bakhytkul | Ayaganov, Dinmukhamed | Lepessova, Marzhan | Bulekbayeva, Sholpan | Idrissova, Zhannat | Mukhambetova, Gulnar | Bayanova, Mirgul | Malfatti, Edoardo | Urtizberea, Andoni

Article Type: Brief Report

Abstract: Background: Neuro-muscular disorders constitutes a group of rare but heterogeneous conditions. The onset of these diseases ranges widely from birth to elderly. Many of them are life threatening and progressive. Neuromuscular science is a very specialised medical field for which specific knowledge and expertise are necessary. Such an expertise is available only partially in Kazakhstan where underdiagnosis, misdiagnosis and mismanagement of patients with muscle diseases are commonplace. Hopefully, times are changing. With the implementation of international guidelines for the diagnosis and treatment of Duchenne Muscular Dystrophy (DMD), patients are now given better care including pharmacological interventions (including steroids in DMD), …respiratory and nutritional support. Objectives: To report on clinical data and genetic variants in a nationwide cohort of DMD patients. To describe and analyse management strategies applied in Kazakhstan in these patients. Methods: The medical records of 84 patients recruited by the national expert-consulting board based at the national multidisciplinary centre of reference in neuro-muscular disorders in Astana, Kazakhstan, have been ascertained for the study. The national expert committee meets monthly to decide over the prescription of disease-modifying therapies in paediatric neuromuscular disorders. Data on the age of disease onset, the age at genetic testing, spectrum of genetic variants, the stage of disease and the serum CK levels have been collected. Results The mean age of 84 examined patients was 10 years. In Kazakhstan, the average age of disease manifestation was 3 years and 3 months. The vast majority of patients passed through genetic test due to the clinical manifestations. The average age of genetic confirmation was 7 years and 6 months. There were 58,33%of gross variations, of which 55,95%were deletions and 2,38%were duplications. Nonsense mutations were identified in 29,7%. Conclusion: The authors contend that strictly keeping the clinical guides in the diagnosis of DMD is essential, as the genetic variations may affect the stage and feasibility of novel therapies. The way of management of neuro-muscular diseases used in Kazakhstan is strictly recommended for implementation in developing countries. Show more

Keywords: Duchenne muscular dystrophy, multiple ligation binding probe amplification, next generation sequencing, DMD gene, genetic spectrum, deletion

DOI: 10.3233/JND-221559

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 263-269, 2023

Authors: Kramer, J.J. | Boon, H.T.M. | Leijten, Q.H. | Ter Laak, Henk | Eshuis, L. | Kusters, B. | van Doorn, J.L.M. | Kamsteeg, E.J. | Eymard, B. | Doorduin, J. | Voermans, N.C.

Article Type: Case Report

Abstract: We here present the case of a patient with a congenital myasthenic syndrome (CMS) due to pathogenic variants in the RAPSN gene. During childhood he experienced recurrent episodes of respiratory failure during respiratory infections. This and other cases were reported as isolated dystrophy of the diaphragmatic musculature. In adulthood, whole exome sequencing revealed two heterozygous pathogenic variants in the RAPSN gene. This led to the revision of the diagnosis to rapsyn CMS11 (OMIM:616326, MONDO:0014588). EMG, muscle ultrasound and the revision of muscle biopsies taken in childhood support this diagnosis. After the revision of the diagnosis, treatment with pyridostigmine was started. …This resulted in a reduction of fatigability and an improvement in functional abilities and quality of life. Show more

Keywords: Congenital myasthenic syndrome, RAPSN, Rapsyn, CMS11, Whole exome sequencing, diaphragmatic dystrophy

DOI: 10.3233/JND-221542

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 2, pp. 271-277, 2023