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Background and Objectives: Muscular dystrophies and myotonic disorders are genetic disorders characterized by progressive skeletal muscle degeneration and weakness. Epidemiologic studies have found an increased cancer risk in myotonic dystrophy, although the cancer risk spectrum is poorly characterized. In patients with muscular dystrophy, the cancer risk is uncertain. We aimed to determine the overall cancer risk and cancer risk spectrum in patients with muscular dystrophy and myotonic dystrophy using data from the Swedish National registers., Methods: We performed a matched cohort study in all patients with muscular dystrophy or myotonic dystrophy born in Sweden 1950-2017 and 50 matched comparisons by sex, year of birth, and birth county per individual. The association with cancer overall and specific malignancies was estimated using stratified Cox proportional hazard models., Results: We identified 2,355 and 1,968 individuals with muscular dystrophy and myotonic dystrophy, respectively. No increased overall cancer risk was found in muscular dystrophy. However, we observed an increased risk of astrocytomas and other gliomas during childhood (hazard ratio [HR] 8.70, 95% CI 3.57-21.20) and nonthyroid endocrine cancer (HR 2.35, 95% CI 1.03-5.34) and pancreatic cancer (HR 4.33, 95% CI 1.55-12.11) in adulthood. In myotonic dystrophy, we found an increased risk of pediatric brain tumors (HR 3.23, 95% CI 1.16-9.01) and an increased overall cancer risk in adults (HR 2.26, CI 1.92.2.66), specifically brain tumors (HR 10.44, 95% CI 7.30-14.95), thyroid (HR 3.92, 95% CI 1.70-9.03), and nonthyroid endocrine cancer (HR 7.49, 95% CI 4.47-12.56), endometrial (HR 8.32, 95% CI 4.22-16.40), ovarian (HR 4.00, 95% CI 1.60-10.01), and nonmelanoma skin cancer (HR 3.27, 95% CI 1.32-8.13)., Discussion: Here, we analyze the cancer risk spectrum of patients with muscular dystrophy and myotonic dystrophy. To the best of our knowledge, this is the first report of an increased risk for CNS tumors in childhood and adult nonthyroid endocrine and pancreatic cancer in muscular dystrophy. Furthermore, for myotonic dystrophy, we confirmed previously reported associations with cancer and expanded the cancer spectrum, finding an unreported increased risk for nonthyroid endocrine cancer. Additional studies confirming the cancer risk and delineating the cancer spectrum in different genetic subtypes of muscular dystrophies are warranted before considering altered cancer screening recommendations than for the general population.

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.

Background: Bethlem Myopathy is a collagen VI-related myopathy presenting as a rare hereditary muscular disorder with progressive muscular weakness and joint contractures. Despite its milder clinical course relative to other myopathies, anaesthetic management can be challenging. High arched palates and fixed flexion deformities may contribute to a difficult airway. A progressive decline in pulmonary function can present later into adulthood. This respiratory decline can carry secondary cardiovascular consequences due to the progressive nature of restrictive lung disease, including right sided heart disease and pulmonary hypertension. We describe a case of a male patient with Bethlem Myopathy undergoing anaesthesia, to contribute to the limited body of literature on this condition and enhance awareness and guidance amongst anaesthesiologists on approaching patients with this condition. This is the first case report within the literature of its kind., Case Presentation: This case details a 33-year-old male with Bethlem Myopathy undergoing tonsillectomy. Diagnosed in childhood following developmental delays, the patient had no prior anaesthetic exposure and no family history of anaesthetic complications. Anaesthetic induction was achieved without complications, avoiding depolarizing muscle relaxants and careful airway management. Extreme care was taken in patient positioning to prevent complications. The surgery proceeded without incident and muscle paralysis was reversed with Suggammadex, resulting in no adverse post-operative respiratory complications. The patient was discharged on the first post-operative day without any respiratory or cardiovascular compromise., Conclusions: Bethlem Myopathy, while often exhibiting a mild clinical course, can present anaesthetic challenges. Awareness of potential complications including a difficult airway, cardiovascular and respiratory implications as well as the need for specialised monitoring and positioning is crucial to ensure a safe peri-operative course., (© 2024. The Author(s).)

Muscular dystrophy encompasses a group of genetic conditions with progressive muscle damage and weakness. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders that affect the production of the protein dystrophin. Emery-Dreifuss muscular dystrophy (EDMD) is typically an X-linked-recessive disorder involving the gene that codes for emerin. Facioscapulohumeral muscular dystrophy and oculopharyngeal muscular dystrophy (OPMD) are both autosomal dominant disorders. Although commonly mistaken as a condition in which patients are susceptible to malignant hyperthermia with volatile inhalational anesthetics, muscular dystrophy is more closely associated with rhabdomyolysis. Providers developing an anesthetic plan for dental patients with muscular dystrophy must take into consideration the patient's baseline cardiac and pulmonary function as well as the potential for abnormalities. Nondepolarizing neuromuscular blocker use is safe but likely to result in prolonged skeletal muscle relaxation. Succinylcholine and volatile anesthetics are generally contraindicated due to the risks of rhabdomyolysis and hyperkalemia with subsequent ventricular fibrillation, cardiac arrest, and death if left untreated. In-depth understanding of the more commonly encountered forms of muscular dystrophy is vital to providing safe and effective ambulatory anesthesia care for patients undergoing dental treatment outside the traditional hospital operating room setting.

Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness. In this study, we performed a comprehensive cell biological analysis of dermal fibroblasts from three different patients with EBS-MD, where PLEC expression analyses revealed preserved mRNA levels in all cases, whereas full-length plectin protein content was significantly reduced or completely absent. Downstream effects of pathogenic PLEC sequence alterations included massive bundling of vimentin intermediate filament networks, including the occurrence of ring-like nuclei-encasing filament bundles, elongated mitochondrial networks, and abnormal nuclear morphologies. We found that essential fibroblast functions such as wound healing, migration, or orientation upon cyclic stretch were significantly impaired in the cells of patients with EBS-MD. Finally, EBS-MD fibroblasts displayed reduced adhesion capacities, which could be attributed to smaller focal adhesion contacts. Our study not only emphasizes plectin's functional role in human skin fibroblasts, it also provides further insights into the understanding of EBS-MD-associated disease mechanisms., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking., Objective: The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care., Methods: In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction., Results: 21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > -18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients., Conclusion: ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise.

Technetium-99m-methoxy isobutyl isonitrile ( 99m Tc-MIBI) myocardial perfusion imaging (MPI) is a functional imaging method with relatively poor specificity but high sensitivity. We present 48-year-old man with cardiac involvement due to muscular dystrophies (MD). Myocardial perfusion imaging rest images revealed regional myocardial perfusion decrease in multiple walls, enlarged heart and decreased left ventricular systolic function. The lesion location of MPI was consistent with that seen on CMR. Our case showed MPI was useful for detection and evaluation of the MD patient with cardiac involvement. In addition, imaging findings in combination with clinical history and other data are important. The case highlight is thevalue of MPI in myocardiopathy.

Background: Congenital muscular dystrophies (CMDs) result from genetically inherited defects in the biosynthesis and/or the posttranslational modification (glycosylation) of laminin-α2 and α-dystroglycan (α-DG), respectively. The interaction between both proteins is responsible for the stability and integrity of the muscle cell. We aimed to study the expression profiles of both proteins in two classes of CMDs., Subjects and Methods: Whole-exome sequencing (WES) was done for four patients with neuromuscular manifestations. The expression of core α-DG and laminin-α2 subunit in skin fibroblasts and MCF-7 cells was assessed by western blot., Results: WES revealed two cases with nonsense mutations; c.2938G > T and c.4348 C > T, in LAMA2 encodes laminin-α2. It revealed also two cases with mutations in POMGNT1 encode protein O-mannose beta-1,2-N-acetylglucosaminyltransferase mutations. One patient had a missense mutation c.1325G > A, and the other had a synonymous variant c.636 C > T. Immunodetection of core α-DG in skin fibroblasts revealed the expression of truncated forms of core α-DG accompanied by reduced expression of laminin-α2 in POMGNT1-CMD patients and one patient with LAMA2-CMD. One patient with LAMA2-CMD had overexpression of laminin-α2 and expression of a low level of an abnormal form of increased molecular weight core α-DG. MCF-7 cells showed truncated forms of core α-CDG with an absent laminin-α2., Conclusion: A correlation between the expression pattern/level of core α-DG and laminin-α2 could be found in patients with different types of CMD., (© 2023. The Author(s).)

Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (<60) with heart block should be evaluated for an underlying systemic disease. These disorders are classified into infiltrative, rheumatologic, endocrine, and hereditary neuromuscular degenerative diseases. Cardiac amyloidosis owing to amyloid fibrils and cardiac sarcoidosis owing to noncaseating granulomas can infiltrate the conduction system leading to heart block. Accelerated atherosclerosis, vasculitis, myocarditis, and interstitial inflammation contribute to heart block in rheumatologic disorders. Myotonic, Becker, and Duchenne muscular dystrophies are neuromuscular diseases involving the myocardium skeletal muscles and can cause heart block., Competing Interests: Disclosure Dr W.Z. Tzou is a consultant for or has received speaker honoraria, or research funding from Abbott, American Heart Association, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr S.R.A. Sabzwari has no relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Muscular dystrophies vary in presentation and severity, but are associated with profound disability in many people. Although characterised by muscle weakness and wasting, there is also a very high prevalence of sleep problems and disorders which have significant impacts on quality of life in these individuals. There are no curative therapies for muscular dystrophies, with the only options for patients being supportive therapies to aid with symptoms. Therefore, there is an urgent need for new therapeutic targets and a greater understanding of pathogenesis. Inflammation and altered immunity are factors which have prominent roles in some muscular dystrophies and emerging roles in others such as type 1 myotonic dystrophy, signifying a link to pathogenesis. Interestingly, there is also a strong link between inflammation/immunity and sleep. In this review, we will explore this link in the context of muscular dystrophies and how it may influence potential therapeutic targets and interventions., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In muscular dystrophies (MD) patients with end-stage heart failure (HF), continuous flow left ventricular assist device (cf-LVAD) therapy is still controversial due to a progressive nature of MD-associated muscle weakness., Methods: All the MD patients who had cf- VAD implants between March 2013 and August 2019 in our hospital were retrospectively studied. Study end points were death, major LVAD-associated complications or respiratory dysfunction caused by muscular weakness., Results: A total of 11 MD patients (Becker type: n = 6; Emery-Dreifuss Myodystrophy: n = 2; Fukuyama subtype: n = 1; Limb-girdle 1B: n = 2) were enrolled., Demographics: median age 41 years (IQR; 29-47); median Japanese Registry for Mechanically Assisted Circulatory Support: level 3 (2-3); a median interval between MD diagnosis and LVAD implantation 9 years (6-18). The pulmonary function test at LVAD implantation showed a median of %VC; 62% (45-82), FEV 1% , 82% (81-88). Survival to discharge was 100% without pulmonary complication and early VAD-related complications. During a median follow-up of 38 months (27-53), re-admissions were needed due to device infection (n = 2), cerebrovascular accidents (disabling, n = 2 and non-disabling, n = 2), ventricular tachycardia (n = 4), and right HF (n = 3), respectively. 7 patients received successful heart transplant after a median waiting time of 44 months (34-61); 3 patients are still on the waiting list (waiting time: 21, 38, and 39 months). One patient died of right HF 15 months after VAD implantation. No one had overt pulmonary dysfunction during LVAD support., Conclusion: In selected MD patients with end-stage HF, cf-LVAD therapy is a viable therapeutic option as bridge to heart transplant., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Introduction/aims: Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's national registry to clarify the current treatment patterns and demographic features of Japanese DM patients., Methods: Using the Japanese National Registry of Muscular Dystrophy (Remudy), we analyzed medical care practice for the multisystemic issues associated with adult DM type 1 patients, excluding congenital DM., Results: We included 809 patients with a median age of 44.2 years. Among these patients, 15.8% used ventilators; 31.7% met the index considered at risk for sudden death due to cardiac conduction defects (PR interval over 240 milliseconds or QRS duration over 120 milliseconds) and 2.8% had implanted cardiac devices. Medication for heart failure was prescribed to 9.6% of patients. Overall, 21.2% of patients had abnormal glucose metabolism, of whom 42.9% were treated with oral medications. Among the oral medications, dipeptidyl peptidase-4 inhibitors were the most common. Cancers were observed in 3.7% of the patients, and endometrial and breast cancers were dominant. Mexiletine was prescribed for myotonia in 1.9% of the patients, and only 1% of the patients received medication for daytime sleepiness., Discussion: This study shows difference in treatment patterns for DM1 in Japan compared with other countries, such as lower rates of use of implantable cardiac devices and higher rates of ventilator use. These data may be useful in discussions aimed at standardizing medical care for patients with DM., (© 2023 Wiley Periodicals LLC.)

Acute hospitalisation may be required to support patients with Neuromuscular disorders (NMDs) mainly experiencing respiratory complications, swallowing difficulties, heart failure, urgent surgical procedures. As NMDs may need specific treatments, they should be ideally managed in specialized hospitals. Nevertheless, if urgent treatment is required, patients with NMD should be managed at the closest hospital site, which may not be a specialized centre where local emergency physicians have the adequate experience to manage these patients. Although NMDs are a group of conditions that can differ in terms of disease onset, progression, severity and involvement of other systems, many recommendations are transversal and apply to the most frequent NMDs. Emergency Cards (EC), which report the most common recommendations on respiratory and cardiac issues and provide indications for drugs/treatments to be used with caution, are actively used in some countries by patients with NMDs. In Italy, there is no consensus on the use of any EC, and a minority of patients adopt it regularly in case of emergency. In April 2022, 50 participants from different centres in Italy met in Milan, Italy, to agree on a minimum set of recommendations for urgent care management which can be extended to the vast majority of NMDs. The aim of the workshop was to agree on the most relevant information and recommendations regarding the main topics related to emergency care of patients with NMD in order to produce specific ECs for the 13 most frequent NMDs., (©2022 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Background: Patients with muscular dystrophy (MD) are at elevated risk of serious cardiac complications and clinical assessment is limited due to inherent physical limitations. We assessed the utility of left ventricular ejection fraction (LVEF) derived from transthoracic echocardiogram (TTE) as a prognostic marker for major adverse cardiac events (MACE) in a mixed adult MD cohort., Methods: One hundred and sixty-five MD patients (median age: 36 (interquartile range [IQR]: 23.0-49.0) years; 65 [39.4%] females) were enrolled in our prospective cohort study. Diagnoses included dystrophinopathies (n = 42), limb-girdle MD (n = 31), type 1 myotonic dystrophy (n = 71), and facioscapulohumeral MD (n = 21). Left ventricular ejection fraction, ventricular dimensions at end-diastole and end-systole, and serial measures (n = 124; follow-up period: 2.19 [IQR: 1.05-3.32] years) stratified patients for MACE risk., Results: Cardiomyopathy was diagnosed in 60 (36.4%) patients of the broader cohort (median LVEF: 45.0 [IQR: 35.0-50.0] %). Ninety-eight MACE occurred over the 7-year study period. At baseline, patients with a LVEF &lt; 55.0% had a high risk of MACE (adjusted odds ratio: 8.30; 95% confidence interval [CI]: 3.18-21.7), concordant with the analysis of LV dimensions. Forty-one percent of these patients showed an improvement in LVEF with the optimization of medical and device therapies. Relative to patients with preserved LVEF, patients with reduced LVEF were at an elevated risk of MACE (adjusted hazard ratio [aHR]: 7.21; 95% CI: 1.99-26.1), and improved LVEF resulted in comparable outcomes (aHR: 1.84; 95% CI: .49-6.91) associated with optimization of medical and device therapies. Reduction in QRS duration by CRT therapy was associated with an improvement in LVEF (average improvement: 12.8 [± 2.30] %; p = .04)., Conclusions: Reduction in LVEF indicates an increased risk of cardiovascular events in patients with MD. Baseline and serial LVEF obtained by TTE can prognosticate patients for MACE and guide clinical management., (© 2022 Wiley Periodicals LLC.)

Purpose of Review: This review summarizes recent advances in our understanding of the genetics of rhabdomyolysis., Recent Findings: Rhabdomyolysis is the acute breakdown of myofibres resulting in systemic changes that can be life-threatening. Environmental triggers, including trauma, exercise, toxins and infections, and/or gene defects can precipitate rhabdomyolysis. A schema (aptly titled RHABDO) has been suggested for evaluating whether a patient with rhabdomyolysis is likely to harbour an underlying genetic defect. It is becoming increasingly recognized that defects in muscular dystrophy and myopathy genes can trigger rhabdomyolysis, even as the sole or presenting feature. Variants in genes not previously associated with human disease have been identified recently as causative of rhabdomyolysis, MLIP , MYH1 and OBSCN . Our understanding of the pathomechanisms contributing to rhabdomyolysis have also improved with an increased awareness of the role of mitochondrial dysfunction in LPIN1 , FDX2 , ISCU and TANGO2 -mediated disease., Summary: An accurate genetic diagnosis is important for optimal clinical management of the patient, avoiding associated triggers and genetic counselling and cascade screening. Despite recent advances in our understanding of the genetics contributing to rhabdomyolysis, many patients remain without an accurate genetic diagnosis, suggesting there are many more causative genes, variants and disease mechanisms to uncover., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Muscular dystrophy (MD) is a group of multiple muscle diseases, which causes severely impaired motor ability, degeneration and dysfunctions in the musculoskeletal system, respiratory failure and feeding difficulties. LAMA2-related MD is caused by pathogenic variants in the LAMA2 gene, encoding laminin a2 chain, a component of the skeletal muscle extracellular matrix protein laminin-α2β1γ1. We performed clinical examination and molecular genetic analysis in a patient with congenital MD (CMD), and autism-like phenotype. We performed whole exome sequencing (WES) to find possible genetic etiology of CMD in an Iranian non-consanguineous patient. The pathogenicity of the variants was assessed using various Bioinformatics tools. American College of Medical Genetics and Genomics (ACMG) guidelines were used to interpret the variant and Sanger sequencing in the patient and her family was applied for the confirmation of the variant. WES results showed a novel frameshift homozygous variant (p.Tyr1313LeufsTer4) in the LAMA2 gene leading to the CMD phenotype. This variant resides in a highly conserved region and was found to be co-segregating in the family. It fulfils the criteria of being pathogenic. We successfully identified a novel LAMA2 pathogenic variant in an Iranian patient suffering from CMD and autism using WES. Identification of disease-causing variant in autosomal recessive disorders such as CMD can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of the disease., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related myopathy (SELENON-RM) are rare neuromuscular diseases caused by mutations in the LAMA2 and SELENON (SEPN1) gene, respectively. Systematic reviews on cardiac features in both neuromuscular diseases are lacking. This scoping review aims to elucidate the cardiac involvement in LAMA2-MD or SELENON-RM. Three electronic databases (PubMed, Embase and Cochrane) were searched. All studies, case reports and case series with information on cardiac features in LAMA2-MD or SELENON-RM patients were included. Study selection and data extraction were performed by two independent reviewers. 31 Articles on LAMA2-MD and 17 articles on SELENON-RM met the inclusion criteria, resulting in the inclusion of 131 LAMA2-MD and 192 SELENON-RM cases. In 41% of LAMA2-RM cases, a cardiac abnormality was present. Left ventricular systolic dysfunction and arrhythmia were most frequently described. In 15% of SELENON-RM cases, a cardiac abnormality was reported, of which pulmonary hypertension, including right ventricular dysfunction secondary to pulmonary failure, was most prevalent. We conclude that in LAMA2-MD primary left ventricular dysfunction and in SELENON-RM secondary right ventricular dysfunction are frequently reported. Optimal cardiorespiratory surveillance by screening of asymptomatic patients every two years with ECG, Holter and echocardiography is necessary for early detection and/or treatment of cardiac manifestations., Competing Interests: Declaration of Competing Interest All other authors declare that they have no competing interests. This work was supported by a grant from Stichting Spieren voor Spieren, Stichting Stofwisselkracht and Stichting Voor Sara, The Netherlands. The funders have no role in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. Several authors of this publication are members of the Radboudumc Center of Expertise for neuromuscular disorders (Radboudumc-NMD), the Netherlands Neuromuscular Center (NL-NMD) and European Reference Network for rare neuromuscular diseases (EURO-NMD)., (Copyright © 2022. Published by Elsevier B.V.)

Transient receptor potential vanilloid 2 (TRPV2) channels are expressed and play functional roles in various immune cells. Physical stimuli leading to TRPV2 activation causes mast cell degranulation. Besides their roles in immune cells, it has been shown that TRPV2 channels are pathophysiologically relevant to degenerative muscular diseases such as dilated cardiomyopathy and muscular dystrophy. Hence, development of drug candidates that inhibit human TRPV2 activation is an urgent matter. NK-4, a cryptocyanine dye, inhibited agonist-induced TRPV2 activity in mouse TRPV2-transfected HEK293 cells. However, it remains unclear whether NK-4 exerts regulatory effects on the activation of human TRPV2 channels. In this study, we show that NK-4 inhibits intracellular Ca 2+ increase in human TRPV2-transfected HEK293 cells preactivated with a TRPV2 agonist. The inhibitory effect of NK-4 (IC 50 =0.27 μM) on human TRPV2 activation was 74-fold stronger than that on mouse TRPV2 activation (IC 50 =20 μM). NK-4 also inhibited the agonist-induced TRPV2 expression at the plasma membrane, when the human TRPV2-expressing cells were stimulated with the agonist in the presence of NK-4. These results suggest that NK-4 abrogates the agonist-induced signaling events leading to human TRPV2 activation. Furthermore, TRPV2 agonist caused degranulation of RBL-2H3 cells, which represents a phenomenon related to physical urticarias. NK-4 suppressed the release of β-hexosaminidases upon degradation with IC 50 of 1.9 μM, 35-fold lower than that determined with an anti-allergic drug, Epinastine. Our results suggest that NK-4 would be a potential therapeutic strategy to resolve dilated cardiomyopathy and its associated heart failure as well as physical urticarias.

Importance: Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is an autosomal recessive disorder caused by pathogenic variants in PLEC1, which encodes plectin. It is characterized by mild mucocutaneous fragility and blistering and muscle weakness. Translational readthrough-inducing drugs, such as repurposed aminoglycoside antibiotics, may represent a valuable therapeutic alternative for untreatable rare diseases caused by nonsense variants., Objective: To evaluate whether systemic gentamicin, at a dose of 7.5 mg/kg/d for 14 consecutive days, is clinically beneficial in a patient with EBS-MD., Design, Setting, and Participants: A single patient in Madrid, Spain, received 2 treatment courses with gentamicin on July 2019 and February 2020 with a follow-up period of 120 and 150 days, respectively., Results: In this case report of a woman in her 30s with EBS-MD, before gentamicin treatment, the patient had mucocutaneous involvement, skeletal and respiratory muscle weakness, and myalgia that negatively affected her quality of life. Outcomes were evaluated with extensive laboratory tests and clinical scales. No nephrotoxic or ototoxic effects were detected after intravenous gentamicin administration. Gentamicin treatment was followed by plectin expression in the skin for at least 5 months. Although minimal changes were noted in skeletal muscle function (as measured by the Hammersmith functional motor scale and its expanded version: 6/40 to 7/40 and from 10/66 to 11/66, respectively) and respiratory musculature (maximal inspiratory and expiratory pressures D0 vs D16, MIP: 2.86 vs 3.63 KPa and MEP: 2.93 vs 4.63 KPa), myalgia disappeared (VAS dropped from 6 to 0), and quality of life improved (EuroQoL-5D-3L pain and anxiety dropped from 2 to 1)., Conclusions and Relevance: The findings of this single case report suggest that gentamicin treatment may help suppress PLEC1 premature termination codons and induce plectin expression in EBS-MD primary keratinocytes and skin. Our study suggests that gentamicin may play an important role in treating EBS-MD owing to nonsense variants.

Diagnostic journey for people with FKRP mutations participating in a dystroglycanopathy natural history study (n = 68; NCT00313677) was analyzed. Earliest symptoms and age at muscular dystrophy diagnosis were abstracted from subject-reported medical history and record review. Initial signs/symptoms were classified as chronic motor dysfunction (e.g., delayed motor milestones, weakness, falling; n = 40, 59%), elevated transaminases (n = 7, 10%), or acute/intermittent symptoms (myoglobinuria, myalgia, febrile illness-associated acute weakness; n = 21, 31%). Median time from sign/symptom onset to diagnosis was 6.5 years and differed by symptom group: 7.5 years for motor group, 9 years for acute/intermittent group, and 4 years for elevated transaminases group. The sign/symptom category that most commonly resulted in a diagnosis was chronic motor dysfunction (n = 45). Of those without clear weakness as first symptom (n = 55), 36.4% were not diagnosed with MD until weakness became apparent. Median time to diagnosis was shortest for those with febrile illness-associated acute weakness (0.25 years). Median time from first sign/symptom to MD diagnosis has decreased incrementally from 18.8 years for those with onset in the 1970s to < 10 years for symptom onset occurring after 2000. Awareness of disease presentation variability will aid in earlier diagnosis, which is increasingly important with treatments in development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic pain is a frequent, yet under-recognized and under-assessed problem in people with muscular dystrophies (MDs). Knowledge of the prevalence and characteristics of chronic pain, and its impact on function and quality of life is limited and lacks systematic exploration. This article aims to systematically review and synthesize existing literature that addresses chronic pain prevalence, characteristics and impact in people with different types of MDs. The present meta-analysis showed that the estimated prevalence of chronic pain in MDs is high and appears to be similar across different diagnostic groups: 68% (95% CI: 52%-82%) in FSHD, 65% (95% CI: 51%-77%) in DM, 62% (95% CI: 50%-73%) in BMD/DMD, and 60% (95% CI: 48%-73%) in LGMD, although it should be noted that heterogeneity was high in some diagnostic groups. On average, people with FSHD and DM present with moderate pain intensity. The lumbar spine, shoulders and legs are the most frequent sites of chronic pain among people with FSHD, DM, BMD/DMD, and LGMD, with little variation. Diffuse pain across multiple body sites was reported by a notable proportion of these individuals. Chronic pain has a negative impact on daily life activities in people with MDs, and may also contribute to decreased quality of life. The protocol for this review has been published on PROSPERO (CRD42020168096). PERSPECTIVES: This is the first systematic review and meta-analysis exploring the prevalence, and nature and impact of chronic pain in people with MDs. The present study demonstrates how common chronic pain is across various MD populations and highlights the need for better recognition and understanding of the nature and impact of pain from health professionals., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Heart disease remains a leading cause of mortality in patients with muscular dystrophy (MD), and cardiac assessment by standard imaging modalities is challenging due to the prominence of physical limitations., Methods: In this prospective cohort study of 169 MD patients and 34 negative control patients, we demonstrate the clinical utility of a 12-lead electrocardiogram (ECG) as an effective modality for the assessment of cardiac status in patients with MD. We assessed the utility of conventional criteria for electrocardiogram-indicated left ventricular hypertrophy (ECG-LVH) as well as ECG morphologies., Results: Cornell voltage, Cornell voltage-duration, Sokolow-Lyon voltage, and Romhilt-Estes point score criteria demonstrated low sensitivity and minimal positive predictive value for ECG-LVH when compared with cardiac imaging. Patients with LBBB had a high probability of a cardiomyopathy (relative risk [RR], 2.75; 95% confidence interval [CI], 2.14-3.53; p < .001), and patients with QRS fragmentation (fQRS) had a high probability of a cardiomyopathy (RR, 1.76; 95% CI, 1.20-2.59; p = .004), requiring cardiac medication and device intervention. We found that an R/S ratio >1 in V1 and V2 is highly specific (specificity, 0.89; negative predictive value [NPV], 0.89 and specificity, 0.82; NPV, 0.89, respectively) for patients with dystrophinopathies compared with other types of MD., Conclusion: The identification of LBBB and fQRS was linked to cardiomyopathy in patients with MD, while ECG-LVH was of limited utility. Importantly, these findings can be applied to effectively screen a broad cohort of MD patients for structural heart disease and prompt further evaluation and therapeutic intervention., (© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Aims: Heart disease is recognized as the leading cause of morbidity and mortality in patients with muscular dystrophy (MD). Our study demonstrates the clinical utility of cardiac biomarkers to improve the diagnosis of cardiomyopathy and prognostication of major adverse cardiac events (MACE) in these vulnerable patients., Methods and Results: We prospectively followed 117 patients [median age, 42 [interquartile range (IQR), 26-50) years; 49 (41.9%) women] at the Neuromuscular Multidisciplinary clinic diagnosed with a dystrophinopathy, limb-girdle MD, type 1 myotonic dystrophy, or facioscapulohumeral MD. We determined that B-type natriuretic peptide (BNP) and high-sensitive troponin I (hsTnI) were effective diagnostic markers of cardiomyopathy [area under the curve (AUC), 0.64; P = 0.017; and AUC, 0.69; P = 0.001, respectively]. Patient risk stratification for MACE was based on cut-off values of BNP and hsTnI defined a priori as 30.5000 pg/mL and 7.6050 ng/L, respectively. Over a median follow-up period of 2.09 (IQR, 1.17-2.81) years there were 36 confirmed MACE. Multivariate regression analyses showed that patients with BNP and hsTnI levels above the respective cut-off values had a 3.70-fold (P = 0.001) and 3.24-fold (P = 0.002) greater risk of MACE, respectively, compared with patients with biomarker levels below. Furthermore, patients with biomarker levels above both cut-off values had a 4.08-fold (P = 0.001) greater risk of MACE. Inflammatory biomarkers did not show clinical utility for heart disease in these patients., Conclusion: Our study demonstrates important diagnostic and prognostic value of BNP and hsTnI as part of a comprehensive cardiac assessment to augment the management and treatment of heart disease in patients with MD., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children., (Copyright © 2021. Published by Elsevier Ltd.)

Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se , respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark is axonal dystrophy occurring at presymptomatic stages in NPC mice. However, the mechanisms underlying this pathologic change remain obscure. Here, we demonstrate that endocytic-autophagic organelles accumulate in NPC dystrophic axons. Using super-resolution and live-neuron imaging, we reveal that elevated cholesterol on NPC lysosome membranes sequesters kinesin-1 and Arl8 independent of SKIP and Arl8-GTPase activity, resulting in impaired lysosome transport into axons, contributing to axonal autophagosome accumulation. Pharmacologic reduction of lysosomal membrane cholesterol with 2-hydroxypropyl-β-cyclodextrin (HPCD) or elevated Arl8b expression rescues lysosome transport, thereby reducing axonal autophagic stress and neuron death in NPC. These findings demonstrate a pathological mechanism by which altered membrane lipid composition impairs lysosome delivery into axons and provide biological insights into the translational application of HPCD in restoring axonal homeostasis at early stages of NPC disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. The genetic diagnosis was established by next generation sequencing (targeted panel or exome; 11 patients) or classic Sanger sequencing (4 patients). In addition to known pathogenic LMNA variants: c.116A > G (p.Asn39Ser), c.745C > T (p.Arg249Trp), c.746G > A (p.Arg249Gln), c.1072G > A (p.Glu358Lys), c.1147G > A (p.Glu383Lys), c.1163G > C (p.Arg388Pro), c.1357C > T (p.Arg453Trp), c.1583C > G (p.Thr528Arg), we have identified three novel ones: c.121C > G (p.Arg41Gly), c.1127A > G (p.Tyr376Cys) and c.1160T > C (p.Leu387Pro). Eleven patients had de novo mutations, 4 - familial. In one family we observed intrafamilial variability of clinical course: severe L-CMD in the male proband, intermediate form in his sister and asymptomatic in their mother. One asymptomatic father had somatic mosaicism. L-CMD should be suspected in children with hypotonia in infancy and delayed motor development, who have poor head control, severe hyperlordosis and unstable and awkward gait. Serum creatine kinase may be high (~1000IU/l). Progression of muscle weakness is fast, leading to early immobilization. In some patients with L-CMD joint contractures can develop with time. MRI shows that the most frequently affected muscles are the serratus anterior, lumbar paraspinal, gluteus, vastus, adductor magnus, hamstrings, medial head of gastrocnemius and soleus. Ultra-rare laminopathies can be a relatively common cause of generalized hypotonia in children. Introduction of wide genome sequencing methods was a breakthrough in diagnostics of diseases with great clinical and genetic variability and allowed approach "from genotype do phenotype". However target sequencing of LMNA gene could be considered in selected patients with clinical picture suggestive for laminopathy., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Respiratory complications are common in the patient with muscular dystrophy. The periodic clinical and instrumental respiratory evaluation is extremely important. Despite the presence in the literature of updated guidelines, patient associations often report lack of knowledge of these pathologies, particularly in peripheral hospitals. The purpose of this work, inspired by the Italian Muscular Dystrophy Association (UILDM) is to improve management of respiratory problems necessary for the management of these patients complex. To this end, the main items that the specialist can meet in the follow-up of these pathologies have been analyzed and discussed, among which the respiratory basal evaluation, the criteria of adaptation to non-invasive ventilation, management of bronchial secretions, situations of respiratory emergency, indications for tracheostomy and the subject of advance directives of treatment (DAT)., Competing Interests: Conflict of interest The Authors declare no conflict of interest, (©2021 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Herein, we describe a case of an elderly patient with muscular dystrophy for whom control of the plasma vancomycin (VCM) concentration proved difficult when he developed a catheter-related bloodstream infection. The pharmacist initially carried out therapeutic drug monitoring using an estimate of the creatinine clearance (CL cr ) level, which was based on the serum creatinine (SCr) and serum cystatin-C (CysC) levels, but was ultimately unable to control the plasma VCM concentration. Therefore, the plasma VCM concentration was predicted ex post facto using population pharmacokinetic parameters as a covariate; that is, directly including the glomerular filtration rate (GFR CysC ) estimated from the CysC level, which is not affected by the muscle mass. As a result, the estimated VCM concentration was closer to the actual concentration than that predicted using CL cr . Furthermore, the results of examining the predictive accuracy according to the assessment of renal function at the time of initial VCM administration suggested that estimation of the trough concentration using GFR CysC might be useful in elderly patients with muscular dystrophy.

The genetic etiology of collagen VI related muscular dystrophies is heterogenous. Genomic deletions in one allele involving COL6A2 or both COL6A1 and COL6A2 unmasking a pathogenic variant in the second nondeleted allele have been described in the etiology. We aimed to report the clinical and molecular findings of a 13-year-old boy with ring chromosome 21 who presented to our clinic with easy fatigability, muscle weakness, and waddling gait. Phenotypic delineation along with chromosomal microarray analysis and DNA sequencing were performed. Affymetrix CytoScan Optima array platform and DNA sequencing revealed a 2,202 kb de novo deletion at 21q22.3, including COL6A1 and COL6A2 , and a novel heterozygous variant at position c.2875G > A;p.(Glu959Lys) in COL6A2 , respectively. Before his admission to our center, the patient was evaluated for hypotonia elsewhere when he was 15 months old. He was diagnosed with ring chromosome 21 on peripheral blood karyotype analysis; however, no further assessment was performed at that time. He had normal growth with mild dysmorphic facial features, distal laxity, gastrocnemius hypertrophy, proximal muscle weakness, increased lordotic posture with mild flexion contractures at the knees, and gait disturbance. Although the phenotype does not fit into classical Ullrich congenital muscular dystrophies, muscle magnetic resonance imaging (MRI) revealed a complementary pattern consistent with collagen VI related myopathies. Genetic testing confirmed the clinical diagnosis as well. This patient yet represents another example of the effect of large genomic deletions leading to recessive disorders through unmasking a pathogenic variant in the second nondeleted allele., Competing Interests: None., (Thieme. All rights reserved.)

Late-onset myopathies are not well-defined since there is no clear definition of 'late onset'. For practical reasons we decided to use the age of 40 years as a cut-off. There are diseases which only manifest as late onset myopathy (inclusion body myositis, oculopharyngeal muscular dystrophy and axial myopathy). In addition, there are diseases with a wide range of onset including 'late onset' muscle weakness. Well-known and rather frequently occurring examples are Becker muscular dystrophy, limb girdle muscular dystrophy, facioscapulohumeral dystrophy, Pompe disease, myotonic dystrophy type 2, and anoctamin-5-related distal myopathy. The above-mentioned diseases will be discussed in detail including clinical presentation - which can sometimes lead someone astray - and diagnostic tools based on real cases taken from the author's practice. Where appropriate a differential diagnosis is provided. Next generation sequencing (NGS) may speed up the diagnostic process in hereditary myopathies, but still there are diseases, e.g. with expansion repeats, deletions, etc, in which NGS is as yet not very helpful., Competing Interests: Conflict of interest The Author declares no conflict of interest, (©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Objective: To characterize natural history of Laminin-α2 related muscular dystrophies (LAMA2-RD) to help anticipating complications and identifying reliable outcome measures for clinical trial design and powering., Methods: We conducted a retrospective, single-center, cross-sectional and longitudinal study on 46 LAMA2-RD pediatric patients (37 families). Patients were seen at the Dubowitz Neuromuscular Centre, London between 1985 and 2019. Data were collected by case note reviews. Time-to-event analysis was performed to estimate median age at complications occurrence., Results: Forty two patients had complete deficiency of Laminin-α2 (CD) and four had partial deficiency (PD). Median age at first and last assessment was 2 years and 12.1 years, respectively. Median follow-up length was 7.8 years (range 0-18 years). Seven CD patients died at median age 12 years. One CD and two PD subjects achieved independent ambulation. We observed a linear increase in elbow flexor contractures in CD subjects. Thirty-two CD and one PD patient developed scoliosis, nine underwent spinal surgery. Twenty-two CD required nocturnal noninvasive ventilation (median age 11.7 years). CD subjects showed a 2.9% linear annual decline in forced vital capacity % predicted. Nineteen CD and one PD patient required gastrostomy insertion for failure to thrive and/or unsafe swallow (median age 10.9 years). Four CD patients had partial seizures. Mild left cardiac ventricular dysfunction and rhythm disturbances were identified in seven CD patients., Interpretation: This retrospective longitudinal study provides long-term natural history of LAMA2-RD. This will help management and identification of key milestones of disease progression that could be considered for future therapeutic intervention., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Limited data exist regarding myopathies with early or prominent dysphagia., Methods: A retrospective study was performed (January 2003 to August 2019) to identify myopathy patients in whom dysphagia was the initial symptom or was disproportionately severe compared with limb weakness., Results: Thirty-two patients were identified. The median age at diagnosis was 65 y (range, 36-80 y). Inclusion body myositis (IBM) (n = 15), immune-mediated necrotizing myopathy (IMNM) (n = 5), and oculopharyngeal muscular dystrophy (n = 4), were the most common diagnoses. In 4 patients (3 IMNM and 1 nonspecific myositis) dysphagia evolved rapidly. At evaluation, 21 patients required diet alterations, 5 required feeding tubes, and 8 had aspiration pneumonia. Follow-up data were available for 20 patients (median, 24 mo). Eight patients received immunosuppressive therapies with improvement in 7, including 3 of 4 with rapidly progressive dysphagia., Conclusions: IBM and IMNM accounted for approximately two-thirds of patients with early or prominent dysphagia at our institution. Rapidly progressive dysphagia may predict immunotherapy responsiveness., (© 2020 Wiley Periodicals, Inc.)

Using MRI, the main aim was to (1) map the pattern of muscle involvement by assessing fat fraction and (2) investigate frequency of target and sandwich signs in 42 muscles of patients with Bethlem myopathy (BM). Fifteen BM patients were included. Results were compared to findings in 8 healthy controls and 50 patients with four other types of muscular dystrophies. All muscles, except one, showed higher fat fraction in BM patients vs healthy controls (p < 0.05) with an overall proximal muscle affection, resembling a limb girdle-like pattern. In moderate patients, the specificity was 90% for the sandwich sign and 98% for the target sign. Sensitivity for both signs was 100%. Twelve BM patients had sandwich sign in other muscles than the vastus lateralis. Muscle strength correlated with fat fraction. Mean fat fraction in the psoas major was 39% in BM patients, which was considerably higher than in 3 of the 4 muscular dystrophy control diseases. The presence of signs in conjunction with severe affection of the psoas major muscle can serve as a diagnostic tool in BM. The high level of STIR lesions in muscles of BM patients warrants further investigations.

Background: There is substantial evidence that pain intensity and sleep are related, with findings generally suggesting more support for the influence of sleep on pain intensity than vice versa. However, the strength and direction of the relationship has been found to vary among different populations, with few studies in individuals with chronic physical disabilities., Objective: Examine the directionality of the sleep and pain relationship in individuals with chronic physical disabilities., Methods: Cross-lagged effects models were generated using data from a longitudinal observational survey study of individuals (N = 1660) with multiple sclerosis (MS), muscular dystrophy (MD), post-polio syndrome (PPS), and spinal cord injury (SCI). Models evaluated the correlational effects of sleep disturbance and pain intensity, as well as the cross-lagged effects of sleep disturbance to pain intensity and vice versa., Results: The effects of pain on sleep were stronger than sleep on pain, although the magnitude of the effects were both relatively weak. Analyses within individual samples were consistent with the overall sample results for MS, MD, and PPS. In the SCI sample the magnitude and direction of the cross-lagged model paths were more variable than in the other samples., Conclusions: The relationship between pain intensity and sleep disturbance appears bi-directional, but the effects are small in a sample of individuals with long-term disabilities. The temporal effects of pain on sleep disturbance appear stronger than the effects of sleep disturbance on pain intensity. Future research is needed to better understand this relationship in the context of pain and/or sleep disturbance treatments., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage. TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells. In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression. Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression., Competing Interests: The author declares no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A postsynaptic dysfunction of the neuromuscular junction has been reported in patients with alpha-dystroglycanopathy associated with mutations in guanosine diphosphate (GDP)-mannose pyrophosphorylase B gene (GMPPB), some of whom benefit from symptomatic treatment. In this study, we determine the frequency of myasthenic and fatigue symptoms and neuromuscular junction transmission defects in a fukutin-related protein (FKRP)-predominant alpha-dystroglycanopathy cohort. Thirty-one patients with alpha-dystroglycanopathies due to mutations in FKRP (n = 25), GMPPB (n = 4), POMGNT1 (n = 1), and POMT2 (n = 1) completed a six-question modified questionnaire for myasthenic symptoms and the PROMIS Short Form v1.0-Fatigue 8a survey, and they underwent 3 Hz repetitive nerve stimulation of spinal accessory nerve-trapezius and radial nerve-anconeus pairs. Results showed that fatigue with activity was common; 63% of the cohort reported fatigue with chewing. A defective postsynaptic neuromuscular junction transmission was not identified in any of the patients carrying FKRP mutations but only in one mildly affected patient with GMPPB mutations (c.79 G>C, p.D27H and c.402+1G>A, splice site variant). We conclude that symptoms of fatigue with activity did not predict abnormal neuromuscular junction transmission on electrodiagnostic studies in this cohort and that, unlike GMPPB subgroup, a defective neuromuscular junction transmission does not appear to be present in patients with FKRP-associated muscular dystrophies., (Published by Elsevier B.V.)

Background: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD)., Methods: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized., Results: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia., Conclusion: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.

Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous POMT1 mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

The purpose of the study is to describe experiences of swallowing with two forms of noninvasive positive-pressure ventilation (NPPV): mouthpiece NPPV (M-NPPV) and nasal bilevel positive airway pressure (BPAP) in people with muscular dystrophy. Ten men (ages 22-42 years; M = 29.3; SD = 7.1) with muscular dystrophy (9 with Duchenne's; 1 with Becker's) completed the Eating Assessment Tool (EAT-10; Ann Otol Rhinol Laryngol 117(12):919-924 [33]) and took part in semi-structured interviews. The interviews were audio recorded, transcribed, and verified. Phenomenological qualitative research methods were used to code (Dedoose.com) and develop themes. All participants affirmed dysphagia symptoms via responses on the EAT-10 (M = 11.3; SD = 6.38; Range = 3-22) and reported eating and drinking with M-NPPV and, to a lesser extent, nasal BPAP. Analysis of interview data revealed three primary themes: (1) M-NPPV improves the eating/drinking experience: Most indicated that using M-NPPV reduced swallowing-related dyspnea. (2) NPPV affects breathing-swallowing coordination: Participants described challenges and compensations in coordinating swallowing with ventilator-delivered inspirations, and that the time needed to chew solid foods between ventilator breaths may lead to dyspnea and fatigue. (3) M-NPPV aids cough effectiveness: Participants described improved cough strength following large M-NPPV delivered inspirations (with or without breath stacking). Although breathing-swallowing coordination is challenging with NPPV, participants reported that eating and drinking is more comfortable than when not using it. Overall, eating and drinking with NPPV delivered via a mouthpiece is preferred and is likely safer for swallowing than with nasal BPAP. M-NPPV (but not nasal BPAP) is reported to improve cough effectiveness, an important pulmonary defense in this population.