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(1) Background: Muscle hypertrophy, swallowing disorders, and gait abnormalities are clinical signs common to many muscle diseases, including muscular dystrophies, non-dystrophic myotonias, genetic myopathies associated with deficiency of myostatin, and acquired inflammatory myopathies. Here, we investigated underlying causes of this triad of clinical signs in four young French bulldogs via muscle histopathology coupled with whole genome and Sanger sequencing. (2) Methods: Dogs were evaluated by veterinary clinical internists and neurologists, and biopsies were obtained for histopathological diagnosis. DNA was submitted for whole genome sequencing, followed by bioinformatics evaluation and confirmation of variants via Sanger sequencing in two cases. (3) Results: Two novel variants were identified. The first, found in two related French bulldogs, was a homozygous variant in the chloride channel gene CLCN1 known to cause non-dystrophic congenital myotonia, and the second, found in an unrelated French bulldog, was a heterozygous variant in the cAMP phosphodiesterase gene PDE4C, which is the major phosphodiesterase expressed in skeletal muscle and may play a role in decreasing muscle atrophy. An underlying molecular basis in one other case has not yet been identified. (4) Conclusions: Here, we identified two novel variants, one in the CLCN1 and one in the PDE4C gene, associated with clinical signs of muscle hypertrophy, dysphagia, and gait abnormalities, and we suggested other bases of these phenotypes in French bulldogs that are yet to be discovered. Identification of genes and deleterious variants associated with these clinical signs may assist breeders in improving the overall health of this very popular breed and may lead to the identification of new therapies to reverse muscle atrophy in people and animals with neuromuscular diseases.

Wooden breast (WB) is a myopathy that occurs in pectoralis major (PM) muscles, predominately affecting large, fast-growing broilers. Severe myodegeneration, increased hypoxia, reduced blood flow, and increased collagen deposition are hallmark characteristics of WB that culminate in unsatisfactory fresh meat quality attributes, such as poor water-holding capacity, tenderness, and processing characteristics. Therefore, WB meat is often downgraded resulting in economic losses for the United States poultry industry. Although WB has been well characterized, its etiology remains undefined. As the scientific community continues to resolve mechanisms responsible for WB onset, understanding biochemical changes associated with WB may facilitate solutions to negate its poor meat quality attributes. Given changes in metabolism of living muscle can alter biochemical processes during the conversion of muscle to meat, this review aims to summarize and discuss the current knowledge of WB muscle and meat biochemistry. For example, it appears metabolic pathways that support combating stress are upregulated in WB muscle at the expense of glycolytic flux, which presumably contributes to the high ultimate pH of WB meat. Further, perturbed function of WB mitochondria, such as altered calcium handling, impacts aspects of postmortem metabolism and proteolysis. Collectively, metabolic dysfunction of WB muscle alters the biochemical processes that occur during the conversion of muscle to meat, and thus contributes to the poor WB meat quality. [ABSTRACT FROM AUTHOR]

DUX4 is the major gene responsible for facioscapulohumeral dystrophy (FSHD). Several mouse models expressing DUX4 have been developed, the most commonly used by academic laboratories being ACTA1-MCM/FLExDUX4. In this study, molecular and histological modifications in the tibialis anterior and quadriceps muscles were investigated in this model at different time points. We investigated several changes that could be used as markers of therapeutic efficacy. Our results confirm the progressive muscular dystrophy previously described but also highlight biases associated with tamoxifen injections and the complexity of choosing the genes used to calculate a DUX4-pathway gene composite score. We also developed a comprehensive force test that better reflects the movements made in everyday life. This functional force–velocity–endurance model, which describes the force production capacities at all velocity and fatigue levels, was applied on 12–13-week-old animals without tamoxifen. Our data highlight that previously unsuspected muscle properties are also affected by the expression of DUX4, leading to a weaker muscle with a lower initial muscle force but with preserved power and endurance capacity. Importantly, this force–velocity–endurance approach can be used in humans for clinical evaluations. [ABSTRACT FROM AUTHOR]

Masticatory myositis (MM) is an inflammatory myopathy reported in dogs and is characterized by inflammation of the masticatory muscles (temporalis, masseter, and pterygoid muscles). Immunosuppressive therapy is the current recommended treatment for MM and may involve glucocorticoids, cyclosporine, azathioprine, mycophenolate mofetil, leflunomide, or a combination of these treatments that are slowly tapered to the lowest effective dose. However, side effects from multimodal medical therapy and complications associated with MM relapses have been reported. The purpose of this case series was to report oclacitinib as a treatment alternative to traditional medical management of MM. The intent of this alternative is to manage side effects from glucocorticoid use. Oclacitinib (1mg/kg per os q12h) was used solely for treatment of MM in three dogs. The dogs were followed up to >6 months after oclacitinib administration. An increase in oral range of motion, as determined by gape angle, was noted in all three dogs. However, a corresponding drop in antibody titers (2M fiber) did not occur. All dogs showed improvement in overall clinical management of MM, side effects from glucocorticoids, and clinical signs related to chronic prednisone use. Larger controlled trials with consistent measurements (interincisal distance, gape angle) and 2M fiber antibody titers are indicated to further assess validation of oclacitinib treatment of MM. The clinical outcome of all dogs was considered successful. [ABSTRACT FROM AUTHOR]

Background Objective Animals Methods Results Conclusion and Clinical Importance Limited information is available regarding the clinical features, treatment, and prognosis of neosporosis in adult dogs.Describe the clinical signs, laboratory findings, magnetic resonance imaging (MRI) findings, treatment and outcome in adult dogs (>6 months) diagnosed with neosporosis based on consistent clinical signs and positive serology (titer ≥1 : 800) at a referral hospital in Sydney, Australia.Twenty‐one client‐owned dogs.Retrospective case series of affected dogs between 2010 and 2023. Survival times were determined from onset of clinical signs to date of death or censoring.Clinical signs varied, and were indicative of generalized myopathy (6 dogs), multifocal intracranial disease (7 dogs), myelopathy (4 dogs), polyneuropathy (2 dogs) and single cases of focal myopathy and cerebellar disease. Serum creatine kinase activity was markedly increased (median, 3369 U/L) in most dogs. The most common MRI abnormalities were multifocal intracranial abnormalities (7/13 dogs) and muscle changes (5/13 dogs) whereas T2‐weighted cerebellar abnormalities (2/13 dogs) and cerebellar atrophy (1/13) were less common. Treatment response was complete (resolution to normal) in 8 dogs, incomplete (persistent neurological deficits) in 6 dogs, but there was minimal response in 7 dogs. Thirteen dogs (62%) were alive after 6 months and 12 dogs (57%) alive after 1 year. Relapse was common, with 4 dogs experiencing at least 1 relapse event during the follow‐up period.Adult‐onset neosporosis is uncommon and has variable clinical presentations. Treatment response also is variable, and relapse can occur, even among patients that respond completely to initial treatment. [ABSTRACT FROM AUTHOR]

Inherited and acquired muscle diseases are an important cause of morbidity and mortality in human medical and veterinary patients. Researchers use models to study skeletal muscle development and pathology, improve our understanding of disease pathogenesis and explore new treatment options. Experiments on laboratory animals, including murine and canine models, have led to huge advances in congenital myopathy and muscular dystrophy research that have translated into clinical treatment trials in human patients with these debilitating and often fatal conditions. Whilst animal experimentation has enabled many significant and impactful discoveries that otherwise may not have been possible, we have an ethical and moral, and in many countries also a legal, obligation to consider alternatives. This review discusses the models available as alternatives to mammals for muscle development, biology and disease research with a focus on inherited myopathies. Cell culture models can be used to replace animals for some applications: traditional monolayer cultures (for example, using the immortalised C2C12 cell line) are accessible, tractable and inexpensive but developmentally limited to immature myotube stages; more recently, developments in tissue engineering have led to three-dimensional cultures with improved differentiation capabilities. Advances in computer modelling and an improved understanding of pathogenetic mechanisms are likely to herald new models and opportunities for replacement. Where this is not possible, a 3Rs approach advocates partial replacement with the use of less sentient animals (including invertebrates (such as worms Caenorhabditis elegans and fruit flies Drosophila melanogaster) and embryonic stages of small vertebrates such as the zebrafish Danio rerio) alongside refinement of experimental design and improved research practices to reduce the numbers of animals used and the severity of their experience. An understanding of the advantages and disadvantages of potential models is essential for researchers to determine which can best facilitate answering a specific scientific question. Applying 3Rs principles to research not only improves animal welfare but generates high-quality, reproducible and reliable data with translational relevance to human and animal patients. [ABSTRACT FROM AUTHOR]

The diaphragm is the primary muscle of respiration. Here, we disclose a fascinating patient's perspective that led, by clinical reasoning alone, to a novel mechanism of spontaneous respiratory arrests termed diaphragm cramp-contracture (DCC). Although the 7-year-old boy survived its paroxysmal nocturnal "bearhug pain apnea" episodes, essentially by breathing out to breathe in, DCC could cause sudden unexpected deaths in children, especially infants. Diaphragm fatigue is central to the DCC hypothesis in SIDS. Most, if not all, SIDS risk factors contribute to it, such as male sex, young infancy, rebreathing, nicotine, overheating and viral infections. A workload surge by a roll to prone position or REM-sleep inactivation of airway dilator or respiratory accessory muscles can trigger pathological diaphragm excitation (e.g., spasms, flutter, cramp). Electromyography studies in preterm infants already show that diaphragm fatigue and sudden temporary failure by transient spasms induce apneas, hypopneas and forced expirations, all leading to hypoxemic episodes. By extension, prolonged spasm as a diaphragm cramp would induce sustained apnea with severe hypoxemia and cardiac arrest if not quickly aborted. This would cause a sudden, rapid, silent death consistent with SIDS. Moreover, a unique airway obstruction could develop where the hypercontracted diaphragm resists terminal inspiratory efforts by the accessory muscles. It would disappear postmortem. SIDS autopsy evidence consistent with DCC includes disrupted myofibers and contraction band necrosis as well as signs of agonal breathing from obstruction. Screening for diaphragm injury from hypoxemia, hyperthermia, viral myositis and excitation include serum CK-MM and skeletal troponin-I. Active excitation could be visualized on ultrasound or fluoroscopy and monitored by respiratory inductive plethysmography or electromyography. [ABSTRACT FROM AUTHOR]

Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). This disease is one of the autophagy-related muscle diseases. Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy. The disease's leading cause of death is heart failure, and its prognostic factor is cardiomyopathy. Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs). Twenty-six families have been found to have this disease in Japan. It has been over 40 years since the first report of this disease by Danon et al. and over 20 years since the identification of the causative gene, LAMP2, by Nishino et al. Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future. [ABSTRACT FROM AUTHOR]

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence‐associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS. [ABSTRACT FROM AUTHOR]

Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well‐known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD. [ABSTRACT FROM AUTHOR]

Statins are widely used crucial drugs for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Although generally well tolerated, statin intolerance can unfortunately limit statin use, with statin-associated muscle symptoms (SAMS) being the most common side effect associated with its discontinuation. Statin intolerance is an inability to tolerate a dose of statin required to sufficiently reduce an individual's cardiovascular risk, limiting the effective treatment of patients at risk of or with cardiovascular disease (CVD). Statin myopathy is a broad entity encompassing self-limited/toxic and autoimmune aetiologies. As statins are a mainstay of therapy in those with or at risk for CVD and offer a mortality benefit, it is critical to determine whether one's symptoms are truly statin-associated before discontinuing the drug. This review article aims to provide an update on the epidemiology, pathophysiology, clinical features, diagnosis, evaluation and management of statin myopathy and to elucidate key differences between autoimmune and self-limited types. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy. We focused on the clinical presentation, biochemical and histopathological findings, and the impact on patient well-being. The spectrum of symptoms of MHS-related myopathy encompasses muscle cramps, stiffness, myalgias, rhabdomyolysis, and weakness, with a wide age range of onset mainly during adulthood. Histopathological analysis can reveal nonspecific abnormalities suggestive of RYR1 involvement, while metabolic profiling reflects altered energy metabolism in MHS muscle. Myopathic manifestations can significantly impact patient quality of life and lead to functional limitations and socio-economic burden. While currently available therapies can provide symptomatic relief, there is a need for further research into targeted treatments addressing the underlying pathophysiology. Counselling early after establishing the MHS diagnosis, followed by multidisciplinary management involving various medical specialties, is crucial to optimise patient care. [ABSTRACT FROM AUTHOR]

Background: Cystinosis is an autosomal recessive lysosomal storage disorder caused by cystine crystals accumulation within lysosomes resulting in multi-organ dysfunction. Infantile nephropathic cystinosis is the most common phenotype of the disease. Cystinosis distal myopathy was first described in 1994 with a 24% prevalence in cystinosis adult patients. Methods: We prospectively evaluated the clinical, biochemical, and radiological data of 22 nephropathic cystinosis pediatric patients from 19 unrelated families (17 males and 5 females, their ages 105.7 ± 41.5 months) recruited at the cystinosis clinic at Cairo University Children's Hospital. Biochemical assessment included several inflammatory biomarkers, such as CRP, ESR, chitotriosidase, and galectin-3. We further performed conventional MRI for the muscles of both upper and lower limbs for potential detection of early myopathic involvement. We compared these findings with 44 CKD children as pathological controls and 22 healthy pediatric controls. Results: Clinically, no evidence of neuromuscular involvement was detected in our cystinosis pediatric cohort. Chitotriosidase was elevated significantly in cystinosis patients compared to CKD controls. Regarding MRI, morphologically, there were no significant differences between the muscles of cystinosis patients and healthy controls. Conclusion: A significantly higher chitotriosidase activity in cystinosis patients seems to better represent the overall disease burden and cannot be linked to neuromuscular involvement. MRI findings in muscles of the cystinosis cohort are not striking and indicate no early changes at a younger age. Follow-up and further studies for higher age groups are required to accurately elucidate the MRI's role in assessing cystinosis myopathy. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis was not reported in clinical trials with Sitagliptin alone. However, several reports in the literature on rhabdomyolysis resulted from the interaction between statins and Sitagliptin. In patients with type 2 diabetes and hyperlipidemia, it is expected to co-prescribe statins and Sitagliptin. Herein, we report the case of a 64-year-old woman with rhabdomyolysis should be caused by a drug-drug interaction between Rosuvastatin and Sitagliptin. The patient denied any history of weakness or myalgia during past medical assessments. [ABSTRACT FROM AUTHOR]

Introduction: Pathogenic variants in the XK gene are associated with dysfunction or loss of XK protein leading to McLeod syndrome (MLS), a rare X-linked neuroacanthocytosis syndrome with multisystemic manifestation. Here we present clinical, genetic and immunological data on a patient originally admitted to our clinic for presumed post-COVID-19 syndrome, where thorough clinical work-up revealed a novel frameshift deletion in XK causal for the underlying phenotype. We additionally review the clinicogenetic spectrum of reported McLeod cases in the literature. Methods: We performed in-depth clinical characterization and flow cytometry of cerebrospinal fluid (CSF) in a patient where multi-gene panel sequencing identified a novel hemizygous frameshift deletion in XK. Additionally, Kell (K) and Cellano (k) antigen expression was analysed by Fluorescence-activated Cell Sorting (FACS). KEL gene expression was examined by RNA sequencing. Results: A novel hemizygous frameshift deletion in the XK gene resulting in premature termination of the amino acid chain was identified in a 46-year old male presenting with decrease in physical performance and persisting fatigue after COVID-19 infection. Examinations showed raised creatine kinase (CK) levels, neuropathy and clinical features of myopathy. FACS revealed the K-k+ blood type and reduced Cellano density. CSF flow cytometry showed elevation of activated T Cells. Conclusion: In-depth clinical, genetic, immunological and ribonucleic acid (RNA) expression data revealed axonal neuropathy, myopathy and raised levels of activated CSF-T-lymphocytes in a patient with a previously unpublished frameshift deletion in the XK gene. [ABSTRACT FROM AUTHOR]

BACKGROUND: McArdle disease, also known as type V glycogen storage disease, is an autosomal recessive hereditary metabolic myopathy, in which there is minimal or no production of the glycogen phosphorylase enzyme in muscle and is characterized by exercise intolerance, in addition to elevated creatine kinase levels, which can lead to rhabdomyolysis. CLINICAL CASE: A 25-year-old male patient, cared at the Internal Medicine service for myopathy and increased creatine kinase in whom the electromyography was normal and the muscle biopsy did not provide specific data, but the diagnosis of McArdle disease was concluded by genetic study. CONCLUSIONS: In McArdle disease laboratory, electrodiagnostic, and imaging studies may be normal and nonspecific. This disease should be suspected in young people with intolerance to physical activity. [ABSTRACT FROM AUTHOR]

Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs. [ABSTRACT FROM AUTHOR]

CCDC78 was identified as a novel candidate gene for autosomal dominant centronuclear myopathy-4 (CNM4) approximately ten years ago. However, to date, only one family has been described, and the function of CCDC78 remains unclear. Here, we analyze for the first time a family harboring a CCDC78 nonsense mutation to better understand the role of CCDC78 in muscle. Methods: We conducted a comprehensive histopathological analysis on muscle biopsies, including immunofluorescent assays to detect multiple sarcoplasmic proteins. We examined CCDC78 transcripts and protein using WB in CCDC78-mutated muscle tissue; these analyses were also performed on muscle, lymphocytes, and fibroblasts from healthy subjects. Subsequently, we conducted RT-qPCR and transcriptome profiling through RNA-seq to evaluate changes in gene expression associated with CCDC78 dysfunction in muscle. Lastly, coimmunoprecipitation (Co-Ip) assays and mass spectrometry (LC-MS/MS) studies were carried out on extracted muscle proteins from both healthy and mutated subjects. Results: The histopathological features in muscle showed novel histological hallmarks, which included areas of dilated and swollen sarcoplasmic reticulum (SR). We provided evidence of nonsense-mediated mRNA decay (NMD), identified the presence of novel CCDC78 transcripts in muscle and lymphocytes, and identified 1035 muscular differentially expressed genes, including several involved in the SR. Through the Co-Ip assays and LC-MS/MS studies, we demonstrated that CCDC78 interacts with two key SR proteins: SERCA1 and CASQ1. We also observed interactions with MYH1, ACTN2, and ACTA1. Conclusions: Our findings provide insight, for the first time, into the interactors and possible role of CCDC78 in skeletal muscle, locating the protein in the SR. Furthermore, our data expand on the phenotype previously associated with CCDC78 mutations, indicating potential histopathological hallmarks of the disease in human muscle. Based on our data, we can consider CCDC78 as the causative gene for CNM4. [ABSTRACT FROM AUTHOR]

As the most frequent cause of acquired myopathy, toxic myopathies are characterised by clinicopathological features that vary depending on the mode of action of the drugs or toxins involved. Although a large number of substances can induce myotoxicity, the main culprits are statins, alcohol, and corticosteroids. A rigorous, well-organised diagnostic approach is necessary to obtain a rapid diagnosis. For early diagnosis and management, it is important for clinicians to be aware that most toxic myopathies are potentially reversible, and the goal of treatment should be to avoid serious muscle damage. [ABSTRACT FROM AUTHOR]

• Most individual neuromuscular disorders are rare, but as a group they are not. • Epidemiological data regarding these disorders, especially incidence, is scarce. • Incidence is underrated whilst just as important as prevalence to describe a disease. • This study researched neuromuscular disorders predominantly diagnosed in adult life. • We provide 15 capture-recapture incidence rates, including 9 previously unavailable. Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands. The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals. This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders. [ABSTRACT FROM AUTHOR]

Poor sleep is frequently reported in children with neuromuscular diseases (NMD) and cerebral palsy (CP) however breathing disorders during sleep are often the clinical focus. Periodic limb movements (PLMs) have an increased prevalence in adults with NMD and may contribute to sleep disturbance in this population. We assessed the prevalence of PLMs in children with NMD or CP. Retrospective review of polysomnography (PSG) with leg electromyography in children age 1–18 years with NMD (including Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy) or CP performed at a paediatric sleep centre 2004–2022. Leg electromyography was available in at least 1 PSG in 239 children (125 NMD, 114 CP), and in 2 PSGs in 105 children (73 NMD, 32 CP). At initial PSG, 72 (30 %) were female with a median age 9y and respiratory disturbance index 3.5/h (interquartile range 1.3–9.9/h). Elevated PLM index (PLMI; >5/h) occurred in 9.6 % of each of the CP and NMD groups, quantified by initial PSG. Overall, PLMI increased from baseline (median 0, maximum 33/h) to follow-up (median 0, maximum 55.8/h; p < 0.05). In those with an elevated PLMI, arousal percentage attributable to PLMs was up to 25 % (median 7.5 %). Elevated PLMI occurred at a higher prevalence in children with NMD and CP than reported in other clinic-referred paediatric populations. It is important that PLMs are not overlooked as identification and treatment may help improve sleep outcomes. Further research is required to understand the pathophysiology and consequences of PLMs specifically in this population. • Children with neuromuscular disease (NMD) or cerebral palsy have high rates of sleep disturbance. • Periodic limb movements are not consistently measured in NMD or cerebral palsy populations. • Children with NMD or cerebral palsy have high prevalence of elevated periodic limb movement index. • Frequency of periodic limb movements increased over time. • Research is needed to understand the consequences and treatment implications in this population. [ABSTRACT FROM AUTHOR]

Abstract Inherited and acquired muscle diseases are an important cause of morbidity and mortality in human medical and veterinary patients. Researchers use models to study skeletal muscle development and pathology, improve our understanding of disease pathogenesis and explore new treatment options. Experiments on laboratory animals, including murine and canine models, have led to huge advances in congenital myopathy and muscular dystrophy research that have translated into clinical treatment trials in human patients with these debilitating and often fatal conditions. Whilst animal experimentation has enabled many significant and impactful discoveries that otherwise may not have been possible, we have an ethical and moral, and in many countries also a legal, obligation to consider alternatives. This review discusses the models available as alternatives to mammals for muscle development, biology and disease research with a focus on inherited myopathies. Cell culture models can be used to replace animals for some applications: traditional monolayer cultures (for example, using the immortalised C2C12 cell line) are accessible, tractable and inexpensive but developmentally limited to immature myotube stages; more recently, developments in tissue engineering have led to three-dimensional cultures with improved differentiation capabilities. Advances in computer modelling and an improved understanding of pathogenetic mechanisms are likely to herald new models and opportunities for replacement. Where this is not possible, a 3Rs approach advocates partial replacement with the use of less sentient animals (including invertebrates (such as worms Caenorhabditis elegans and fruit flies Drosophila melanogaster) and embryonic stages of small vertebrates such as the zebrafish Danio rerio) alongside refinement of experimental design and improved research practices to reduce the numbers of animals used and the severity of their experience. An understanding of the advantages and disadvantages of potential models is essential for researchers to determine which can best facilitate answering a specific scientific question. Applying 3Rs principles to research not only improves animal welfare but generates high-quality, reproducible and reliable data with translational relevance to human and animal patients.

Abstract Background Cystinosis is an autosomal recessive lysosomal storage disorder caused by cystine crystals accumulation within lysosomes resulting in multi-organ dysfunction. Infantile nephropathic cystinosis is the most common phenotype of the disease. Cystinosis distal myopathy was first described in 1994 with a 24% prevalence in cystinosis adult patients. Methods We prospectively evaluated the clinical, biochemical, and radiological data of 22 nephropathic cystinosis pediatric patients from 19 unrelated families (17 males and 5 females, their ages 105.7 ± 41.5 months) recruited at the cystinosis clinic at Cairo University Children’s Hospital. Biochemical assessment included several inflammatory biomarkers, such as CRP, ESR, chitotriosidase, and galectin-3. We further performed conventional MRI for the muscles of both upper and lower limbs for potential detection of early myopathic involvement. We compared these findings with 44 CKD children as pathological controls and 22 healthy pediatric controls. Results Clinically, no evidence of neuromuscular involvement was detected in our cystinosis pediatric cohort. Chitotriosidase was elevated significantly in cystinosis patients compared to CKD controls. Regarding MRI, morphologically, there were no significant differences between the muscles of cystinosis patients and healthy controls. Conclusion A significantly higher chitotriosidase activity in cystinosis patients seems to better represent the overall disease burden and cannot be linked to neuromuscular involvement. MRI findings in muscles of the cystinosis cohort are not striking and indicate no early changes at a younger age. Follow-up and further studies for higher age groups are required to accurately elucidate the MRI’s role in assessing cystinosis myopathy.

Two (male and female) 10-month-old American Staffordshire Terrier littermates presented for progressive weakness, joint contracture, and distal limb joint hyperlaxity beginning around 6 months of age. Neurological examination, serum creatine kinase activity, infectious disease titers, cerebrospinal fluid analysis, and electrodiagnostic testing were performed. Muscle biopsies were collected for histopathology and immunofluorescence staining for localization of dystrophy associated proteins. Whole-genome sequencing (WGS) was performed on 1 affected dog. Variants were compared to a database of 671 unaffected dogs of multiple breeds. Histopathology confirmed a dystrophic phenotype and immunofluorescence staining of muscle cryosections revealed an absence of staining for collagen-6. WGS identified a homozygous 1 bp deletion in the COL6A3 gene, unique to the first affected dog. Sanger sequencing confirmed the homozygous presence of the frameshift variant in both affected dogs. This report describes the clinical features and most likely genetic basis of an Ullrich-like recessively inherited form of congenital muscular dystrophy in American Staffordshire Terriers.

Muscular dystrophies represent a group of disorders characterized by progressive muscle degeneration and weakness. An important subgroup are the dystrophin‐related muscular dystrophies caused by variants in the DMD gene. They can be divided into the more severe Duchenne muscular dystrophy and the milder Becker muscular dystrophy. Here, we characterize the clinical, histopathological and molecular genetic aspects of two male Entlebucher Mountain Dogs with clinical signs of muscular dystrophy. The two dogs presented with marked dysphagia starting at the age of several weeks and in the later course recognizable exercise intolerance with highly increased serum creatine kinase levels. Histopathological signs of a dystrophic myopathy represented by degeneration of muscle fibers and signs of regeneration were present. Whole genome sequencing of one affected dog identified an intragenic 8.6 kb duplication in the X‐chromosomal DMD gene, c.7528‐4048_7645 + 4450dup. No other protein‐changing variants in candidate genes for muscular dystrophy were identified. The duplication includes exon 52 of DMD and is predicted to lead to a frameshift and truncation of 30% of the wild‐type open reading frame. Genotyping of the whole family confirmed the presence of the mutant allele in both affected dogs and the unaffected dam. The correct co‐segregation of the mutant allele in the affected family as well as knowledge from humans and other species suggest the identified DMD variant as the most likely candidate variant for the muscular dystrophy phenotype in the two investigated dogs. [ABSTRACT FROM AUTHOR]

Tubular aggregate myopathy (TAM) is a rare myopathy characterized by muscle weakness and myalgia. Muscle fibers from TAM patients show characteristic accumulation of membrane tubules that contain proteins from the sarcoplasmic reticulum (SR). Gain-of-function mutations in STIM1 and ORAI1, the key proteins participating in the Store-Operated Ca2+ Entry (SOCE) mechanism, were identified in patients with TAM. Recently, the CASQ1 gene was also found to be mutated in patients with TAM. CASQ1 is the main Ca2+ buffer of the SR and a negative regulator of SOCE. Previous characterization of CASQ1 mutants in non-muscle cells revealed that they display altered Ca2+dependent polymerization, reduced Ca2+storage capacity and alteration in SOCE inhibition. We thus aimed to assess how mutations in CASQ1 affect calcium regulation in skeletal muscles, where CASQ1 is naturally expressed. We thus expressed CASQ1 mutants in muscle fibers from Casq1 knockout mice, which provide a valuable model for studying the Ca2+ storage capacity of TAM-associated mutants. Moreover, since Casq1 knockout mice display a constitutively active SOCE, the effect of CASQ1 mutants on SOCE inhibition can be also properly examined in fibers from these mice. Analysis of intracellular Ca2+ confirmed that CASQ1 mutants have impaired ability to store Ca2+and lose their ability to inhibit skeletal muscle SOCE; this is in agreement with the evidence that alterations in Ca2+entry due to mutations in either STIM1, ORAI1 or CASQ1 represents a hallmark of TAM. [ABSTRACT FROM AUTHOR]

Purpose of Review: This paper reviews the existing literature on statin-related myopathy in children and adolescents, to inform development of a practical management approach. Recent Findings: Reports of statin treatment in the pediatric population revealed no evidence of muscle pathology, with asymptomatic elevation of creatine kinase(CK) levels and symptoms of muscle pain without CK elevation seen equally in subjects and controls in RCTs. By contrast, rare cases of rhabdomyolysis have now been documented in statin-treated children; this serious problem had never been previously reported. Summary: Statin-induced myopathy is rare in childhood so routine monitoring of CK levels is unnecessary in asymptomatic patients, reserved for those with muscle pain. Rare case reports of rhabdomyolysis in statin-treated children and adolescents suggest that parent and patient education on symptoms of adverse statin effects should include immediate physician contact with the appearance of dark urine, with or without muscle pain. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. Methods To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. Results Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical–histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. Conclusions Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.

The aim of this study was to investigate the short-term effects of statins on rat skeletal muscle with the use of electrophysiological methods. A total of 28 adult male Wistar albino rats were given atorvastatin, rosuvastatin, and pravastatin (40 mg/kg each) intragastrically for four weeks. At the end of the study, the gastrocnemius muscle was isolated from the surrounding tissues under deep anaesthesia. It was tied with silk thread in the Achilles tendon area and then connected to an isometric force transducer. The contractile properties of the gastrocnemius muscle were assessed. Serum levels of total cholesterol and creatine kinase (CK) were measured. The muscle tissue samples were stained with hematoxylin eosin and histopathologically evaluated under light microscope. The findings revealed that cholesterol levels were significantly lower in all groups except the control group, whereas CK levels were higher in the statin groups than the control group. All three statins decreased the contractile strength and caused fatigue quickly in the gastrocnemius muscle. Histopathological changes in gastrocnemius muscle were more related to early moderate necrosis in rats that were received statins. This study demonstrates that all three statins decrease the ability of skeletal muscle to generate force and its resistance to fatigue in rats.

Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder characterized by widespread hyaline deposition in various tissues, resulting in multi-organ dysfunction. We present a case of a 6-month-old male child with minimal limb movements and skin lesions, emphasizing the diagnostic challenges and multidisciplinary approach involved in managing ISH. Medical history revealed intrauterine growth retardation and a neonatal intensive care unit admission, prompting referral to a tertiary care hospital. A comprehensive evaluation, including imaging, electrophysiological studies, and histology, confirmed the diagnosis of ISH-associated myopathy. Dermatological manifestations and genetic implications are discussed, highlighting the need for early recognition and genetic counseling. Our case contributes to the limited literature on ISH, emphasizing the importance of collaborative efforts in diagnosing and managing this complex disorder.

Genetic selection for high growth rate, breast muscle yield, and feed efficiency in modern broilers has been a double-edged sword. While it has resulted in marked benefits in production, it has also introduced widespread incidence of breast muscle myopathies. Broiler myopathies are phenotypically characterized by myodegeneration and fibrofatty infiltration, which compromise meat quality. These lesions resemble those of various myopathies found in humans, such as Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, and sarcopenia. Fibroadipogenic progenitors (FAPs) are interstitial muscle-resident mesenchymal stem cells that are named because of their ability to differentiate into both fibroblasts and adipocytes. This cell population has clearly been established to play a role in the development and progression of myopathies in mice and humans. Gene expression studies of wooden breast and other related disorders have implicated FAPs in broilers, but to our knowledge this cell population have not been characterized in chickens. In this review, we summarize the evidence that FAPs may be a novel, new target for interventions that reduce the incidence and development of chicken breast muscle myopathies. [ABSTRACT FROM AUTHOR]

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3–4% and 0.5–1% (5/1–10/1 ratio), with medium-chain triglyceride supplementation at 10–25% of total energy (total MCT+LCT ratio = 20–35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation. [ABSTRACT FROM AUTHOR]

In order to understand abnormal gait, this article will first review normal gait, discuss how neuromuscular diseases disturb gait patterns and review orthotic interventions. In normal gait, concentric contractions accelerate and eccentric contractions decelerate the limb. Neuromuscular gait disorders can be grouped into (1) proximal weakness, (2) distal weakness, (3) nonlength‐dependent or generalized weakness, (4) asymmetric weakness, and (5) sensory disorders. Identification of gait disturbance type in neuromuscular diseases leads to the appropriate orthotic prescription since orthotic strategies are grouped into (1) proximal weakness, (2) distal weakness, and (3) sensory disturbances. Orthotics is not indicated in all types of gait disturbance. Weakness in proximal hip musculature can be managed with gait aids such as walkers. In contrast, distal muscle weakness can be managed with orthotics. Preservation of gait assists in maintenance of daily function and integration in society. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. Objectives: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. Methods: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. Results: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. Conclusions: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany. [ABSTRACT FROM AUTHOR]

• Muscle excitability testing is a technique that provides in vivo information about membrane potential and ion channel function. • Multi-fibre muscle velocity recovery cycles, frequency ramp and repetitive stimulation protocols are automated and fast methods. • Muscle excitability testing is used mainly in research but it may have diagnostic uses, particularly in muscle channelopathies. Conventional electrophysiological methods, i.e. nerve conduction studies and electromyography are suitable methods for the diagnosis of neuromuscular disorders, however, they provide limited information about muscle fibre membrane properties and underlying disease mechanisms. Muscle excitability testing is a technique that provides in vivo information about muscle fibre membrane properties such as membrane potential and ion channel function. Since the 1960s, various methodologies have been suggested to examine muscle membrane properties but technical difficulties have limited its use. In 2009, an automated, fast and simple application, the so-called multi-fibre muscle velocity recovery cycles (MVRC) has accelerated the use of muscle excitability testing. Later, frequency ramp and repetitive stimulation protocols have been developed. Though this method has been used mainly in research for revealing disease mechanisms across a broad range of neuromuscular disorders, it may have additional diagnostic uses; value has been shown particularly in muscle channelopathies. This review will provide a description of the state-of-the art of methodological and clinical studies for muscle excitability testing. [ABSTRACT FROM AUTHOR]

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies, where mutations in genes involved in RNA metabolism or characterized by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN , plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle MRI, with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterized by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although inter-individual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganization. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS. Patients and methods: Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m², and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems). Results: In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%. Conclusion: MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo, may serve as an independent noninvasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission. [ABSTRACT FROM AUTHOR]

Background: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. Methods: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. Results: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical–histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. Conclusions: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the short-term effects of statins on rat skeletal muscle with the use of electrophysiological methods. A total of 28 adult male Wistar albino rats were given atorvastatin, rosuvastatin, and pravastatin (40 mg/kg each) intragastrically for four weeks. At the end of the study, the gastrocnemius muscle was isolated from the surrounding tissues under deep anaesthesia. It was tied with silk thread in the Achilles tendon area and then connected to an isometric force transducer. The contractile properties of the gastrocnemius muscle were assessed. Serum levels of total cholesterol and creatine kinase (CK) were measured. The muscle tissue samples were stained with hematoxylin eosin and histopathologically evaluated under light microscope. The findings revealed that cholesterol levels were significantly lower in all groups except the control group, whereas CK levels were higher in the statin groups than the control group. All three statins decreased the contractile strength and caused fatigue quickly in the gastrocnemius muscle. Histopathological changes in gastrocnemius muscle were more related to early moderate necrosis in rats that were received statins. This study demonstrates that all three statins decrease the ability of skeletal muscle to generate force and its resistance to fatigue in rats. [ABSTRACT FROM AUTHOR]

Using virtual reality (VR) for Muscular Dystrophy (MD) rehabilitation promises to be a novel therapeutic approach, potentially enhancing motor learning, functional outcomes, and overall quality of life. This systematic review primarily aimed to provide a comprehensive summary of the current understanding regarding the application of VR in supporting MD rehabilitation. A systematic search was performed in PubMed, Scopus, Cochrane Library, and Web of Science to identify relevant articles. The inclusion criteria encompassed studies involving individuals diagnosed with MD who underwent VR interventions, with a primary focus on assessing functional improvement. Methodological quality of the studies was assessed by using the Physiotherapy Evidence Database (PEDro) scale. Seven studies, involving 440 individuals with Duchenne Muscular Dystrophy (DMD), were included in the review. Among these studies, six primarily explored the motor learning potential of VR, while one study investigated the impact of VR training on functional abilities. In conclusion, the qualitative synthesis supports VR-based interventions' potential positive effects on motor learning, performance improvement, and functional outcomes in individuals with DMD. However, current usage mainly focuses on assessing the potential mechanisms' benefits, suggesting the importance of expanding clinical adoption to harness their therapeutic potential for MD patients. [ABSTRACT FROM AUTHOR]

Background: Severity and nature of cognitive impairments in Myotonic dystrophy type 1 (DM1) are heterogeneous among studies. We hypothesized that this heterogeneity is explained by different cognitive profiles in DM1, with different clinical, biological and behavioral features. Methods: Adult patients with genetically proven DM1 underwent a clinical, neuropsychological and behavioral assessment. We conducted a k-means clustering analysis on 9 cognitive tests representative of different domains (verbal/non-verbal episodic memory, visuo-constructive abilities, visual gnosis, executive functions, information processing speed). Results: We included 124 DM1 patients. Mean age was 45.1 ± 13.5 years [19.8–73.2], mean age of onset was 30.4 ± 15.7 years [5–72], and mean CTG triplets' expansion size was 489.7 ± 351.8 [50–1600]. We found 3 cognitive clusters, including, respectively, 84, 29 and 11 patients. The first cluster included patients with more preserved cognitive functions; the second included patients with worse cognitive performances which predominate on executive functions; and the third even more pronounced and diffuse cognitive deficits. Younger patients, with a more recent DM1 clinical onset, higher educational level were more frequently classified in the cluster with more preserved cognitive functions. There were no significant differences between clusters regarding CTG triplets' expansion, neither age at DM1 onset, nor most of behavioral measures. Conclusions: We found different cognitive profiles in our DM1 population, which seem influenced by age and DM1 duration. Our findings may explain the heterogeneity of studies about cognition in DM1, and suggest a potential neurodegenerative mechanism in DM1 adults. [ABSTRACT FROM AUTHOR]

Skeletal muscle is an important motor organ with multinucleated myofibers as its smallest cellular units. Myofibers are formed after undergoing cell differentiation, cell–cell fusion, myonuclei migration, and myofibril crosslinking among other processes and undergo morphological and functional changes or lesions after being stimulated by internal or external factors. The above processes are collectively referred to as myogenesis. After myofibers mature, the function and behavior of skeletal muscle are closely related to the voluntary movement of the body. In this review, we systematically and comprehensively discuss the physiological and pathological processes associated with skeletal muscles from five perspectives: molecule basis, myogenesis, biological function, adaptive changes, and myopathy. In the molecular structure and myogenesis sections, we gave a brief overview, focusing on skeletal muscle‐specific fusogens and nuclei‐related behaviors including cell–cell fusion and myonuclei localization. Subsequently, we discussed the three biological functions of skeletal muscle (muscle contraction, thermogenesis, and myokines secretion) and its response to stimulation (atrophy, hypertrophy, and regeneration), and finally settled on myopathy. In general, the integration of these contents provides a holistic perspective, which helps to further elucidate the structure, characteristics, and functions of skeletal muscle. [ABSTRACT FROM AUTHOR]

Aim: To understand the bullying experiences of youth with neuromuscular conditions. Method: Fourteen participants with neuromuscular conditions (10 male; 10-19 years old) participated in semistructured interviews that were analyzed using inductive thematic analysis. Results: Four overarching themes were identified: (1) participants experienced stigma-based bullying; (2) participants exhibited resilience despite bullying victimization; (3) participants identified personally and theoretically helpful and unhelpful supports with regard to bullying; and (4) participants proposed bullying interventions. Interpretation: Individuals with neuromuscular conditions had unique experiences and perspectives on bullying. This qualitative study provides health care professionals with insight into the bullying experiences of patients with neuromuscular conditions. Findings highlight the role for formal and informal education to mitigate stigma-based bullying and increased opportunities for peer support as a protective factor against bullying. [ABSTRACT FROM AUTHOR]

Aim The study aims to review all the genetically confirmed STAC3-related myopathy being followed in a single center in the Eastern Province of Saudi Arabia. Methodology A retrospective review of all genetically confirmed STAC3-related myopathy followed in our clinic has been conducted. Results 7 patients with STAC3-related myopathy have been found in our cohort, with all the patients presenting with infantile hypotonia, myopathic facies, and muscle weakness in the first year of life. Feeding difficulties and failure to thrive were found in all patients except one who died during the neonatal period. Respiratory muscle involvement was also found in 5 out of 6 formally tested patients while cleft palate was found in 5 patients. Conclusion STAC3-related myopathy is a relatively rare, malignant hyperthermia (MH)--causing muscle disease described in specific, highly consanguineous populations. Making the diagnosis in myopathic patients with cleft palate preoperatively can prevent MH-induced, anesthesia-related perioperative complications. [ABSTRACT FROM AUTHOR]

Introduction/Aims: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual‐energy x‐ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1. Methods: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T‐score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first‐degree relatives serving as controls (n = 6). Results: In the VCP disease group, significant declines in left hip BMD and Z‐scores were noted versus the control group (p ≤.03). The VCP disease group showed decreased whole body lean mass % (p =.04), and increased total body fat % (p =.04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1‐L4 T‐score values than the myopathy group. Discussion: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research. [ABSTRACT FROM AUTHOR]

Aims: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin‐1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin‐1 deficiency. Methods: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro‐dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45‐year‐old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy. Results: The muscle tissue exhibited a complete absence of glycogenin‐1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo‐exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen. Conclusions: The absence of glycogenin‐1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders. [ABSTRACT FROM AUTHOR]

SUMMARY This case series describes an emerging and ongoing lameness condition observed in broiler breeder males in flocks owned by a broiler integrator in the United States between February 2021 and April 2023. The lameness is characterized by an upright, penguin-like posture and gait. Affected flocks are typically 12–22 wk of age at presentation, but birds with similar stance and gross lesions can be observed as early as 1 day of age. Male mortality associated with this condition ranges from 0.01% to 6% per flock. The condition is infrequently observed in pullets from the female line but has not been observed in males (sex slips) from the female line. On postmortem examination, affected birds have bilateral hemorrhage due to a tearing of the iliotibialis muscles and fascia. In one case, a higher proportion of affected birds had unilateral lesions concurrently with broken legs or severe inguinal vaccine reaction. In this case, the affected leg was the weight-bearing leg. Histopathology confirmed the presence of hemorrhage in fascial sheaths surrounding major muscles, in addition to muscle fiber necrosis, edema, fibroplasia, and dissociation of tendon collagen. Bacteriology, histopathology, and clinical presentation identified no factors that were suggestive of an infectious etiology for this condition. No etiology has been established, but a suggested pathogenesis involves excessive biomechanical force resulting in tendon structural stress, leading to separation of tendon collagen fibers and associated muscle fiber stretching, separation, necrosis, and hemorrhage. The condition has been reported in multiple genetic lines, but the role of inheritance in the condition has not been fully evaluated. RESUMEN Miotendinopatía de etiología desconocida en machos reproductores pesados. Esta serie de casos describe una condición de cojera emergente y recurrente observada en parvadas de machos reproductores pesados propiedad de un integrador de pollo de engorde en los Estados Unidos entre febrero del 2021 y abril del 2023. La cojera se caracteriza por una postura y desplazamientos corporales en forma erguida, parecidos a los de los pingüinos. Las parvadas afectadas suelen tener entre 12 y 22 semanas de edad en el momento de la presentación, pero se han podido observar aves con similar postura corporal y lesiones macroscópicas tan temprano como al primer día de edad. La mortalidad de los machos asociada con esta condición oscila entre el 0.01% y el 6% por parvada. La condición se observa con poca frecuencia en pollitas de la línea hembra, pero no se ha observado en machos provenientes de la misma línea hembra (errores de sexado). En el examen post mortem, las aves afectadas presentan hemorragia bilateral debido a un desgarramiento de los músculos iliotibiales y la fascia. En un caso, una mayor proporción de aves afectadas tuvieron lesiones unilaterales simultáneamente con patas rotas o una reacción postvacunal severa en la región inguinal. En este caso, la pierna afectada era la misma que soportaba peso. La histopatología confirmó la presencia de hemorragia en las vainas fasciales que rodean los músculos principales, además de necrosis de fibras musculares, edema, fibroplasia y disociación del colágeno del tendón. Mediante la bacteriología, la histopatología y la presentación clínica no se identificaron factores que sugirieran una etiología infecciosa para esta afección. No se ha establecido una etiología, pero una patogénesis sugerida implica una fuerza biomecánica excesiva que produce estrés estructural del tendón, lo que lleva a la separación de las fibras de colágeno del tendón y al estiramiento, separación, necrosis y hemorragia de las fibras musculares asociadas. La afección se ha informado en múltiples líneas genéticas, pero no se ha evaluado completamente el papel de la genética en esta condición. [ABSTRACT FROM AUTHOR]

High-intensity statin (HIS) is recommended for high-risk patients in current guidelines. However, the risk of hemorrhagic stroke (HS) with HIS is a concern for Asians. Pitavastatin carries pharmacological differences compared with other statins. We compared the risk of HS in patients treated with pitavastatin-ezetimibe vs. HIS. We conducted a population-based, propensity score-matched cohort study using data from the Taiwan National Health Insurance Research Database. From January 2013 to December 2018, adults (= 18 years) who received pitavastatin 2-4 mg/day plus ezetimibe 10 mg/day (combination group, N = 3,767) and those who received atorvastatin 40 mg/day or rosuvastatin 20 mg/day (HIS group, N = 37,670) were enrolled. The primary endpoint was HS. We also assessed the difference of a composite safety endpoint of hepatitis or myopathy requiring hospitalization and new-onset diabetes mellitus. Multivariable Cox proportional hazards model was used to evaluate the relationship between study endpoints and different treatment. After a mean follow-up of 3.05 ± 1.66 years, less HS occurred in combination group (0.74%) than in HIS group (1.35%) [adjusted hazard ratio (aHR) 0.65, 95% confidence interval (CI) 0.44-0.95]. In subgroup analysis, the lower risk of HS in combination group was consistent among all pre-specified subgroups. There was no significant difference of the composite safety endpoint between the 2 groups (aHR 0.91, 95% CI 0.81-1.02). In conclusion, pitavastatin-ezetimibe combination treatment had less HS compared with high-intensity atorvastatin and rosuvastatin. Pitavastatin-ezetimibe may be a favorable choice for Asians who need strict lipid control but with concern of HS. [ABSTRACT FROM AUTHOR]

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra‐rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346–3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates. A crucial player of CASA is HSPB8 (heat shock protein family B (small) member 8), which acts in a complex with HSPA, their cochaperone BAG3, and the E3 ubiquitin ligase STUB1. Recently, four novel HSPB8 frameshift (fs) gene mutations have been linked to neuromyopathies, and encode carboxy-terminally mutated HSPB8, sharing a common C-terminal extension. Here, we analyzed the biochemical and functional alterations associated with the HSPB8_fs mutant proteins. We demonstrated that HSPB8_fs mutants are highly insoluble and tend to form proteinaceous aggregates in the cytoplasm. Notably, all HSPB8 frameshift mutants retain their ability to interact with CASA members but sequester them into the HSPB8-positive aggregates together with two autophagy receptors SQSTM1/p62 and TAX1BP1. This copartitioning process negatively affects the CASA capability to remove its clients and causes a general failure in proteostasis response. Further analyses revealed that the aggregation of the HSPB8_fs mutants occurs independently of the other CASA members or from the autophagy receptors interaction, but it is an intrinsic feature of the mutated amino acid sequence. HSPB8_fs mutants aggregation alters the differentiation capacity of muscle cells and impairs sarcomere organization. Collectively, these results shed light on a potential pathogenic mechanism shared by the HSPB8_fs mutants described in neuromuscular diseases.Abbreviations : ACD: α-crystallin domain; ACTN: actinin alpha; BAG3: BAG cochaperone 3; C: carboxy; CASA: chaperone-assisted selective autophagy; CE: carboxy-terminal extension; CLEM: correlative light and electron microscopy; CMT2L: Charcot-Marie-Tooth type 2L; CTR: carboxy-terminal region; dHMNII: distal hereditary motor neuropathy type II; EV: empty vector; FRA: filter retardation assay; fs: frameshift; HSPA/HSP70: heat shock protein family A (Hsp70); HSPB1/Hsp27: heat shock protein family B (small) member 1; HSPB8/Hsp22: heat shock protein family B (small) member 8; HTT: huntingtin; KO: knockout; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MTOC: microtubule organizing center; MYH: myosin heavy chain; MYOG: myogenin; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NSC34: Neuroblastoma X Spinal Cord 34; OPTN: optineurin; polyQ: polyglutamine; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1: Tax1 binding protein 1; TUBA: tubulin alpha; WT: wild-type.