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Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB‐NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super‐relaxed state was significantly impaired in NEB‐NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small‐molecule Mavacamten is known to promote the myosin super‐relaxed state and reduce the ATP demand, we tested its potency in the context of NEB‐NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short‐term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild‐type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short‐term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short‐term efficacy in vivo. Key points: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins.Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane‐permeabilized muscle fibres from human patients restored myosin energetic disturbances.Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins.Short‐term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy. [ABSTRACT FROM AUTHOR]

Sarcopenia is an age‐related loss of skeletal muscle mass, strength, and function that causes various health problems. In contrast, late‐onset primary myopathies, which occur in the older population, are caused by a variety of factors, including genetic mutations, autoimmune processes, and metabolic abnormalities. Although sarcopenia and primary myopathy are two distinct disease processes, their symptoms can overlap, making differentiation challenging. The diagnostic criteria for sarcopenia have evolved over time, and various criteria have been proposed by expert groups. Late‐onset primary muscle diseases such as inclusion body myositis, sporadic late‐onset nemaline myopathy, muscular dystrophies, distal myopathies, myofibrillar myopathies, metabolic myopathies, and mitochondrial myopathies share common pathogenic mechanisms with sarcopenia, further complicating the diagnostic process. Appropriate clinical evaluation, including detailed history‐taking, physical examination, and diagnostic testing, is essential for accurate diagnosis and management. Treatment approaches, including exercise, nutritional support, and disease‐specific therapies, must be tailored to the characteristics of each disease. Despite these differences, sarcopenia and primary myopathies require careful consideration in the clinical setting for proper diagnosis and management. This review outlines the evolution of diagnostic criteria and diagnostic items for sarcopenia, late‐onset primary myopathies that should be differentiated from sarcopenia, common pathomechanisms, and diagnostic algorithms to properly differentiate primary myopathies. Geriatr Gerontol Int 2024; ••: ••–••. [ABSTRACT FROM AUTHOR]

• We performed detailed clinical assessments in Dutch nemaline myopathy patients. • Half of the cohort uses a wheelchair and/or mechanical ventilation. • Patients have a reduced experienced quality of life and a high experienced fatigue. • The results provide important recommendations for future trial design. Nemaline myopathy (NM) is a congenital myopathy with generalised muscle weakness, most pronounced in neck flexor, bulbar and respiratory muscles. The aim of this cross-sectional study was to assess the Dutch NM patient cohort. We assessed medical history, physical examination, quality of life (QoL), fatigue severity, motor function (MFM), and respiratory muscle function. We included 18 of the 28 identified patients (13 females (11–67 years old); five males (31–74 years old)) with typical or mild NM and eight different genotypes. Nine patients (50 %) used a wheelchair, eight patients (44 %) used mechanical ventilation, and four patients (22 %) were on tube feeding. Spinal deformities were found in 14 patients (78 %). The median Medical Research Council (MRC) sum score was 38/60 [interquartile range 32–51] in typical and 48/60 [44–50] in mild NM. The experienced QoL was lower and fatigue severity was higher than reference values of the healthy population. The total MFM score was 55 % [49–94] in typical and 88 % [72–93] in mild NM. Most of the patients who performed spirometry had a restrictive lung function pattern (11/15). This identification and characterisation of the Dutch NM patient cohort is important for international collaboration and can guide the design of future clinical trials. [ABSTRACT FROM AUTHOR]

The article discusses a rare skin condition called papular epidermal naevus with 'skyline' basal cell layer (PENS). The authors describe five patients with PENS who had a specific genetic mutation called mosaic EGFR exon 20 in-frame insertion. This mutation was found in skin biopsy samples but not in blood samples, suggesting that it may be a somatic mutation. The authors also note that PENS may be associated with other neurological disorders. The findings suggest that the EGFR exon 20 in-frame insertion mutation could be a specific genetic marker for PENS. [Extracted from the article]

This article presents a case of a 47-year-old man who was admitted to the hospital with confusion and kidney failure. The patient had experienced fatigue and muscle pain prior to admission, and his symptoms worsened over time. Upon examination, the patient exhibited confusion, difficulty finding words, and garbled speech. Laboratory tests revealed abnormalities in blood and urine, and imaging studies showed consolidation in the right lower lobe of the lung. The article discusses the possible causes of the patient's symptoms, including nontraumatic, nonexertional rhabdomyolysis. It also explores the diagnosis and treatment of Legionella pneumonia, which was ultimately confirmed in this case. The patient's history of living in a converted factory and using dietary supplements, as well as the presence of lung consolidation, suggested a possible diagnosis of legionella infection. The article provides information on the transmission and diagnostic methods of legionella infection, as well as the treatment and prevention strategies. It also highlights the challenges in diagnosing the infection in this particular case due to the patient's altered mental state and poor sample quality. The patient's myopathy may have contributed to the severity of the infection. [Extracted from the article]

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies. [ABSTRACT FROM AUTHOR]

A recent study published in Acta Neuropathologica identified a novel missense mutation of the small muscle protein X-linked (SMPX) gene in a Chinese pedigree. The affected individuals in the pedigree exhibited symptoms of scapuloperoneal myopathy and myofibrillar myopathy, with both proximal and distal muscle weakness and mild sensorineural deafness. Muscle biopsies revealed characteristic pathological features, including atrophic round fibers, rimmed vacuoles, and eosinophilic substances. This study expands our understanding of SMPX-related myopathy and highlights the need for further research to establish a relationship between the mutation and deafness. [Extracted from the article]

Objective Methods Results Interpretation Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD.The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD.The expert‐reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case‐level data that help clarify disputed or novel LGMD associations. [ABSTRACT FROM AUTHOR]

Background: The ryanodine receptor 3 (RYR3) is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum and subsequent T-tubule depolarization. It is also expressed in the brain, and variants in the RYR3 gene can lead to congenital myopathy type 20 (MIM: #620310). Methods: We retrospectively analyzed the clinical characteristics and prognosis of a case of West syndrome, developmental and epileptic encephalopathy (DEE) caused by a missense variant in the RYR3 gene. We also reviewed and summarized the literature on epilepsy cases caused by RYR3 gene variants. Results: A 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. Treatment with various antiepileptic drugs resulted in initial improvement but ultimately failed to control the seizures. Whole-exome sequencing revealed a novel heterozygous variant c.10943C  >  T/p.T3648M in the RYR3 gene, and genome-wide sequencing ruled out other potentially pathogenic variants. Three previous reports have described RYR3 variants causing DEE, two of which were attributed to de novo heterozygous variants, and one was a compound heterozygote. Conclusion: The present case of DEE caused by a RYR3 heterozygous variant is consistent with previous rare cases of epilepsy caused by RYR3 gene variants in terms of pathogenesis and clinical features, but significantly different from congenital myopathy type 20. Our findings provide important evidence for the diagnosis of RYR3-related DEE, and we hypothesize that RYR3 gain-of-function variants resulting in “leaky” Ca2+ release channels may be a molecular genetic feature leading to DEE rather than myopathy. [ABSTRACT FROM AUTHOR]

Background: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive neuromuscular disorder that arises in early childhood and is characterized by congenital cataracts, myopathy associated with muscle weakness, and degeneration of Purkinje neurons leading to ataxia. About 60% of MSS patients have loss-of-function mutations in the SIL1 gene. Sil1 is an endoplasmic reticulum (ER) protein required for the release of ADP from the master chaperone Bip, which in turn will release the folded proteins. The expression of non-functional Sil1 leads to the accumulation of unfolded proteins in the ER and this triggers the unfolded protein response (UPR). A dysfunctional UPR could be a key element in the pathogenesis of MSS, although our knowledge of the molecular pathology of MSS is still incomplete. Methods: RNA-Seq transcriptomics was analysed using the String database and the Ingenuity Pathway Analysis platform. Fluorescence confocal microscopy was used to study the remodelling of the extracellular matrix (ECM). Transmission electron microscopy (TEM) was used to reveal the morphology of the ECM in vitro and in mouse tendon. Results: Our transcriptomic analysis, performed on patient-derived fibroblasts, revealed 664 differentially expressed (DE) transcripts. Enrichment analysis of DE genes confirmed that the patient fibroblasts have a membrane trafficking issue. Furthermore, this analysis indicated that the extracellular space/ECM and the cell adhesion machinery, which together account for around 300 transcripts, could be affected in MSS. Functional assays showed that patient fibroblasts have a reduced capacity of ECM remodelling, reduced motility, and slower spreading during adhesion to Petri dishes. TEM micrographs of negative-stained ECM samples from these fibroblasts show differences of filaments in terms of morphology and size. Finally, structural analysis of the myotendinous junction of the soleus muscle and surrounding regions of the Achilles tendon revealed a disorganization of collagen fibres in the mouse model of MSS (woozy). Conclusions: ECM alterations can affect the proper functioning of several organs, including those damaged in MSS such as the central nervous system, skeletal muscle, bone and lens. On this basis, we propose that aberrant ECM is a key pathological feature of MSS and may help explain most of its clinical manifestations. [ABSTRACT FROM AUTHOR]

The article focuses on the enigmatic role of Fragile X Messenger Ribonucleoprotein (FMRP) in nucleolar localization and its potential functions beyond the cytoplasm. Topics include the structural similarities and differences between FMRP and its related proteins FXR1P and FXR2P, the debate over FMRP's involvement in ribosome biogenesis within the nucleolus, and the implications of these findings for understanding Fragile X Syndrome.

Key Clinical Message: Homozygous variants of Calcium Voltage‐Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation were previously identified as causes of periodic paralysis and congenital early‐onset myopathy, while it could be manifested as a late‐onset congenital core myopathy. Calcium Voltage‐Gated Channel Subunit Alpha1 S (CACNA1S) gene mutation has been linked to various neuromuscular conditions in recent years. Congenital myopathy with core‐like features is one of the cardinal associations reported previously, causing severe respiratory insufficiency and death in neonates. Informed consent was received from the patients. Subsequently, peripheral blood leukocytes were utilized to extract genomic DNA. Moreover, exome enrichment was implemented through the Twist Human Core Exome Kit (Twist Bioscience) and exome sequenced using Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA). Sanger sequencing using BIG Dye Terminators confirmed the presence of the final variant. Finally, the candidate variants were classified based on the American College of Medical Genetics and Genomics (ACMG) guidelines. In this report, we describe two siblings, who presented with childhood and late‐onset progressive muscle weakness, and had a homozygous variant in exon 2 of the CACNA1S gene defined as c.188C > A (p.Ala63Asp) (NM_000069.3). The SIFT, Polyphen2, CADD PHRED, and Mutation Taster analysis tools classified the variant as pathogenic/damaging. The muscle biopsy of the younger brother revealed intermyofibrillar network pattern disruption as cytoplasmic core‐like lesions. The muscle magnetic resonance imaging (MRI) reported grade IIa and IIb fatty changes. Finally, the electromyography (EMG) findings suggested a myopathic change pattern. This report illustrates the clinical variability in CACNA1S‐related myopathy by reviewing prior reports and adding newly found aspects, additionally expanding the gene defects associated with core myopathy. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders. Case presentation A 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level. Conclusion Genetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.

Background: Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. Muscle degeneration involves a complex interplay between multiple cell lineages spatially located within areas of damage, termed the degenerative niche, including inflammatory cells, satellite cells (SCs) and fibro-adipogenic precursor cells (FAPs). FAPs are mesenchymal stem cell which have a pivotal role in muscle homeostasis as they can either promote muscle regeneration or contribute to muscle degeneration by expanding fibrotic and fatty tissue. Although it has been described that FAPs could have a different behavior in DMD patients than in healthy controls, the molecular pathways regulating their function as well as their gene expression profile are unknown. Methods: We used single-cell RNA sequencing (scRNAseq) with 10X Genomics and Illumina technology to elucidate the differences in the transcriptional profile of isolated FAPs from healthy and DMD patients. Results: Gene signatures in FAPs from both groups revealed transcriptional differences. Seurat analysis categorized cell clusters as proliferative FAPs, regulatory FAPs, inflammatory FAPs, and myofibroblasts. Differentially expressed genes (DEGs) between healthy and DMD FAPs included upregulated genes CHI3L1, EFEMP1, MFAP5, and TGFBR2 in DMD. Functional analysis highlighted distinctions in system development, wound healing, and cytoskeletal organization in control FAPs, while extracellular organization, degradation, and collagen degradation were upregulated in DMD FAPs. Validation of DEGs in additional samples (n = 9) using qPCR reinforced the specific impact of pathological settings on FAP heterogeneity, reflecting their distinct contribution to fibro or fatty degeneration in vivo. Conclusion: Using the single-cell RNA seq from human samples provide new opportunities to study cellular coordination to further understand the regulation of muscle homeostasis and degeneration that occurs in muscular dystrophies. [ABSTRACT FROM AUTHOR]

Cofilin, an actin-severing protein, plays key roles in muscle sarcomere addition and maintenance. Our previous work found that Drosophila cofilin (DmCFL) knockdown in muscle causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA-sequencing analysis that unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL muscle knockdown causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown resulted in mislocalization of GluRIIA class glutamate receptors in more deteriorated muscles and strongly impaired NMJ transmission strength. These findings expand our understanding of the roles of cofilin in muscle to include NMJ structural development and suggest that NMJ defects may contribute to the pathophysiology of nemaline myopathy. [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]

This article summarizes a study that explores the role of the PACSIN3 gene in a rare muscle disorder. The study focuses on two families with children who experience exercise intolerance and early fatigue. Genetic testing reveals that the children have loss-of-function variants in the PACSIN3 gene, which is involved in cytoskeleton organization and intracellular trafficking. The study suggests that PACSIN3 deficiency can cause a myopathy with elevated creatine kinase levels in children. Further research is needed to fully understand the mechanisms and implications of PACSIN3 deficiency in muscle function. [Extracted from the article]

Background: GNE myopathy is an ultra-rare autosomal recessive distal myopathy caused by pathogenic variants of the GNE gene, which encodes a key enzyme in sialic acid biosynthesis. The present study aimed to examine the long-term progression of GNE myopathy, genotype–phenotype correlations, and complications to provide useful information for predicting patient progression and designing clinical trials using a large collection of registry data over a 10-year period. Methods: We analyzed 220 Japanese patients with GNE myopathy from a national registry in Japan. Diagnoses were confirmed by genetic curators based on genetic analysis reports. We analyzed registration sheets and annually updated items completed by attending physicians. Results: In total, 197 of 220 participants (89.5%) carried p.D207V or p.V603L in at least one allele. The median disease duration to loss of ambulation was estimated to be 10 years in p.V603L homozygotes (n = 48), whereas more than 90% of p.D207V/p.V603L compound heterozygotes were estimated to be ambulatory even 20 years after disease onset according to Kaplan–Meier analysis (p < 0.001). Moreover, participants with a younger age of onset lost ambulation earlier regardless of genotype. A decline in respiratory function was observed as the disease progressed, particularly in p.V603L homozygotes, whereas none of the p.D207V/p.V603L compound heterozygotes showed a decline. Conclusions: The present study demonstrated large differences in disease progression and respiratory function between genotypes. Moreover, age of onset was found to be an indicator of disease severity regardless of genotype in GNE myopathy patients. These results may help stratify patients in clinical trials and predict disease progression. [ABSTRACT FROM AUTHOR]

Objective: Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results: Fixed‐effects meta‐analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT‐O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta‐analysis results. Finally, several tail in‐frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. Interpretation: We showed that NEFH tail missense and in‐frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered. [ABSTRACT FROM AUTHOR]

X-Linked Myotubular Myopathy (XLMTM) is a severe congenital myopathy, potentially fatal within the first years. Patients present several complications and their cognitive development has never been explored deeply so far. An in-depth knowledge on the disease natural history, including the neurocognitive and adaptive profile, is essential in light of the promising new therapeutic perspectives. We included all XLMTM patients seen in our clinical Unit between January 2021 and December 2023, irrespective to their disease's severity. Demographic and clinical data, including motor, respiratory and swallowing functions were collected. Patients were assessed with gold-standard international scales, according to their age and communication skills. We assessed nine patients in total, four with a severe phenotype, four with an intermediate phenotype and one with mild phenotype. The cognitive profile was within the lower limits or lower than the norm, with a global adaptive deficit for the majority of patients. A perseverative behavioural trait was also observed in some patients. This study shows that XLMTM patients in the cohort had a neurodevelopmental profile within the lower limits of the norm, irrespective to the disease's severity, while the adaptive difficulties seems to be related to patients' global clinical impairment. Our observation would deserve a confirmation on a wider range of patients and we consider it essential for better defining the XLMTM phenotype, also considering the incoming promising therapeutic approaches. • Cognitive delay noted in XLMTM1, impacting adaptive functioning. • Communication severely impaired by motor and respiratory issues. • Potential positive trajectory in learning abilities observed. • Discrepancy in non-verbal cognitive abilities among older children. • Behavioral peculiarities explored, suggestive of neurodevelopmental traits. [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]

Introduction: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism. Methods: A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mdx mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach. Results and Discussion: We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant linked to RBCK1 gene mutations. Understanding the clinical diversity of PGBM1 aids in better characterization of the disease. Two unrelated Iranian families with individuals exhibiting progressive muscle weakness underwent clinical evaluations, genetic analysis using whole exome sequencing (WES), and histopathological examinations of muscle biopsies. In one case, a novel homozygous RBCK1 variant was identified, presenting with isolated myopathy without cardiac or immune involvement. Conversely, the second case harbored a known homozygous RBCK1 variant, displaying a broader phenotype encompassing myopathy, cardiomyopathy, inflammation, and immunodeficiency. Histopathological analyses confirmed characteristic skeletal muscle abnormalities consistent with PGBM1. Our study contributes to the expanding understanding of RBCK1‐related diseases, illustrating the spectrum of phenotypic variability associated with distinct RBCK1 variants. These findings underscore the importance of genotype–phenotype correlations in elucidating disease mechanisms and guiding clinical management. Furthermore, the utility of next‐generation sequencing techniques in diagnosing complex neurogenetic disorders is emphasized, facilitating precise diagnosis and enabling tailored genetic counseling for affected individuals and their families. [ABSTRACT FROM AUTHOR]

Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions by providing elastic support and/or through signaling. An elastic region at the C-terminus of filamin is called the mechanosensitive region and has been proposed to sense and counteract contractile damage. Here we use molecularly defined mutants and microscopy analysis of the Drosophila indirect flight muscles to investigate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region to interrogate the mechanosensitive region and detected three Z-disc phenotypes: dissociation of actin filaments, Z-disc rupture, and Z-disc enlargement. We tested a constitutively closed filamin mutant, which prevents the elastic changes in the mechanosensitive region and results in ruptured Z-discs, and a constitutively open mutant which has the opposite elastic effect on the mechanosensitive region and gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, stabilizes the Z-disc, and counteracts contractile damage at the Z-disc. Author summary: Muscles work by contracting and relaxing in response to signals from the nervous system. Muscles are made up of long, slender cells called muscle fibers. Inside these fibers are even smaller units called sarcomeres, which are responsible for the actual contraction of the muscle. The sliding of actin and myosin filaments shortens the sarcomeres, causing the muscles to contract. As sarcomeres contract, the entire muscle shortens, pulling on the tendons attached to it. This pulling action is what creates movement. Sarcomeres however are prone to contractile damage and so they have proteins to hold the sarcomere together. One of these proteins is filamin, a large protein which has a special elastic part called the mechanosensitive region, which might be crucial for providing stability to the sarcomeres as they contract. To test this hypothesis, we made versions of filamin with increased or decreased elasticity and studied how muscles behaved with these changes. We find that when filamin lost its elasticity, sarcomeres are more prone to breaking while when filamin has extra elasticity, the sarcomeres do not break and instead form large protein aggregates which we think represent the sarcomere response to contractile damage. This research gives us a better understanding of how our muscles sustain contractile damage, which is important for everyone from athletes to people recovering from injuries. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is a slowly progressive disorder belonging to the idiopathic inflammatory myopathies, and it represents the most common adult-onset acquired myopathy. The main clinical features include proximal or distal muscular asymmetric weakness, with major involvement of long finger flexors and knee extensors. The main histological findings are the presence of fiber infiltrations, rimmed vacuoles, and amyloid inclusions. The etiopathogenesis is a challenge because both environmental and genetic factors are implicated in muscle degeneration and a distinction has been made previously between sporadic and hereditary forms. Here, we describe an Italian patient affected with a hereditary form of IBM with onset in his mid-forties. Next-generation sequencing analysis disclosed a heterozygous mutation c.76C>T (p.Pro26Ser) in the PDZ motif of the LDB3/ZASP gene, a mutation already described in a family with a late-onset myopathy and highly heterogenous degree of skeletal muscle weakness. In the proband's muscle biopsy, the expression of ZASP, myotilin, and desmin were increased. In our family, in addition to the earlier age of onset, the clinical picture is even more peculiar given the evidence, in one of the affected family members, of complete ophthalmoplegia in the vertical gaze. These findings help extend our knowledge of the clinical and genetic background associated with inclusion body myopathic disorders. [ABSTRACT FROM AUTHOR]

Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify l-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swim speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest l-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy. [ABSTRACT FROM AUTHOR]

The molecular motor myosin is post‐translationally modified in its globular head, its S2 hinge, and its thick filament domain during human skeletal muscle aging. To determine the importance of such modifications, we performed an integrative analysis of transgenic Drosophila melanogaster expressing myosin containing post‐translational modification mimic mutations. We determined effects on muscle function, myofibril structure, and myosin biochemistry. Modifications in the homozygous state decreased jump muscle function by a third at 3 weeks of age and reduced indirect flight muscle function to negligible levels in young flies, with severe effects on flight muscle myofibril assembly and/or maintenance. Expression of mimic mutations in the heterozygous state or in a wild‐type background yielded significant, but less severe, age‐dependent effects upon flight muscle structure and function. Modification of the residue in the globular head disabled ATPase activity and in vitro actin filament motility, whereas the S2 hinge mutation reduced actin‐activated ATPase activity by 30%. The rod modification diminished filament formation in vitro. The latter mutation also reduced proteostasis, as demonstrated by enhanced accumulation of polyubiquitinated proteins. Overall, we find that mutation of amino acids at sites that are chemically modified during human skeletal muscle aging can disrupt myosin ATPase, myosin filament formation, and/or proteostasis, providing a mechanistic basis for the observed muscle defects. We conclude that age‐specific post‐translational modifications present in human skeletal muscle are likely to act in a dominant fashion to affect muscle structure and function and may therefore be implicated in degeneration and dysfunction associated with sarcopenia. [ABSTRACT FROM AUTHOR]

• We report a recurrent intronic homozygous c.1023+5G> A desmin mutation in indian patients. • Second report of recessive desminopathy associated with mixed limb girdle CMS – myofibrillar myopathy. • Partial loss of desmin leading to NMJ dysfunction and CMS phenotype. • Leaky splice site with intron retention leads to partial desmin loss. Recessive desminopathies are rare and often present as severe early-onset myopathy. Here we report a milder phenotype in three unrelated patients from southern India (2 M, 1F) aged 16, 21, and 22 years, who presented with childhood-onset, gradually progressive, fatigable limb-girdle weakness, ptosis, speech and swallowing difficulties, without cardiac involvement. Serum creatine kinase was elevated, and repetitive nerve stimulation showed decrement in all. Clinical improvement was noted with pyridostigmine and salbutamol in two patients. All three patients had a homozygous substitution in intron 5: DES(NM_001927.4):c.1023+5G> A , predicted to cause a donor splice site defect. Muscle biopsy with ultrastructural analysis suggested myopathy with myofibrillar disarray, and immunohistochemistry showed partial loss of desmin with some residual staining, while western blot analysis showed reduced desmin. RT-PCR of patient muscle RNA revealed two transcripts: a reduced normal desmin transcript and a larger abnormal transcript suggesting leaky splicing at the intron 5 donor site. Sequencing of the PCR products confirmed the inclusion of intron 5 in the longer transcript, predicted to cause a premature stop codon. Thus, we provide evidence for a leaky splice site causing partial loss of desmin associated with a unique phenotypic presentation of a milder form of desmin-related recessive myopathy overlapping with congenital myasthenic syndrome. [ABSTRACT FROM AUTHOR]

Congenital myopathy type 13 (CMYO13), also known as Native American myopathy, is a rare muscle disease characterized by early-onset hypotonia, muscle weakness, delayed motor milestones, and susceptibility to malignant hyperthermia. The phenotypic spectrum of congenital myopathy type 13 is expanding, with milder forms reported in non-native American patients. The first description of the disease dates to 1987 when Bailey and Bloch described an infant belonging to a Native American tribe with cleft palate, micrognathia, arthrogryposis, and general-anesthesia-induced malignant hyperthermia reaction; the cause of the latter remains poorly defined in this rare disease. The pan-ethnic distribution, as well as its predisposition to malignant hyperthermia, makes the identification of CMYO13 essential to avoid life-threatening, anesthesia-related complications. In this article, we are going to review the clinical phenotype of this disease and the pathophysiology of this rare disease with a focus on two unique features of the disease, namely cleft palate and malignant hyperthermia. We also highlight the importance of recognizing this disease's expanding phenotypic spectrum—including its susceptibility to malignant hyperthermia—and providing appropriate care to affected individuals and families. [ABSTRACT FROM AUTHOR]

Bridging integrator 1 (BIN1) is a ubiquitous BIN–amphiphysin–Rvs (BAR) domain protein with tissue-specific isoforms and functions that is implicated in various diseases such as myopathies, heart failure, Alzheimer's disease, and cancer. In skeletal muscle, the inclusion of a phosphatidylinositol binding domain enables BIN1 to elongate transverse membrane tubules (T-tubules) linked to the sarcoplasmic reticulum. In cardiac muscle, BIN1 forms T-tubule microdomains and recruits the essential components of excitation–contraction coupling via the cytoskeleton. The tubulation properties of BIN1 are balanced by myotubularin 1 and dynamin 2 during tubulogenesis in cardiac and skeletal muscles. Modulation of the gene encoding either of these is a potential therapy for BIN1-linked myopathies. Amphiphysin-2 is a ubiquitously expressed protein also known as bridging integrator 1 (BIN1), playing a critical role in membrane remodeling, trafficking, and cytoskeleton dynamics in a wide range of tissues. Mutations in the gene encoding BIN1 cause centronuclear myopathies (CNM), and recent evidence has implicated BIN1 in heart failure, underlining its crucial role in both skeletal and cardiac muscle. Furthermore, altered expression of BIN1 is linked to an increased risk of late-onset Alzheimer's disease and several types of cancer, including breast, colon, prostate, and lung cancers. Recently, the first proof-of-concept for potential therapeutic strategies modulating BIN1 were obtained for muscle diseases. In this review article, we discuss the similarities and differences in BIN1's functions in cardiac and skeletal muscle, along with its associated diseases and potential therapies. [ABSTRACT FROM AUTHOR]

Introduction We report a series of patients in three different Libyan families diagnosed with congenital myopathy to study the wide clinical variability between these families, and the genetic heterogeneity. Description of Cases We describe six patients, one patient presented with severe neonatal-onset RYR1-associated myopathy while the other five patients came mainly due to delay in motor development; genetic testing confirmed the diagnosis of CMY-1B disease due to RYR1 mutation in all patients. Clinical features of congenital widely varied between the families ranging from profound hypotonia during the neonatal period in one family to a motor delay and abnormal gait during childhood in other two families. Whereas the clinical picture is quite similar in the patients of same family, the patient who presented with severe neonatal presentation of RYR1-associated myopathy also had gastrostomy feeding, respiratory involvement, clubfeet, cleft palate, and undescended testes. The five patients who presented due to delay in motor development all were ambulatory without the need of support, except the youngest one aged 4 years still walking with support. The genetic study in the form of whole-exon sequencing as well as next-generation sequencing showed homozygosity of a gene mutation in five patients and a compound heterozygosity in one patient which presented with neonatal severe hypotonia. Conclusion CMY-1B disease is a rare autosomal dominant and recessive genetic disorder that has variable clinical presentations. The early diagnosis is very important for genetic counseling as well as avoiding malignant hyperthermia. We also report rare and unusual presentations that may further delay the diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to examine the effects of in ovo nicotinamide riboside (NR) feeding on high-yield broiler growth and meat quality. Methods: Fertilized Cobb 700 by-product eggs (N = 3,240) were randomly assigned to one of four in ovo treatments and injected with 0 (0NR), 250 (250NR), 500 (500NR), or 1,000 (1,000NR) mM NR at incubation-day 10. Chicks were hatched, vent sexed, and randomly placed 18 per pen in one of 32 floor pens. On day 48, birds were processed and deboned. Results: There were dose effects for all part weights (p < 0.05). Pectoralis major weight of 250, 500, and 1,000NR carcasses were heavier than 0NR (p < 0.03) but did not differ from remaining NR doses (p > 0.26). Pectoralis minor weight of 250NR carcasses was greater (p < 0.01) than 0NR and did not differ from other NR tenders (p > 0.21). Pectoralis minor weight of 500 and 1,000NR carcasses was greater than 0NR (p < 0.09), but did not differ (P = 0.82) from each other. There were no dose effects for all Pectoralis major and minor myopathy scores and incidence except incidence of tenders scoring "0" and "1" for woody-like tender. Percentage of NR1,000 tenders scoring 0 and 1 for woody-like tender were less than and greater than all other treatments, respectively (p < 0.05). There were no differences among remaining NR doses and NR0 tenders (p > 0.10). There were dose effects for muscle fiber number (P = 0.03). There tended to be more muscle fibers within 250 and 1,000NR muscles compared to 0NR (p < 0.09). Pectoralis major muscle from 500NR did not differ in muscle fiber number compared to 250 and 1,000NR (p > 0.18), but had more (p < 0.01) fibers than 0NR muscle. There tended to be more fibers in 250 and 1,000NR muscles compared to 0NR muscle (p < 0.09). Discussion: Nicotinamide riboside in ovo feeding caused birds to produce heavier parts; however, myopathy scores and incidence were minimally affected which may have been due greater muscle fiber number. [ABSTRACT FROM AUTHOR]

Background: Muscular dystrophies and congenital myopathies encompass various inherited muscular disorders that present diagnostic challenges due to clinical complexity and genetic heterogeneity. Methods: This study aimed to investigate the use of whole exome sequencing (WES) in diagnosing muscular disorders in pediatric patients in Taiwan. Out of 161 pediatric patients suspected to have genetic/inherited myopathies, 115 received a molecular diagnosis through conventional tests, single gene testing, and gene panels. The remaining 46 patients were divided into three groups: Group 1 (multiplex ligation-dependent probe amplification-negative Duchenne muscular dystrophy) with three patients (6.5%), Group 2 (various forms of muscular dystrophies) with 21 patients (45.7%), and Group 3 (congenital myopathies) with 22 patients (47.8%). Results: WES analysis of these groups found pathogenic variants in 100.0% (3/3), 57.1% (12/21), and 68.2% (15/22) of patients in Groups 1 to 3, respectively. WES had a diagnostic yield of 65.2% (30 patients out of 46), detecting 30 pathogenic or potentially pathogenic variants across 28 genes. Conclusion: WES enables the diagnosis of rare diseases with symptoms and characteristics similar to congenital myopathies and muscular dystrophies, such as muscle weakness. Consequently, this approach facilitates targeted therapy implementation and appropriate genetic counseling. [ABSTRACT FROM AUTHOR]

• Since 2014, several natural history studies and clinical trials have been conducted in centronuclear myopathies (CNM). Many members of international patient organizations dedicated to CNM have been involved as (parents of) participants. • Understanding the participants' experience as well as barriers and facilitators of participation are important to optimize future research and to inform clinical trial management. • The most common barriers to trial participation of patients with various neuromuscular disorders comprise concerns about potential harmful effects, opportunity loss and the expected burden on daily life. • The most common facilitators are an expected benefit on the disease course, altruism and collateral benefit. The limited availability of relevant literature suggest that future research should focus on (qualitative) studies regarding trial experience of CNM patients. The design of a clinical trial for a rare disease can be challenging. An optimal study design is required to effectively study the clinical outcomes for possible therapies for these types of disorders. Understanding the study participants' experiences as well as barriers and facilitators of participation are important to optimize future research and to inform clinical trial management. Centronuclear myopathies (CNMs) including X-linked myotubular myopathy (XLMTM) are a group of rare congenital myopathies for which there is no cure currently. Since 2014, a number of natural history studies and clinical trials have been conducted in CNMs. Two trials have been prematurely terminated because of severe adverse events. Since no research has been conducted regarding trial experience in CNM, we performed a scoping literature research on clinical trial experience of patients with neuromuscular disorders in general. The most common barriers to trial participation of patients comprise concerns about potential harmful effects, opportunity loss and the expected burden on daily life. The most common facilitators were an expected benefit on the disease course, altruism and collateral benefit. While several results are in line with trial experiences of other types of patients, for example oncological patients, distinctions can be made for patients with CNM and other neuromuscular disorders. However, the limited availability of relevant literature suggests that future (qualitative) research should focus on trial experiences in CNM patients. [ABSTRACT FROM AUTHOR]

TAR DNA binding protein of 43 kDa (TDP-43)-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their fifth to seventh decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro , and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy, but not ALS, implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype. [ABSTRACT FROM AUTHOR]

Mutations in the LMNA gene-encoding A-type lamins can cause Limb–Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in coiled-coil domain containing protein 78 (CCDC78). This variant was given priority because another mutation in CCDC78 causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the LMNA mutation and the CCDC78 variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the LMNA mutation. Taken together, our findings suggest that a relatively common variant in CCDC78 can impart profound muscle pathology in combination with a LMNA mutation and accounts for variability in skeletal muscle disease phenotypes. [ABSTRACT FROM AUTHOR]

Duchenne Muscular Dystrophy (DMD) is the most common primary myopathy of children. There are many muscular diseases in children which are inherited through generations. All those are known as congenital myopathy. This disease is an X-linked recessive disorder produced by the abnormality of the gene Xp21. It is a severe condition that poses a life-threatening risk and significantly reduces a patient's lifespan. It is characterised by progressive symmetrical muscular weakness, with proximal muscles being more affected than distal ones. Additionally, individuals with DMD often exhibit pseudohypertrophy of the calf muscles. The compilation of data from classical Ayurvedic texts contributes to a holistic understanding of potential interventions, aiming to improve patient quality of life and prevent contractures. The study is crucial in bridging traditional and contemporary healthcare practices, offering valuable insights for clinicians and the wider medical community in addressing the multifaceted challenges posed by DMD. This research underscores the need for an integrative and comprehensive approach to enhance therapeutic strategies for this prevalent X-linked recessive disorder. In pursuit of this objective, concerted efforts have been directed towards raising awareness among both the general public and the medical community. Furthermore, the review delves into the exploration of various Panchakarma treatments, a traditional therapeutic approach rooted in Ayurveda. By consolidating and synthesising data derived from classical Ayurvedic texts pertaining to DMD, this review seeks to provide a holistic understanding of potential interventions. The goal is to contribute to the advancement of therapeutic strategies that can ameliorate the impact of DMD on patients' lives, fostering a more comprehensive and integrated approach to managing this challenging condition. [ABSTRACT FROM AUTHOR]

Proline substitutions within the coiled-coil rod region of the ß-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators. [ABSTRACT FROM AUTHOR]

Drug-induced myopathies are a common cause of muscle pain, and the range of drugs that can cause muscle side effects is constantly expanding. In this article, the authors comprehensively discuss the diagnostic and therapeutic process in patients with myalgia, and present the spectrum of drug-induced myopathies. The review provides a detailed analysis of the literature on the incidence of myopathy during treatment with hypolipemic drugs, beta-blockers, amiodarone, colchicine, glucocorticosteroids, antimalarials, cyclosporine, zidovudine, and checkpoint inhibitors, a group of drugs increasingly used in the treatment of malignancies. The article considers the clinical course of the different types of myopathies, their pathogenesis, histopathological features, and treatment methods of these disorders. The aim of this paper is to gather from the latest available literature up-to-date information on the course, pathophysiology, and therapeutic options of drug-induced myopathies, to systematize the knowledge of drug-induced myopathies and to draw the attention of internists to the fact that these clinical issues are an important therapeutic problem. [ABSTRACT FROM AUTHOR]

Nemaline myopathy (NM) is a rare congenital muscle disease that leads to muscle damage, resulting in muscle weakness and atrophy. Cases of scoliosis induced by muscle weakness and atrophy are exceedingly uncommon. The author clinically treated one patient with NM complicated by scoliosis and analyzed its clinical characteristics through a literature review. The pathogenic genes of this patient originated from compound heterozygous mutations c.12471 + 3A>G from the mother and c.7727G>A from the father, leading to the diagnosis of NM accompanied by scoliosis, which represents a relatively rare clinical phenotype.

This article discusses myopathies associated with Streptococcus equi equi (S. equi) infection in horses, specifically focusing on complications such as purpura haemorrhagica (PH) and myosin heavy chain myopathy (MYHM). PH is characterized by fever, lethargy, and limb swelling due to immune complexes in vessel walls, while MYHM is a genetic condition that causes muscle atrophy. Quarter Horse-related breeds are particularly susceptible to these complications. Treatment options, such as antibiotics and corticosteroids, are discussed, as well as the importance of early detection and genetic testing. [Extracted from the article]

BackgroundNemaline myopathies are congenital or acquired muscle disorders that typically present in childhood but can occasionally occur in adults with underlying malignant, infectious or autoimmune disorders. There is a great genetic heterogeneity as well as clinical variability among the disease.Case presentationHere, we present a case of nemaline myopathy in a young woman who was newly diagnosed with systemic lupus erythematosus (SLE) and Sjögren's overlap syndrome complicated by macrophage activation syndrome (MAS). She had no personal or family history of myopathy and was reporting progressive thigh weakness. A muscle biopsy revealed type 1 myofiber predominance with granular material in atrophic myocytes consistent with nemaline myopathy. Her symptoms markedly improved with immunotherapy for her SLE and MAS supporting the diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with her autoimmune disease.ConclusionsSLONM is a type of nemaline myopathy that presents in adults and can occasionally be associated with autoimmune disease. In these cases, treatment of the underlying disorder with immunosuppression appears to improve symptoms of myopathy.

Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)—a natural compound found in cacao—has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA‐IR and IL‐6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients. [ABSTRACT FROM AUTHOR]

Myopathy refers to a large group of heterogeneous, rare muscle diseases. Bulk RNA-sequencing has been utilized for the diagnosis and research of these diseases for many years. However, the existing valuable sequencing data often lack integration and clinical interpretation. In this study, we integrated bulk RNA-sequencing data from 1221 human skeletal muscles (292 with myopathies, 929 controls) from both databases and our local samples. By applying a method similar to single-cell analysis, we revealed a general spectrum of muscle diseases, ranging from healthy to mild disease, moderate muscle wasting, and severe muscle disease. This spectrum was further partly validated in three specific myopathies (97 muscles) through clinical features including trinucleotide repeat expansion, magnetic resonance imaging fat fraction, pathology, and clinical severity scores. This spectrum helped us identify 234 genuinely healthy muscles as unprecedented controls, providing a new perspective for deciphering the hallmark genes and pathways among different myopathies. The newly identified featured genes of general myopathy, inclusion body myositis, and titinopathy were highly expressed in our local muscles, as validated by quantitative polymerase chain reaction. This study analysed bulk RNA-sequencing data from 1221 human skeletal muscles and validated the progressive spectrum of myopathy diseases. [ABSTRACT FROM AUTHOR]

This document contains abstracts and summaries of various research studies related to muscle regeneration, muscle function, and muscular dystrophy. The studies cover topics such as enhanced regenerative capacity of satellite cells, the use of extracellular vesicles for correcting muscle cell division, regenerative potential of postmortem human muscle cells, and the role of CaVβ1 isoforms in muscle mass homeostasis. Other topics include microtubule detyrosination, muscle performance in fish compared to mice, muscle regeneration in tadpoles, satellite cell dysfunction in neuromuscular disorders, age-dependent decline in muscle regenerative capacities, and rehabilitation regimes for the elderly. The research explores molecular, cellular, and mechanistic factors related to muscle wasting, fibrosis, and disease modeling, providing insights into potential therapeutic approaches and personalized medicine applications. Additionally, the document includes information about an association that supports patients and families affected by muscular dystrophy through research and educational programs. [Extracted from the article]

The given document contains information about keynote lecturers at the 20th IIM Meeting, focusing on topics related to muscle stem cells and their interactions with the microenvironment. The lecturers include Philippos Mourikis, who discusses the role of Notch signaling in muscle stem cell maintenance; Dada Pisconti, who explores the molecular mechanisms regulating muscle stem cell quiescence; Shahragim Tajbakhsh, who examines the dynamics of muscle stem cells and niche cells in developmental and regenerative myogenesis; and Saverio Tedesco, who studies skeletal muscle regeneration and develops novel therapies for neuromuscular disorders. The document also includes information about the research backgrounds and expertise of each lecturer. [Extracted from the article]

Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti‐inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight‐week‐old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF‐κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF‐κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the RBCK1 gene. Methods: The clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. Results: Through whole‐exome sequencing, we found that there were c.919G>T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the RBCK1 gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with RBCK1 gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases. Conclusions: The patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the RBCK1 gene were discovered through whole‐exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole‐exome sequencing technology in disease diagnosis and genetic counseling was emphasized. [ABSTRACT FROM AUTHOR]