Mutational spectrum and genotype-phenotype correlation in Mexican patients with infantile-onset and late-onset Pompe disease.

BACKGROUND: Pompe Disease (PD) is a metabolic myopathy caused by variants in the GAA gene, resulting in deficient enzymatic activity. We aimed to characterize the clinical features and related genetic variants in a series of Mexican patients. METHODS: We performed a retrospective study of clinical records of patients diagnosed with LOPD, IOPD or pseudodeficiency. RESULTS: Twenty-nine patients were included in the study, comprising these three forms. Overall, age of symptom onset was 0.1 to 43 years old. The most frequent variant identified was c.-32-13T>G, which was detected in 14 alleles. Among the 23 different variants identified in the GAA gene, 14 were classified as pathogenic, 5 were likely pathogenic, and 1 was a variant of uncertain significance. Two variants were inherited in cis arrangement and 2 were pseudodeficiency-related benign alleles. We identified two novel variants (c.1615 G>A and c.1076-20_1076-4delAAGTCGGCGTTGGCCTG). CONCLUSION: To the best of our knowledge, this series represent the largest phenotypic and genotypic characterization of patients with PD in Mexico. Patients within our series exhibited a combination of LOPD and IOPD associated variants, which may be related to genetic diversity within Mexican population. Further population-wide studies are required to better characterize the incidence of this disease in Mexican population.

Characterisation of phenotypic patterns in equine exercise-associated myopathies.

BACKGROUND: Equine exercise-associated myopathies are prevalent, clinically heterogeneous, generally idiopathic disorders characterised by episodes of myofibre damage that occur in association with exercise. Episodes are intermittent and vary within and between affected horses and across breeds. The aetiopathogenesis is often unclear; there might be multiple causes. Poor phenotypic characterisation hinders genetic and other disease analyses. OBJECTIVES: The aim of this study was to characterise phenotypic patterns across exercise-associated myopathies in horses. STUDY DESIGN: Historical cross-sectional study, with subsequent masked case-control validation study. METHODS: Historical clinical and histological features from muscle samples (n = 109) were used for k-means clustering and validated using principal components analysis and hierarchical clustering. For further validation, a blinded histological study (69 horses) was conducted comparing two phenotypic groups with selected controls and horses with histopathological features characterised by myofibrillar disruption. RESULTS: We identified two distinct broad phenotypes: a non-classic exercise-associated myopathy syndrome (EAMS) subtype was associated with practitioner-described signs of apparent muscle pain (p < 0.001), reluctance to move (10.85, p = 0.001), abnormal gait (p < 0.001), ataxia (p = 0.001) and paresis (p = 0.001); while a non-specific classic RER subtype was not uniquely associated with any particular variables. No histological differences were identified between subtypes in the validation study, and no identifying histopathological features for other equine myopathies identified in either subtype. MAIN LIMITATIONS: Lack of an independent validation population; small sample size of smaller identified subtypes; lack of positive control myofibrillar myopathy cases; case descriptions derived from multiple independent and unblinded practitioners. CONCLUSIONS: This is the first study using computational clustering methods to identify phenotypic patterns in equine exercise-associated myopathies, and suggests that differences in patterns of presenting clinical signs support multiple disease subtypes, with EAMS a novel subtype not previously described. Routine muscle histopathology was not helpful in sub-categorising the phenotypes in our population.

CONTEXTE: Les myopathies induites à l'exercice demeurent fréquentes, hétérogènes cliniquement et représentent des désordres idiopathiques caractérisés par des épisodes de dommages myofibrillaires en lien avec l'exercice. Les épisodes sont intermittents et varient à la fois chez le même cheval, entre chevaux et entre les différentes races. L'étiopathogénie demeure obscure et pourrait être multifactorielle. La pauvre caractérisation phénotypique des myopathies ne simplifie pas les analyses génétiques ni celles d'autres maladies. OBJECTIFS: Le but de cette étude est de caractériser les patrons phénotypiques en lien avec les myopathies induites à l'exercice chez le cheval. TYPE D'ÉTUDE: Étude transversale historique et étude subséquente de validation de cas témoins aveugle. MÉTHODES: Les facteurs clés cliniques et histologiques provenant d'échantillons de muscles (n = 109) ont été utilisés pour l'algorithme de K­moyennes et validés par le biais d'analyse des composantes principales et de classification hiérarchique. Pour validation additionnelle, une étude histologique à l'aveugle (69 chevaux) a été faite comparant les deux groupes phénotypiques avec des contrôles sélectionnés et des chevaux avec éléments histopathologiques caractérisés par de la discontinuité myofibrillaire. RÉSULTATS: Deux phénotypes distincts ont été identifiés: un premier sous­type de syndrome de myopathie induite à l'exercice non­classique (EAMS) associé à de la douleur musculaire telle que décrite par le praticien suivant le cheval (χ2 (df=1,n=109) = 19.33, p < 0.001), difficulté à se déplacer (χ2 (df=1,n=109) = 10.85, p = 0.001), démarche anormale (χ2 (df=1,n=109) = 34.61, p < 0.001), ataxie (χ2 (df=1,n=109) = 10.88, p = 0.001) et parésie (χ2 (df=1,n=109) = 10.88, p = 0.001); alors qu'un sous­type RER classique non­spécifique n'était associé à aucune variable en particulier. Aucune différente histologique n'a été identifié entre les sous­types dans l'étude de validation et aucune caractéristique histopathologique d'autres myopathies équines n'a été identifiées dans les différents sous­types. LIMITES PRINCIPALES: Aucune population indépendante pour validation; petite taille d'échantillon pour les sous­types peu nombreux identifiés; aucun cas contrôles positifs de myopathie fibrillaire; description des cas provenant de multiples praticiens indépendants et non­aveugles. CONCLUSION: Cette étude est la première utilisant des méthodes de regroupement informatique pour identifier des patrons phénotypiques de myopathies équines induites à l'exercice et suggère que des différences existent dans les patrons de signes cliniques en faveur de multiples sous­types de maladie, incluant EAMS qui représente un nouveau sous­type non décrit jusqu'à maintenant. L'histopathologie musculaire de routine n'a pas permis de sous­catégoriser les phénotypes dans cette population.

A protocol for scoping reviews on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies.

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

Phenotype-Genotype Correlation of a Cohort of Patients with Congenital Myopathy: A Single Centre Experience from India.

Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking. Objectives: This study aims to describe the clinical and histopathological characteristics of a cohort of genetically confirmed CMs from India and attempts to do phenotype-genotype correlation. Methods: A retrospective chart review of genetically confirmed CMs was evaluated between January 2016 and December 2020 at the neuromuscular clinic. The clinical, genetic, and follow-up data were recorded in a pre-structured proforma as per the medical records, and the data was analyzed. Results: A total of 31(M: F = 14 : 17) unrelated patients were included. The median age at onset and duration of illness are 2.0(IQR:1-8) years and 6.0(IQR:3-10) years respectively. Clinical features observed were proximodistal weakness (54.8%), facial weakness (64.5%), and myopathic facies (54.8%), followed by ptosis (33.3%), and ophthalmoplegia (19.4%). Muscle histopathology was available in 38.7% of patients, and centronuclear myopathy was the most common histopathology finding. The pathogenic genetic variants were identified in RYR1 (29.0%), DNM2 (19.4%), SELENON (12.9%), KBTBD13 (9.7%), NEB (6.5%), and MYPN (6.5%) genes. Novel mutations were observed in 30.3% of the cohort. Follow-up details were available in 77.4% of children, and the median duration of follow-up and age at last follow-up was 4.5 (Range 0.5-11) years and 13 (Range 3-35) years, respectively. The majority were ambulant with minimal assistance at the last follow-up. Mortality was noted in 8.3% due to respiratory failure in Centronuclear myopathy 1 and congenital myopathy 3 with rigid spines (SELENON). Conclusion: This study highlights the various phenotypes and patterns of genetic mutations in a cohort of pediatric patients with congenital myopathy from India. Centronuclear myopathy was the most common histological classification and the mutations in RYR1 followed by DNM2 gene were the common pathogenic variants identified. The majority were independent in their activities of daily living during the last follow-up, highlighting the fact that the disease has slow progression irrespective of the genotype.

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

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.

A novel mutation alters GNE bifunctional enzyme activity and leads to familial inherited GNE diseases.

Distal myopathies are a group of rare heterogeneous diseases that are mostly caused by genetic factors. At least 20 genes have been associated with distal myopathies. We performed whole-exome sequencing to identify the genetic cause of disease in a family with distal myopathy. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we analyzed the sequencing results and screened suspicious mutations based on mutation frequency, functional impact, and disease inheritance pattern. The harmfulness of the mutations was predicted using bioinformatics methods, and the pathogenic mutations were determined. We identified a novel amino acid mutation (NP_005467.1:p.S663L) on the GNE gene that may cause familial distal myopathy. This mutation is the result of the simultaneous mutation of two adjacent nucleotides (c.1988C > T, c.1989C > A) in the codon. First, we measured the mRNA and protein expression of the GNE gene in the lymphoblastoid cell lines (LCLs) of the probands and their family members. Second, GNE vectors carrying the novel mutation, two other known pathogenic mutations, and the wild-type gene were constructed and transfected into HEK293T cells. The enzymatic activity of these GNE variants was investigated and showed that the p.S663L mutation significantly reduced the activity of the bifunctional GNE enzyme without altering the expression level of the GNE protein. Furthermore, the mutation may also alter the immunogenicity of the 3' end of the GNE protein, potentially affecting its oligomer formation. In this study, a novel GNE gene mutation that may cause distal myopathy was identified, expanding the spectrum of genetic mutations associated with this disease.

Neonatal X-linked myotubular myopathy with a de novo mutation: A case report and literature review. / æ–°å‘çªå˜åŸºå› çš„æ–°ç”Ÿå„¿X-è¿žé”è‚Œå°ç®¡è‚Œç— 1例并文献回顾.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy. In February 2021, a male neonate was admitted to the West China Second University Hospital, Sichuan University, with clinical manifestations of hypotonia, accompanied by distinctive facial features, and requiring continuous ventilatory support. He was born prematurely at 36+2 weeks gestation and developed respiratory distress postnatally, followed by difficulty in weaning from mechanical ventilation. Additional clinical features included hypotonia of the limbs, swallowing dysfunction, and specific facial characteristics (elongated limbs, narrow face, high-arched palate, wrist drop, empty scrotum, elongated fingers/toes). Genetic testing confirmed the diagnosis of XLMTM. Whole-exome sequencing analysis of the family revealed no mutations in the father, paternal grandfather, or paternal grandmother, while the mother had a heterozygous mutation. The pathogenic mutation was identified as MTM1 gene (OMIM: 300415), chromosome position chrX-150649714, with a nucleotide change of c.868-2A>C. The patient exhibited typical facial features. Genetic testing is crucial for accurate diagnosis of XLMTM in infants presenting with abnormal muscle tone and distinctive facial features.

Hydroxychloroquine-induced generalized myopathy in a patient with lupus tumidus: a case report.

A subtype of cutaneous lupus erythematosus known as lupus erythematosus tumidus (LET) is characterized by sun-exposed areas that typically display urticaria-like papules and plaques. For LET, systemic therapy with antimalarials - particularly hydroxychloroquine (HCQ) - is the first line of treatment. Even though the safety profile of these medications appears to be high, there have been very few reports of side effects in the literature, including hemolytic anemia, retinal toxicity, maculopapular rash, gastrointestinal disturbance, and blue-gray discoloration of the skin or mucous membranes. Here, we report a unique instance of a 46-year-old LET smoker who, following HCQ treatment, developed a generalized myopathy.

Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort.

BACKGROUND AND PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on MADD that describes the phenotypic and genetic features of a Malaysian cohort. METHODS: Among the >2,500 patients in a local muscle biopsy database, patients with LSM were identified and their genomic DNA were extracted from muscle samples and peripheral blood. All 13 exons of the electron-transfer flavoprotein dehydrogenase gene (ETFDH) were subsequently sequenced. Fifty controls were included to determine the prevalence of identified mutations in the normal population. RESULTS: Fourteen (82%) of the 17 LSM patients had MADD with ETFDH mutations. Twelve (86%) were Chinese and two were Malay sisters. Other unrelated patients reported that they had no relevant family history. Nine (64%) were females. The median age at onset was 18.5 years (interquartile range=16-37 years). All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. Three patients experienced a metabolic crisis at their presentation. Sanger sequencing of ETFDH revealed nine different variants/mutations, one of which was novel: c.998A>G (p.Y333C) in exon 9. Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China. All of the patients responded well to riboflavin therapy. CONCLUSIONS: Most of our Malaysian cohort with LSM had late-onset, riboflavin-responsive MADD with ETFDH mutations, and they demonstrated phenotypic and genetic features similar to those of cases reported in southern China. Furthermore, we report a novel ETFDH mutation and possibly the first ever MADD patients of Malay descent.

Intensive care unit-acquired weakness and mechanical ventilation: A reciprocal relationship.

Intensive care unit-acquired weakness (ICU-AW; ICD-10 Code: G72.81) is a syndrome of generalized weakness described as clinically detectable weakness in critically ill patients with no other credible cause. The risk factors for ICU-AW include hyperglycemia, parenteral nutrition, vasoactive drugs, neuromuscular blocking agents, corticosteroids, sedatives, some antibiotics, immobilization, the disease severity, septicemia and systemic inflammatory response syndrome, multiorgan failure, prolonged mechanical ventilation (MV), high lactate levels, older age, female sex, and pre-existing systemic morbidities. There is a definite association between the duration of ICU stay and MV with ICU-AW. However, the interpretation that these are modifiable risk factors influencing ICU-AW, appears to be flawed, because the relationship between longer ICU stays and MV with ICU-AW is reciprocal and cannot yield clinically meaningful strategies for the prevention of ICU-AW. Prevention strategies must be based on other risk factors. Large multicentric randomized controlled trials as well as meta-analysis of such studies can be a more useful approach towards determining the influence of these risk factors on the occurrence of ICU-AW in different populations.

Diffuse Large B-cell Lymphoma Complicated with Anti-3-hydroxy-3-methylglutaryl-Coenzyme A Reductase Immune-mediated Necrotizing Myopathy: A Case Report.

A 75-year-old woman presented with significant muscle weakness after statin use. A muscle biopsy revealed necrotizing myopathy, and the patient tested positive for serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, leading to a diagnosis of anti-HMGCR immune-mediated necrotizing myopathy (IMNM). Computed tomography revealed intraperitoneal lymphadenopathy, which was diagnosed as a diffuse large B-cell lymphoma. Immunostaining confirmed HMGCR expression in the lymphoma cells. The patient received chemotherapy and achieved complete remission of the lymphoma, along with nearly complete recovery from IMNM. Although the etiologies of IMNM and lymphoma remain unclear, HMGCR expression in lymphoma cells is likely to be associated with the development of IMNM.

Intensive care unit-acquired weakness - preventive, and therapeutic aspects; future directions and special focus on lung transplantation.

In this editorial, comments are made on an interesting article in the recent issue of the World Journal of Clinical Cases by Wang and Long. The authors describe the use of neural network model to identify risk factors for the development of intensive care unit (ICU)-acquired weakness. This condition has now become common with an increasing number of patients treated in ICUs and continues to be a source of morbidity and mortality. Despite identification of certain risk factors and corrective measures thereof, lacunae still exist in our understanding of this clinical entity. Numerous possible pathogenetic mechanisms at a molecular level have been described and these continue to be increasing. The amount of retrievable data for analysis from the ICU patients for study can be huge and enormous. Machine learning techniques to identify patterns in vast amounts of data are well known and may well provide pointers to bridge the knowledge gap in this condition. This editorial discusses the current knowledge of the condition including pathogenesis, diagnosis, risk factors, preventive measures, and therapy. Furthermore, it looks specifically at ICU acquired weakness in recipients of lung transplantation, because - unlike other solid organ transplants- muscular strength plays a vital role in the preservation and survival of the transplanted lung. Lungs differ from other solid organ transplants in that the proper function of the allograft is dependent on muscle function. Muscular weakness especially diaphragmatic weakness may lead to prolonged ventilation which has deleterious effects on the transplanted lung - ranging from ventilator associated pneumonia to bronchial anastomotic complications due to prolonged positive pressure on the anastomosis.

Uncovering the BIN1-SH3 interactome underpinning centronuclear myopathy.

Truncation of the protein-protein interaction SH3 domain of the membrane remodeling Bridging Integrator 1 (BIN1, Amphiphysin 2) protein leads to centronuclear myopathy. Here, we assessed the impact of a set of naturally observed, previously uncharacterized BIN1 SH3 domain variants using conventional in vitro and cell-based assays monitoring the BIN1 interaction with dynamin 2 (DNM2) and identified potentially harmful ones that can be also tentatively connected to neuromuscular disorders. However, SH3 domains are typically promiscuous and it is expected that other, so far unknown partners of BIN1 exist besides DNM2, that also participate in the development of centronuclear myopathy. In order to shed light on these other relevant interaction partners and to get a holistic picture of the pathomechanism behind BIN1 SH3 domain variants, we used affinity interactomics. We identified hundreds of new BIN1 interaction partners proteome-wide, among which many appear to participate in cell division, suggesting a critical role of BIN1 in the regulation of mitosis. Finally, we show that the identified BIN1 mutations indeed cause proteome-wide affinity perturbation, signifying the importance of employing unbiased affinity interactomic approaches.

Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.

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.

Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases.

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.

STIM1: A new player in nuclear dynamics? Lessons learnt from tubular aggregate myopathy.

Two recent papers have highlighted that STIM1, a key component of Store-operated Ca2+-entry, is able to translocate to the nucleus and participate in nuclear Ca2+-handling and in DNA repair. These finding opens new avenues on the role that this Ca2+-sensing protein may have in health and disease.

Clinicopathological Profile of Muscle Diseases Presenting the Adult Population in Northern India: Preliminary Analysis in a Limited Resource Setting.

BACKGROUND: Muscle diseases are of various types, viz., muscular dystrophies, inflammatory myopathies, myotonic disorders, congenital myopathies, and metabolic myopathies. They all present with muscle weakness, be it proximal or distal. The assessment of muscle biopsy with the help of enzyme histochemistry, histopathological, and immunohistochemical methods is an essential component in the diagnosis of neuromuscular disorders. The authors outline brief data on muscle diseases prevalent in the North Indian region. METHODS: Muscle biopsy was done, and the biopsy was freshly frozen in liquid nitrogen and sections were taken on a cryostat. Slides were then stained with hematoxylin and eosin (H&E), modified Gomori trichome (MGT), nicotinamide adenine dinucleotide hydrogenase (NADH), and succinic dehydrogenase (SDH) stains. Further specific immunohistochemistry tests were also done. RESULT: Out of n=16 cases, three cases were diagnosed as Becker's muscular dystrophy, two cases were diagnosed as inflammatory myopathy, four cases were diagnosed as Facioscapulohumeral muscular dystrophy, and one each case of dysferlinopathy and alpha sarcoglycanopathy. CONCLUSION: Muscle diseases can cause different levels of physical disability and thus it is important to diagnose at the appropriate time to ensure proper treatment.

RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.

Pneumatosis Cystoides Intestinalis in Muscular Dystrophy and Congenital Myopathies: A Report of Five Cases.

Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.

Predictive risk factors for one-year mortality in idiopathic inflammatory myopathy patients with interstitial lung disease: A retrospective, single-center cohort study.

Objectives: This study aimed to analyze the risk factors for mortality of idiopathic inflammatory myopathy (IIM) patients admitted with interstitial lung disease (ILD) to guide rapid and accurate judgment of clinical prognosis. Patients and methods: This retrospective, single-center cohort study was conducted with 135 participants (37 males, 98 females; mean age: 54.8±11.1 years; range, 24 to 85 years) between June 1, 2016, and June 30, 2021. The participants were categorized into the survival group (n=111) and nonsurvivors (n=24) according to whether they survived during the one-year follow-up. The independent risk factors for mortality in one year after discharge were analyzed. Receiver operating characteristic curve analysis was used to determine the accuracy of oxygenation index at baseline combined with pulmonary infection (PI) at follow-up to indicate death in IIM-ILD patients. Results: Compared to the survival group, nonsurvivors were older (p=0.006) and had a higher proportion of anti-MDA5 (melanoma differentiation-associated protein 5) positivity (p<0.001). The ILD duration was shorter (p=0.006), the oxygenation index was lower (p<0.001), and the intensive care unit occupancy rate (p<0.001) and ventilator utilization rate (p<0.001) were elevated in nonsurvivors compared to the survival group. Oxygenation index at baseline (odds ratio [OR]=1.021, 95% confidence interval [CI]: 1.001-1.023, p=0.040) and PI (clinical judgment) at follow-up (OR=16.471, 95% CI: 1.565-173.365, p=0.020) were found as independent risk factors for death in the year after discharge in IIM inpatients with ILD. An oxygenation index ≤279 mmHg at baseline combined with PI at follow-up exhibited a promising predictive value for all-cause death in IIM-ILD patients within one year. Conclusion: Oxygenation index at baseline and PI during follow-up were independent risk factors for death of IIM-ILD patients within one year after discharge. Patients with an oxygenation index ≤279 mmHg at baseline had an increased risk of death once they developed PI during the one-year follow-up.