Intramuscular Venous Malformation Associated with Muscle Herniation of the Left Masseter Muscle in a 12-Year-Old Boy.

BACKGROUND Muscle hernias are an uncommon condition typically found in the extremities; masseter muscle hernia is even rarer. However, it is important for clinicians and radiologists to be aware of this possibility. Intramuscular venous malformation (IMVM) is also uncommon and mostly found in the head, neck, and extremities. The simultaneous presence of both conditions is extraordinary uncommon, and, to our knowledge, this has not been reported before in the masseter muscle. Due to their rarity, vague presentation, and inaccurate clinical diagnosis, radiological evaluation is needed to avoid inappropriate surgical planning. CASE REPORT A 12-year-old boy had a long-standing focal left cheek swelling exacerbated by teeth clenching. Lateral X-ray revealed a round calcification over the left mandibular region. Ultrasonography indicated a bulky left masseter muscle with focal heterogeneous structure and 2 rounded calcified foci. During teeth clenching, ultrasonography detected focal muscular herniation through the left masseter muscle facia that reduced with rest. The patient was diagnosed with left masseteric muscle hernia coexistent with IMVM. Surgical excision of the IMVM was performed, and the hernia defect was repaired. Histopathology confirmed the diagnosis, and the patient was discharged without postoperative complications on short-term follow-up. CONCLUSIONS Despite their rarity, masseter hernias and IMVMs should be considered in the differential diagnosis of any masseter lesion, especially in children. We reported a very rare coexistence of both pathologies. Comprehensive diagnosis can be achieved through a combination of clinical examination, X-ray, and ultrasound assessments.

Association of anti-HMGCR antibodies of the IgM isotype with refractory immune-mediated necrotizing myopathy.

OBJECTIVE: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies are one of the myositis-specific antibodies which is associated with immune-mediated necrotizing myopathy (IMNM). However, the relationship between anti-HMGCR isotypes and prognosis has not yet been fully investigated. This study was conducted to gain insight into the association between anti-HMGCR isotypes and clinical, and prognosis in IMNM patients who were positive for anti-HMGCR antibodies. METHODS: Levels of anti-HMGCR isotypes (IgG, IgA and IgM) were assessed by enzyme-linked immunosorbent assay (ELISA) in 123 consecutive serum samples obtained from 71 patients who were positive for anti-HMGCR IgG at baseline. Disease activity was assessed by manual muscle testing (MMT) 8, Physician's Global Assessment (PGA) visual analog scale (VAS), and muscle VAS. RESULTS: Baseline anti-HMGCR IgG levels were correlated with PGA VAS (r = 0.24; p = 0.04), muscle VAS (r = 0.32; p < 0.01), and MMT8(r=-0.24; p = 0.04), and baseline anti-HMGCR IgM levels were positively correlated with PGA VAS (r = 0.27, p = 0.02), muscle VAS (r = 0.24, p = 0.04). Anti-HMGCR IgM positive patients had a lower age of onset [29(25,46) vs. 51(33,65), p = 0.006], and a higher proportion of neck weakness (63.5% vs. 34.6%, p = 0.031) compared with anti-HMGCR IgM negative patients. Longitudinal analysis showed that the changes in anti-HMGCR IgG levels were correlated with the changes in the PGA VAS (ß = 3.830; p < 0.0001), muscle VAS (ß = 2.893; p < 0.0001), MMT8 (ß=-19.368; p < 0.0001), and creatine kinase (CK) levels (ß = 3900.05, p < 0.0001). Anti-HMGCR IgM levels were weakly correlated with anti-HMGCR IgA levels at baseline (r = 0.33, p < 0.01), and the variations in anti-HMGCR IgA levels were correlated with the changes in anti-HMGCR IgM levels during follow-up (ß = 0.885; p < 0.0001). There were more patients with anti-HMGCR IgM who showed a refractory course than those who were with anti-HMGCR IgM negative (polycyclic course: 40% vs. 25%; chronic continuous course: 46.7% vs. 20.5%, p = 0.018). CONCLUSION: In anti-HMGCR IgG-positive IMNM patients, the levels of anti-HMGCR IgG are associated with disease activity, and anti-HMGCR IgM is associated with refractory outcome and poor prognosis.

CCDC78: Unveiling the Function of a Novel Gene Associated with Hereditary Myopathy.

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

An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species.

Current adeno-associated virus (AAV) gene therapy using nature-derived AAVs is limited by non-optimal tissue targeting. In the treatment of muscular diseases (MD), high doses are often required but can lead to severe adverse effects. Here, we rationally design an AAV capsid that specifically targets skeletal muscle to lower treatment doses. We computationally integrate binding motifs of human integrin alphaV beta6, a skeletal muscle receptor, into a liver-detargeting capsid. Designed AAVs show higher productivity and superior muscle transduction compared to their parent. One variant, LICA1, demonstrates comparable muscle transduction to other myotropic AAVs with reduced liver targeting. LICA1's myotropic properties are observed across species, including non-human primate. Consequently, LICA1, but not AAV9, effectively delivers therapeutic transgenes and improved muscle functionality in two mouse MD models (male mice) at a low dose (5E12 vg/kg). These results underline the potential of our design method for AAV engineering and LICA1 variant for MD gene therapy.

Incorporating Next-Generation Sequencing as a Second-Tier Test for Primary Carnitine Deficiency.

BACKGROUND: Newborn screening (NBS) for primary carnitine deficiency (PCD) has poor performance. This study aimed to evaluate the feasibility of incorporating next-generation sequencing (NGS) as a second-tier PCD test. METHODS: Between March and December 2020, 60,070 newborns were screened for inherited metabolic disorders. Newborns with free carnitine (C0) levels below 8.5 µmol/L were selected for second-tier genetic testing. RESULTS: In total, 130 (0.22%) newborns with low C0 levels underwent second-tier genetic testing, 87 (66.92%) had positive genetic testing results, and 30 (23.08%) carried pathogenic variants of the SLC22A5 gene. Six newborns were diagnosed with PCD. The incidence of PCD was approximately 1 in 1:10,012 newborns. The PPV reached 20% after combining with second-tier NGS. Of the eight variants identified in patients with PCD, the three most common variants were c.760C>T (p.Arg254*), c.51C>G (p.Phe17Leu), and c.1400C>G (p.Ser467Cys). The C0 levels of patients with PCD were significantly lower than those of PCD carriers (p = 0.0026) and PCD-negative individuals (p = 0.0005). CONCLUSIONS: Our results showed that the PPV reached 20% after combining with second-tier NGS. The MS/MS-based NBS and second-tier NGS combination can effectively reduce the false-positive rate and detect PCD in patients.

Statin-Induced Autoimmune Myopathy: A Diagnostic Challenge in Muscle Weakness.

BACKGROUND Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. Muscle-related adverse effects of statins have been very challenging in clinical practice and they necessitate high clinical suspicion. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. CASE REPORT We present a 69-year-old man with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months, with a creatinine kinase of 8323 U/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, he did not show significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A reductase antibody was ordered and he was started on IV steroids. Anti-HMG Co-A reductase antibody was positive, and the rest of myopathy workup was negative. Meanwhile, the patient's muscle weakness significantly improved with IV steroid. He was discharged on methylprednisolone with close outpatient rheumatology follow-up. CONCLUSIONS Muscle-related adverse effects of statins, including rhabdomyolysis and myopathy, can fail to respond to conservative management. It is crucial to identify and manage statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness and elevated CK while on statin therapy who do not respond to intravenous fluid alone.

Clinical and genetic evaluation of hereditary myopathies in an adult Saudi cohort.

BACKGROUND: Diagnosis of hereditary myopathy is often challenging owing to overlapping clinical phenotypes and muscle histopathological findings. This retrospective study aimed to identify the phenotypic and genotypic spectra of hereditary myopathies at a tertiary hospital in Riyadh, Saudi Arabia. METHODS: We reviewed the medical records of patients with hereditary myopathy who were evaluated between January 2018 and December 2022. RESULTS: Eighty-seven patients (78 families) were included, two-thirds were men with a mean age of 35 (SD 14.2) years. Limb-girdle muscular dystrophy (LGMD) was the most prevalent clinical diagnosis (25 cases; 29%), of whom, a genetic diagnosis was achieved in 15 of 22 patients tested (68%). In genetically confirmed LGMD, the most prevalent disorders were dysferlinopathy (27%) followed by fukutin-related protein (FKRP) - related limb girdle muscular dystrophy (20%), sarcoglycanopathy (20%), lamin A/C related myopathy (13%), and calpain-3 myopathy (13%). In 26 patients with pathogenic/likely pathogenic variants, the genetic testing method was whole exome sequencing (WES) (42%), Next generation sequencing (NGS) (31%), and targeted single gene analysis (27%). The sensitivity of each genetic testing method was as follows: 100% for targeted single-gene analysis, 100% for targeted analysis of D4Z4 repeat array units, 88% for myotonic dystrophy protein kinase (DMPK) repeat expansion analysis, 42% for NGS-neuromuscular panel, and 46% for WES. CONCLUSION: The prevalent types of hereditary myopathies were consistent with those reported locally and internationally. This study highlights the diagnostic yield of various molecular genetic tests for the diagnosis of hereditary myopathy in an adult cohort and the need for improved access to advanced molecular testing in cases suspected to have facioscapulohumeral muscular dystrophy (FSHD) or mitochondrial myopathies.

Role of mesenchymal stem cells in sepsis and their therapeutic potential in sepsis­associated myopathy (Review).

Sepsis­induced myopathy (SIM) is one of the leading causes of death in critically ill patients. SIM mainly involves the respiratory and skeletal muscles of patients, resulting in an increased risk of lung infection, aggravated respiratory failure, and prolonged mechanical ventilation and hospital stay. SIM is also an independent risk factor associated with increased mortality in critically ill patients. At present, no effective treatment for SIM has yet been established. However, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach and have been utilized in the treatment of various clinical conditions. A significant body of basic and clinical research supports the efficacy of MSCs in managing sepsis and muscle­related diseases. This literature review aims to explore the relationship between MSCs and sepsis, as well as their impact on skeletal muscle­associated diseases. Additionally, the present review discusses the potential mechanisms and therapeutic benefits of MSCs in the context of SIM.

Congenital myopathies: pathophysiological mechanisms and promising therapies.

Congenital myopathies (CMs) are a kind of non-progressive or slow-progressive muscle diseases caused by genetic mutations, which are currently defined and categorized mainly according to their clinicopathological features. CMs exhibit pleiotropy and genetic heterogeneity. Currently, supportive treatment and pharmacological remission are the mainstay of treatment, with no cure available. Some adeno-associated viruses show promising prospects in the treatment of MTM1 and BIN1-associated myopathies; however, such gene-level therapeutic interventions target only specific mutation types and are not generalizable. Thus, it is particularly crucial to identify the specific causative genes. Here, we outline the pathogenic mechanisms based on the classification of causative genes: excitation-contraction coupling and triadic assembly (RYR1, MTM1, DNM2, BIN1), actin-myosin interaction and production of myofibril forces (NEB, ACTA1, TNNT1, TPM2, TPM3), as well as other biological processes. Furthermore, we provide a comprehensive overview of recent therapeutic advancements and potential treatment modalities of CMs. Despite ongoing research endeavors, targeted strategies and collaboration are imperative to address diagnostic uncertainties and explore potential treatments.

A case report on congenital hypothyroidism and alpha thalassemia in children with anemia and muscle damage as the main manifestation.

RATIONALE: This study reports the first case of congenital hypothyroidism (CH) and alpha thalassemia in a child in China, with anemia and muscle damage as the main manifestations. Analyzing and studying this case is of great significance in reducing missed and misdiagnosed CH and will provide a clinical strategy for treating these patients. PATIENT CONCERNS: Child, female, 2 years and 7 months old, the child appeared dispirited, had poor appetite, shallow complexion, reduced activities with anemia, elevated muscle enzymes, height, and growth retardation. DIAGNOSES: The child was diagnosed with CH with alpha thalassemia. INTERVENTIONS: The patient was treated with levothyroxine sodium and anemia correction. OUTCOMES: The children's current spirit, appetite, red face, normal limb activity, physical development, and intelligence were significantly better than those of normal children of the same age. CONCLUSIONS: CH with alpha thalassemia, especially anemia and muscle damage as the main manifestations, has not been reported. Administration of levothyroxine sodium is effective in correcting anemia in patients with CH and alpha thalassemia. LESSON: Due to CH and alpha thalassemia, there are no specific symptoms and they are prone to missed diagnosis and misdiagnosis. Therefore, patients with anemia and elevated muscle enzyme levels should be routinely tested for thyroid function to diagnose them early and provide proper treatment to avoid negative consequences.

Secondary mitochondrial dysfunction across the spectrum of hereditary and acquired muscle disorders.

Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenosine triphosphate (ATP) through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function.

Management of calcific myonecrosis using vacuum sealing drainage: A rare case report and 5-year follow-up.

 Calcific myonecrosis (CM), a rare post-traumatic sequel of the lower limb, is characterized by calcified lesions. A diagnosis of CM can be difficult owing to the longtime span from the emergence of the original trauma to the onset of the symptoms of CM. This case report aimed to feature a case of a 55-year-old gentleman who presented with a progressive painful swelling in the anterolateral aspect of the right lower leg with the initial trauma arising 11 years ago. In the conservative treatment, a fluid-filled mass was formed. The histological examination of the biopsy suggested a diagnosis of CM. The patient underwent a complete debridement operation, after which vacuum sealing drainage was used to manage the space left. Three weeks later, direct wound closure was achieved. Five-year follow-ups showed an excellent outcome without recurrence. Complete surgical debridement combined with primary closure is recommended to manage CM. Cite this article as: Wang C, Hao D, Wang S. Management of calcific myonecrosis using vacuum sealing drainage: A rare case report and 5-year follow-up. Acta Orthop Traumatol Turc., 2024;58(2):135-139.

Levothyroxine sodium tablets reversed Hashimoto thyroiditis-induced kidney injury, muscle injury, and lipid metabolism disorder: A case report and literature review.

RATIONALE: Hashimoto thyroiditis (HT), a common cause of hypothyroidism, has shown an increasing incidence in recent years, particularly among women. In addition to the common complications such as lipid metabolism disorders, patients with HT may also experience some serious complications, acute kidney injury and severe muscle damage for instance. This article explored the effectiveness of levothyroxine sodium tablets (L-T4) replacement therapy in severe complications of hypothyroidism, including treatment dosage, duration of complication recovery, and whether additional treatment is needed. PATIENT CONCERNS, DIAGNOSES, AND INTERVENTIONS: We described a case of a 52-year-old woman with HT who exhibited kidney injury, muscle injury, and lipid metabolism disorders. The increased levels of serum creatinine, creatine kinase, cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and the decreased levels of estimated glomerular filtration rate were obviously observed. This patient was started on L-T4 (75 and 100 µg, alternate). OUTCOMES AND LESSONS: Following a two-month treatment, the serum creatine kinase level decreased to within normal range. The estimated glomerular filtration rate level was restored, and the serum creatinine level was down-regulated, although slightly higher than the normal range. L-T4 partially reversed HT-induced the disorders of muscle, renal function, and lipid profile of this patient and remarkably alleviated her HT-related symptoms.

Myostatin's marvels: From muscle regulator to diverse implications in health and disease.

Myostatin, a member of the transforming growth factor-ß superfamily, is a pivotal regulator of skeletal muscle growth in mammals. Its discovery has sparked significant interest due to its multifaceted roles in various physiological processes and its potential therapeutic implications. This review explores the diverse functions of myostatin in skeletal muscle development, maintenance and pathology. We delve into its regulatory mechanisms, including its interaction with other signalling pathways and its modulation by various factors such as microRNAs and mechanical loading. Furthermore, we discuss the therapeutic strategies aimed at targeting myostatin for the treatment of muscle-related disorders, including cachexia, muscular dystrophy and heart failure. Additionally, we examine the impact of myostatin deficiency on craniofacial morphology and bone development, shedding light on its broader implications beyond muscle biology. Through a comprehensive analysis of the literature, this review underscores the importance of further research into myostatin's intricate roles and therapeutic potential in human health and disease.

Intramuscular cysticercosis of the forearm mimicking a soft tissue tumour.

A man in his 20s presented with a painless, slow-growing firm swelling in the anterolateral aspect of his left forearm. The swelling had been present for 1 year and measured 10×12 cm. Clinically, a differential diagnosis of soft tissue sarcoma, lipoma, neurofibroma, dermoid cyst and hydatid cyst of the extremity was considered. MRI suggested a primary intramuscular hydatid cyst. However, fine-needle aspiration was inconclusive, and ELISA for immunoglobulin G antibodies to echinococcal antigen in serum was negative. A wide-local complete surgical excision of the lesion was planned. Intraoperatively, a well-defined, tense cystic swelling with surrounding dense adhesions was found within the intramuscular plane. Histopathological examination of the cyst wall revealed cysticercosis. The patient recovered uneventfully. This case highlights that solitary intramuscular cysticercosis, although rare, should be included in the differential diagnosis of an isolated soft tissue mass, particularly in endemic areas.

HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy.

HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.

18F-FDG PET/CT imaging and curative effect evaluation of multiple muscular tuberculosis.

Tuberculosis continues to be a significant global health concern, impacting various parts of the body aside from the lungs. Muscular tuberculosis (MT), while rare, poses diagnostic hurdles due to its nonspecific imaging features. Presenting a case of a 66-year-old man with multiple MT lesions, we underscore the vital contribution of positron emission tomography/computed tomography (PET/CT) in both diagnosis and treatment assessment. Fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT imaging revealed hypermetabolism in bilateral chest and back muscles, facilitating accurate diagnosis and monitoring treatment response. This highlights the pivotal role of 18F-FDG PET/CT in managing MT, especially in cases with multiple lesions.

Two PNPLA2 heterozygous mutations result in neutral lipid storage disease with myopathy: a case report.

BACKGROUND: Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients' attention due to the increased risk of cardiomyopathy. CASE PRESENTATION: We herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet. CONCLUSIONS: In conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

Diagnosing X-Linked Myopathy With Excessive Autophagy After 30 years: Genetic, Ultrasonographic, and Electrodiagnostic Findings.

ABSTRACT: X-linked myopathy with excessive autophagy is a rare disorder caused by a mutation in the vacuolar ATPase assembly factor gene which causes slowly progressive early onset proximal weakness and loss of ambulation by the age of 50-70 years. Electrodiagnostic (EDx) testing usually shows widespread complex repetitive and myotonic discharges, even in muscles unaffected clinically. We report a 65-year-old man who presented with progressive proximal weakness since his teenage years. Extensive workup over 30 years revealed inconclusive EDx and muscle histopathology findings. The diagnosis was finally made with genetic testing. Subsequent neuromuscular ultrasound was more informative of disease severity than repeat EDx and directed a muscle biopsy that showed an autophagic vacuolar myopathy and the novel identification of vacuoles in capillary endothelial cells. Although genetic testing is required for confirmation, in milder cases of X-linked myopathy with excessive autophagy, neuromuscular ultrasound may aid in diagnosis even when EDx findings are inconclusive.