Muscle Weakness Research Articles

Anti-synthetase and myelodysplastic syndromes with deep morphea: an example of shared immunopathogenesis? A case-based review.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient.

Characterizing Mechanical Changes in the Biceps Brachii Muscle in Mild Facioscapulohumeral Muscular Dystrophy Using Shear Wave Elastography.

There is no general consensus on evaluating disease progression in facioscapulohumeral muscular dystrophy (FSHD). Recently, shear wave elastography (SWE) has been proposed as a noninvasive diagnostic tool to assess muscle stiffness in vivo. Therefore, this study aimed to characterize biceps brachii (BB) muscle mechanics in mild-FSHD patients using SWE. Eight patients with mild FSHD, the BB were assessed using SWE, surface electromyography (sEMG), elbow moment measurements during rest, maximum voluntary contraction (MVC), and isometric ramp contractions at 25%, 50%, and 75% MVC across five elbow positions (60°, 90°, 120°, 150°, and 180° flexion). The mean absolute percentage deviation (MAPD) was analyzed as a measure of force control during ramp contractions. The shear elastic modulus of the BB in FSHD patients increased from flexed to extended elbow positions (e.g., p < 0.001 at 25% MVC) and with increasing contraction intensity (e.g., p < 0.001 at 60°). MAPD was highly variable, indicating significant deviation from target values during ramp contractions. SWE in mild FSHD is influenced by contraction level and joint angle, similar to findings of previous studies in healthy subjects. Moreover, altered force control could relate to the subjective muscle weakness reported by patients with dystrophies.

Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease

Pompe disease (PD) is a rare autosomal recessive glycogen storage disorder that causes proximal muscle weakness and loss of respiratory function. While enzyme replacement therapy (ERT) is the only effective treatment, biomarkers for disease monitoring are scarce. Following ex vivo biomarker validation in phantom studies, we apply multispectral optoacoustic tomography (MSOT), a laser- and ultrasound-based non-invasive imaging approach, in a clinical trial (NCT05083806) to image the biceps muscles of 10 late-onset PD (LOPD) patients and 10 matched healthy controls. MSOT is compared with muscle magnetic resonance imaging (MRI), ultrasound, spirometry, muscle testing and quality of life scores. Next, results are validated in an independent LOPD patient cohort from a second clinical site. Our study demonstrates that MSOT enables imaging of subcellular disease pathology with increases in glycogen/water, collagen and lipid signals, providing higher sensitivity in detecting muscle degeneration than current methods. This translational approach suggests implementation in the complex care of these rare disease patients.

Case Analysis of Hypokalemia Induced by Irbesartan-Hydrochlorothiazide: A Case Study

Irbesartan-hydrochlorothiazide is a commonly used antihypertensive drug, but potential adverse reactions such as hypokalemia should not be overlooked. This study analyzes a case of hypokalemia induced by irbesartan-hydrochlorothiazide, exploring the drug’s association with hypokalemia and clinical treatment strategies. The patient experienced symptoms of muscle weakness and palpitations after taking irbesartan-hydrochlorothiazide and was diagnosed with hypokalemia through laboratory tests. Reviewing the patient’s medication history and disease progression, it was hypothesized that the drug’s potassium-wasting effect was the direct cause of the hypokalemia. After discontinuing the medication and initiating potassium supplementation, the patient’s potassium levels returned to normal, and symptoms significantly improved, further confirming the link between hypokalemia and the medication. This case suggests that clinicians should consider the risk of hypokalemia when treating hypertension, especially in patients with chronic kidney disease, the elderly, or those at risk for electrolyte disturbances. For patients who have already developed hypokalemia, potassium supplementation and adjustment of the treatment regimen are recommended to prevent further deterioration. Timely discontinuation of potential causative drugs is also advised. In summary, ensuring medication safety and preventing potential complications has significant clinical importance in recognizing and managing hypokalemia induced by irbesartan-hydrochlorothiazide. Future research should focus on optimizing treatment protocols and developing more effective strategies for preventing and managing related adverse reactions to improve patient quality of life.

Evaluation of fatigue and fatigability in people with Duchenne muscular dystrophy using a dynamic arm support – a pilot study

Background Due to progressive muscle wasting and weakness in patients with Duchenne Muscular Dystrophy (DMD), physical fatigability increases, upper extremity function reduces, which negatively impacts quality of life. Assistive technology such as dynamic arm supports (DAS) may help reduce this fatigability. This study aims to assess whether the novel Yumen ‘EXone’ DAS can reduce upper extremity fatigue and fatigability in DMD patients and healthy controls (HC), both with and without the DAS. Additionally, longitudinal changes in DMD patients were evaluated. Methods Five DMD patients from the Yumen Bionics pioneer program and five HCs participated. Two submaximal tests simulating drinking and reaching were performed for two minutes, each with and without DAS. DMD participants completed these tests twice, at baseline (T0) and after 6-9 months (T1), while HCs completed them once. Physical fatigability was measured by the number of repetitions and changes in surface electromyography (sEMG) amplitude. Subjective fatigue was assessed using the Borg Scale (6-20) Rate of Perceived Exertion (RPE). Results DMD participants generally performed more repetitions with the DAS than without. HCs showed similar or increased repetitions with the DAS. Assessing fatigability with sEMG was difficult due to the compensatory mechanisms used for the tests. Subjective fatigue scores on the Borg Scale were lower with the DAS for both DMD patients and HCs. Conclusion The Yumen ‘EXone’ DAS effectively reduces both fatigue and fatigability in DMD patients and healthy controls. Despite the methodological shortcomings, this research is one of the first studies investigating the impact of DAS on fatigue and fatigability.

Comparative Analysis of the Six-Strand Hamstring and Peroneus Longus in Sports Medicine and Rehabilitation

The anterior cruciate ligament (ACL) is crucial for knee stability and is often injured in sports, leading to significant issues like degenerative changes and meniscal tears. ACL tears are prevalent in high-school sports injuries, accounting for 50% of knee injuries in the U.S. Surgical reconstruction, often involving bone-patellar tendon-bone (BPTB) or hamstring autografts, is common, with varying success rates and complications. Emerging alternatives like the peroneus longus tendon show promise but require further comparative studies. This prospective and multicentric study included 110 patients who underwent ACL reconstruction from 2020 to 2022. Fifty-five patients received hamstring tendon autografts (Group H) and fifty-five received peroneus longus tendon autografts (Group P). Surgeries were performed by experienced surgeons using standardized techniques. Patients were evaluated using clinical tests and functional scores including the Lysholm Knee Questionnaire and IKDC-2000 at various postoperative intervals up to 24 months. Data were analyzed using SPSS with a significance level set at p &lt; 0.05. Group H showed superior knee function preoperatively and at 24 months postoperatively compared to Group P. Group H had higher Lysholm and IKDC scores consistently throughout the study period. The anterior drawer and Lachman’s tests indicated better knee stability for Group H. Complications were comparable between groups, with specific issues related to donor site morbidity and muscle weakness observed in each. The six-strand hamstring tendon autograft (Group H) demonstrated superior functional outcomes and knee stability compared to the peroneus longus tendon autograft (Group P) for ACL reconstruction. Despite some donor site morbidity, the hamstring tendon showed better long-term recovery and fewer complications. Future studies should explore larger, multicentric cohorts and integrate regenerative medicine techniques to further enhance ACL reconstruction outcomes.

Case report: Multi-antibody–positive myasthenia gravis concomitant myositis associated with thymoma

Myasthenia gravis (MG) and idiopathic inflammatory myopathy (IIM) are autoimmune diseases of the nervous system, and their main clinical manifestation is muscle weakness. The concurrent presence of both conditions in the same patient is clinically rare and easily missed. Here, we report the case of a 74-year-old woman who went to the doctor with fluctuating weakness of the limbs and muscle pain. By analyzing the patient’s history and the results of repeated frequency electrical stimulation, chest computed tomography, thigh muscle magnetic resonance imaging, serum antibody detection, lymph node biopsy, etc., she was finally diagnosed with MG-concomitant IIM with squamous cell carcinoma of the thymus. Acetylcholine receptor antibody, titin antibody, ryanodine receptor antibody, anti–JO-1 antibody, and Ro-52 antibody tests were positive. MG-concomitant IIM is often associated with thymoma. The immunopathology mechanism may be different from that of pure MG or IIM, which needs further research.

Factors correlating with positive electrodiagnostic findings for neurogenic thoracic outlet syndrome

IntroductionDiagnosis of neurogenic thoracic outlet syndrome (nTOS) remains a challenge. The role of electrodiagnostic studies (EDX) in the workup of nTOS remains controversial. The aim of this study was to report EDX findings in a cohort of patients undergoing surgery for nTOS and also analyse patient related and intraoperative factors associated with positive EDX findings supportive of a diagnosis of NTOS. MethodsBaseline characteristics of patients including age, sex, duration of symptoms, type of nTOS, and pattern of brachial plexus involvement were gathered and analysed. All patients received a preoperative EDX evaluation and were divided into two groups based on positive or negative EDX results for comparison. ResultsA total of 30 consecutive patients were included in this study comprising 11 (36.7%) male and 19 (63.3%) female patients, with a mean age of 44.6 ± 17.6 years. When classified by type of nTOS, 22 (73.3%) patients had type 1 nTOS with muscle weakness and atrophy, followed by 7 (23.4%) patients with type 3, and one (3.3%) patient with type 2 nTOS. In terms of the pattern of nTOS, 26 (86.7%) patients had lower plexus pattern of involvement (C8-T1), followed by 17 (56.7%) with upper-middle plexus pattern (C6-C7), and 13 (43.3%) with upper plexus pattern (C5-dorsal scapular nerve (DSN)). When comparing the characteristics of patients with positive and negative EDX findings suggestive of nTOS, only older age and type 1 nTOS (P<0.05) were significantly associated with positive EDX findings. ConclusionsEDX assessment, at this point in time, may not be the best modality for diagnosis of nTOS. Interindividual variation in findings reported by different clinicians performing the EDX remains a significant limiting factor. Older patients and those with more severe nTOS (type 1) are more likely to have positive results with EDX.

A novel variant of biallelic MME gene associated with autosomal recessive late-onset distal hereditary motor neuropathy in Chinese families

Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous diseases and previous studies have reported that the compound heterozygous recessive MME variants cause dHMN. Our study found a novel homozygous MME variant and a reported compound heterozygous MME variant in two Chinese families, respectively. Next-generation sequencing and nerve conduction studies were performed for two probands. The probands in two families presented with the muscle weakness and wasting of both lower limbs and carried a c.2122 A > T (p.K708*) and c.1342 C > T&c.2071_2072delinsTT (p.R448*&p.A691L) variant, respectively. Prominently axonal impairment of motor nerves and slight involvement of sensory nerves were observed in nerve conduction study. Our study reported a “novel” nonsense mutation and a missense variant of autosomal recessive late-onset dHMN and reviewed reported MME variants associated with dHMN phenotype.

Plasma metabolites associated with biopsychosocial parameters in overweight/obese women with severe knee osteoarthritis.

Obesity aligned with quadriceps muscle weakness contributes to the high incidence of knee osteoarthritis (KOA), which is prevalent in women. Although molecular signatures of KOA have been suggested, the association between biopsychosocial responses and the plasma metabolomic profile in overweight/ obese women with KOA remains in its early stages of investigation. This study aims to associate the plasma metabolome with biopsychosocial parameters of overweight/obese women diagnosed with KOA. Twenty-eight overweight/obese women (Control-n = 14; KOA-n = 14) underwent two visits to the laboratory. Functional tests and questionnaires assessing biopsychosocial parameters were administered during the first visit. After 48h, the participants returned to the laboratory for blood collection. Specific to the KOA condition, the Numerical Pain Rating Scale (NPRS), Tampa Scale for Kinesiophobia (TSK), and Knee injury and Osteoarthritis Outcome Score (KOOS) were applied. Thirteen molecules were different between groups, and four correlated with KOA's biopsychosocial parameters. DG 22:4-2OH and gamma-Glutamylvaline were inversely associated with KOSS leisure and TSK score, respectively. LysoPE 18:0 and LysoPE 20:5 were positively associated with KOSS symptoms and TSK score, respectively. While the correlations of LysoPE 18:0 and gamma-Glutamylvaline are supported by existing literature, this is not the case for DG 22:4-2OH and LysoPE 20:5. Further studies are recommended to better elucidate these correlations before dismissing their potential involvement in the biopsychosocial factors of the disease.

Characterization of Clinical Phenotypes in Congenital Myasthenic Syndrome Associated with the c.1327delG Frameshift Mutation in CHRNE Encoding the Acetylcholine Receptor Epsilon Subunit.

Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.

Progressive Acute Lower Extremity Ischemia Resulting From Cardiac Myxoma Embolization: A Case Report.

Cardiac myxomas are the most common primary benign tumors of the heart. The occlusion of peripheral arteries and complete obstruction of the abdominal aorta by a tumor embolus presents with distinct clinical manifestations. Herein, we present the case of a 38-year-old male with acute paresthesia, muscle weakness, erythematous, and violaceous changes in skin color localized to the dorsum of the left forefoot initially treated as cutaneous vasculitis. Further studies revealed the total occlusion of the terminal abdominal aorta by a saddle embolus from a cardiac myxoma. A multidisciplinary team consisting of cardiothoracic and vascular surgeons were involved in treating the patient, which resulted in full resolution of the case. This paper details the progression of acute bilateral limb ischemia to chronic limb threatening ischemia resulting from the total occlusion of the terminal abdominal aorta by a saddle embolus.

Charcot-Marie-Tooth type 2CC misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

GNE Myopathy: Genotype - Phenotype Correlation and Disease Progression in an Indian Cohort.

GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10-20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India. Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales - IBMFRS and MDFRS. 157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor's sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups. This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression.

Changes in Physiopathological Markers in Myotonic Dystrophy Type 1 Skeletal Muscle: A 3-Year Follow-up Study.

Myotonic dystrophy type 1 (DM1) is a slowly progressive disease caused by abnormal CTG repetitions on the dystrophia myotonica protein kinase (DMPK) gene. Long mRNA from CTG repetitions stabilizes in nuclear foci and sequester muscleblind-like splicing regulator 1 (MBNL1). Cardinal signs of DM1 include muscle wasting and weakness. The impacts of DM1 progression on skeletal muscle are under-researched. Identifying physiopathological markers related to maximal strength loss over time in DM1. Twenty-two individuals with DM1 participated in two maximal isometric muscle strength (MIMS) evaluations of their knee extensors and two vastus lateralis muscle biopsies, 3 years apart. Muscle fiber typing, size (including minimal Feret's diameter [MFD] and atrophy/hypertrophy factors [AF/HF]), and nuclear foci and MBNL1 colocalization (foci/MBNL1+) were evaluated. Immunoblotting was used to measure glycogen synthase kinase-3 beta (GSK3β), p62, LC3BI, LC3BII, and oxidative phosphorylation proteins. There are significant correlations between the fold changes of MIMS with type 1 fiber MFD (ρ= 0.483) and AF (ρ= -0.514). Regression analysis shows that baseline percentage of foci/MBNL1+ nuclei and strength training explain 44.1% of foci/MBNL1+ nuclei percentage variation over time. There are fair to excellent correlations between the fold changes of MIMS and GSK3β (ρ= 0.327), p62 (ρ= 0.473), LC3BI (ρ= 0.518), LC3BII (ρ= -0.391) and LC3BII/LC3BI (ρ= -0.773). Type 1 MFD decrease and AF increase are correlated with MIMS loss. There seems to be a plateau effect in foci/MBNL1+ nuclei accumulation and strength training helps decrease this accumulation. Autophagy marker LC3BII/LC3BI ratio has a good biomarker potential of MIMS loss, but more investigations are needed.

Cardiac Involvement in LAMA2-Related Muscular Dystrophy and SELENON-Related Congenital Myopathy: A Case Series.

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

Induced Muscle and Liver Absence of Gne in Postnatal Mice Does Not Result in Structural or Functional Muscle Impairment.

GNE Myopathy is a unique recessive neuromuscular disorder characterized by adult-onset, slowly progressive distal and proximal muscle weakness, caused by mutations in the GNE gene which is a key enzyme in the biosynthesis of sialic acid. To date, the precise pathophysiology of the disease is not well understood and no reliable animal model is available. Gne KO is embryonically lethal in mice. To gain insights into GNE function in muscle, we have generated an inducible muscle Gne KO mouse. To minimize the contribution of the liver to the availability of sialic acid to muscle via the serum, we have also induced combined Gne KO in liver and muscle. A mouse carrying loxp sequences flanking Gne exon3 was generated by Crispr/Cas9 and bred with a human skeletal actin (HSA) promoter driven CreERT mouse. Gne muscle knock out was induced by tamoxifen injection of the resulting homozygote GneloxpEx3loxp/HSA Cre mouse. Liver Gne KO was induced by systemic injection of AAV8 vectors carrying the Cre gene driven by the hepatic specific promoter of the thyroxine binding globulin gene. Characterization of these mice for a 12 months period showed no significant changes in their general behaviour, motor performance, muscle mass and structure in spite of a dramatic reduction in sialic acid content in both muscle and liver. We conclude that post weaning lack of Gne and sialic acid in muscle and liver have no pathologic effect in adult mice. These findings could reflect a strong interspecies versatility, but also raise questions about the loss of function hypothesis in Gne Myopathy. If these findings apply to humans they have a major impact on therapeutic strategies.

A case of postpartum dermatomyositis with onset at three months: expanding the clinical spectrum

Introduction and importance: Dermatomyositis (DM) is an autoimmune disorder affecting all age groups, with a higher prevalence in women. Diagnosis typically occurs around age 40. Manifestation can be acute or chronic. Diagnosis relies on clinical, laboratory, EMG, and histopathological tests. Limited information exists regarding DM’s occurrence during pregnancy and its connection to pregnancy. Case presentation: A 31-year-old, 3-month postpartum female presented with features of proximal muscle weakness and generalized erythematous itchy rash. The weakness was associated with muscle tenderness. Laboratory evaluation and skin biopsy revealed features consistent with Dermatomyositis. Pulmonary pathology and occult tumors were investigated. Symptoms gradually improved on steroids and azathioprine. Clinical discussion: The relationship between dermatomyositis and pregnancy remains poorly understood, with only a few documented cases highlighting the impact of pregnancy on the development and progression of the disease. From the available literature, it is evident that postpartum dermatomyositis is uncommon yet significant, necessitating careful attention during pregnancy to enhance outcomes for both the mother and the unborn child. Conclusion: Our experience highlights a rare case of postpartum dermatomyositis, with symptoms emerging three months after childbirth, differing from documented cases. More research is needed to understand pregnancy’s role in dermatomyositis development and improve treatment for pregnant women with autoimmune skin diseases.

GSDMD knockout alleviates sepsis-associated skeletal muscle atrophy by inhibiting IL18/AMPK signaling.

Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis. The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after CLP. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture (CLP). The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 hours after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 hours after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide (LPS) to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades. This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared to the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared to the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms (in vivo) and in laboratory conditions (in vitro) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway. The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the UPS and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.