Influence of a 12week at-home resistance exercise program on 13C-glucose metabolism in patients with metabolic myopathies.

First reported case of adult-onset very long-chain acyl-coa dehydrogenase (vlcad) deficiency in Vietnam: a rare metabolic myopathy

Background: Sarcopenic obesity (SO) is a metabolic myopathy characterized by the coexistence of obesity and decline of muscle mass and function. Obesity-related muscle atrophy represents a central pathological feature of this condition. Polygonati Rhizoma is widely used as a dietary herb with tonic effects in traditional Asian medicine. This study aims to investigate the effects and underlying molecular mechanisms of the water extract of Polygonati Rhizoma (WPR) on obesity-related muscle atrophy. Methods: The effects and potential mechanisms of WPR were explored using an obesity-induced muscle atrophy (OIMA) mouse model, palmitic acid (PA)- or lipopolysaccharide (LPS)-induced myotube atrophy models, and a myogenic differentiation model in C2C12 cells. Results: In OIMA mice, WPR attenuated obesity-related skeletal muscle atrophy and improved muscle strength and endurance. In the gastrocnemius muscle, WPR-treated mice showed lower levels of oxidative stress and inflammation, increased markers of mitochondrial biogenesis, and an improved balance between protein synthesis and degradation. In PA- or LPS-induced myotube atrophy models, WPR treatment suppressed the ubiquitin–proteasome system (UPS)-mediated proteolysis and NFκB/MAPK-related inflammatory signaling. In addition, WPR promoted myogenic differentiation in C2C12 myoblasts, which was associated with regulation of the p38 MAPK/MyoD/Myogenin axis. Conclusions: Our study suggests that WPR exerts a potential mitigating effect on obesity-related muscle atrophy, and this effect may be associated with the modulation of skeletal muscle inflammatory signaling, mitochondrial function, and protein metabolic balance. These findings are exploratory and provide mechanistic clues for future research aimed at developing potential intervention strategies for obesity-related muscle atrophy.

Biochemical and Histological assessments of Ursolic acid versus Nano-CoQ10 therapy in Metabolic Myopathy using Animal Model

Urinary glucose tetrasaccharide tracks disease activity in late-onset Pompe disease.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a hereditary disorder of mitochondrial long-chain fatty acid oxidation. It is a syndrome characterized by rhabdomyolysis, muscle necrosis, and release of intracellular muscle components into the circulation. A 29-year-old male patient with hypertension, arrhythmia, and preemptive renal transplantation history was admitted to our clinic with complaints of recurrent hematuria attacks, body pain, and dizziness. No erythrocytes were observed in the microscopic field of urine sediment. In genetic analysis, a homozygous mutation was detected in the ACADVL gene in the NM_000018.4 C.1500_1502del CCT p. L502del variation, and VLCAD deficiency was diagnosed. We planned to discuss the case with the literature in order to emphasize that metabolic myopathies should also be evaluated in the etiology of patients who develop acute renal failure presenting with recurrent non-traumatic exercise-associated rhabdomyolysis.

Skeletal muscle dysfunction is a major peripheral determinant of exercise intolerance and physical disability in heart failure with preserved ejection fraction (HFpEF). Metabolic and mitochondrial dysfunction are considered to be key components of skeletal muscle dysfunction, but comprehensive profiling of metabolic pathways has not been conducted. Elucidation of dysregulated metabolic pathways is essential to determine viable targets for the treatment of exercise intolerance in HFpEF. Male ZSF1 Obese rats (HFpEF) and Wistar Kyoto (WKY) lean normotensive controls were studied at 26 weeks of age. Gastrocnemius was subjected to bulk RNA-seq, proteomics, metabolomics, and lipidomics analysis. The R package limma was used to determine differential expression in all omics layers (absolute fold-change>1.5, FDR0.05, unless otherwise indicated). Additional targeted plasma and skeletal muscle (soleus and EDL) metabolomics and lipidomics were performed on HFpEF and control rats. Pathway level analysis for RNA seq and proteomics revealed significant downregulation of oxidative phosphorylation (NES -2.1, p<0.005), electron transport chain (NES -2.0, p<0.005), and TCA cycle (-1.8, p<0.05). The most upregulated pathways were PPAR signaling (NES 2.2, p<0.0001), tryptophan metabolism (NES 1.8, P<0.005), and amino acid oxidation (NES 1.8, p<0.005) pathways. Metabolomics revealed an accumulation of TCA cycle intermediate, isocitrate, and phosphate reduction. Branched-chain amino acids were significantly increased, whereas amino acids related to tryptophan metabolism were reduced and shifted towards increased serotonin accumulation. Phospholipid species were differentially regulated with increased palmitoylated phosphatidylcholines but reduced arachidonoyl-PC species. Phosphatidylethanolamines (PE) species (16:0/16:1-18:0/18:2) were increased. Our multiomics analysis of skeletal muscle in HFpEF revealed severe mitochondrial dysfunction that was characterized by reduced complex I and II activity. Mitochondrial and peroxisomal lipid overload results in a shift in membrane phospholipid accumulation and composition. Reduced BCAA oxidation and dysregulation of tryptophan metabolism are key features of amino acid metabolism that reduce anaplerosis and promote the accumulation of toxic metabolites. Comparative analysis of other skeletal muscle disorders suggests that an acquired metabolic myopathy exists in cardiometabolic HFpEF.

Background/Objectives: Muscle biopsy is traditionally considered a cornerstone in the diagnosis of myopathies. Advances in the clinical and laboratory evaluation of myopathies warrant re-evaluation of the diagnostic yield. Methods: Results of muscle biopsies performed between 1 January 2009 and 31 January 2023 in patients with symptoms indicative of myopathy were evaluated and set in relation to clinical diagnosis, based on phenotype, electromyography, laboratory results, and available antibody testing. Biopsies were classified as diagnostic (changed or specified clinical diagnosis), confirmative (same as clinical diagnosis), or non-informative (normal/unspecific findings). Genetic testing followed muscle biopsy at later follow-up, upon availability of genetic testing. Results: One-hundred sixty-two patients were included and divided into five groups based on clinical phenotype: inflammatory myopathy, n = 54; mitochondrial myopathy, n = 33; muscular dystrophy, n = 23; metabolic myopathy, n = 3; and non-specific phenotype (isolated hyperCKemia/myalgia), n = 49. Muscle biopsy was diagnostic in 21.0%, confirmative in 38.3% and non-informative in 40.7% of patients. The percentage of diagnostic biopsies was 66.7% in metabolic myopathy, 54.5% in mitochondrial myopathy, 17.4% in muscular dystrophy, 14.8% in inflammatory myopathy, and 4.1% in the non-specific phenotype. Conclusions: Overall, in our cohort, muscle biopsy yielded a new diagnosis or additional information in 21.0% of patients. In the majority, a diagnosis was established based on clinical and laboratory evaluation, and muscle biopsy was either confirmative or non-informative. We propose muscle biopsy in cases where serological and genetic tests are inconclusive, in the presence of specific signs indicative of myopathy, or when in-tissue genetic testing is necessary to obtain a comprehensive diagnosis.

BackgroundLate-onset Pompe’s disease (LOPD) is a progressive treatable metabolic myopathy due to partial acid α-glucosidase (GAA) deficiency, with potential onset during the pediatric age. To date, Pompe’s disease is not widely included in newborn screening panels, so that clinical suspect remains essential for timely diagnosis and management. Clinical identification of LOPD was shown to be challenging in adult patients, whereas data in children and adolescents are scanty. We conducted an Italian nationwide multicentric survey in order to delineate the characteristics of LOPD in the pediatric population. This prompted us to propose a diagnostic algorithm to facilitate the identification of LOPD in pediatrics.ResultsThe survey provided information on 38 Italian pediatric patients with a definite biochemical and molecular diagnosis of LOPD firstly suspected based on clinical approach. Nineteen patients (50%) reached medical attention because of clinical symptoms of LOPD (79% within 3 years of age; 21% at 3–18 years of age) and 19 (50%) because of incidental finding of asymptomatic hyperCKemia. All the 38 LOPD patients showed hyperCKemia (56%: range 500–1000 U/l; 18%; range 250–500 U/l; 18% range 1000–2000 U/l; 8% >2000 U/l), almost invariably accompained by concomitant hypertransaminasemia (91%). Main clinical symptoms before 3 years of age were inability to (1) sit at 8 months, (2) walk indipendently at 18 months, and (3) climb stairs at 30 months. Later pediatric presentations (3–18 years of age) were limitation to (1) get up from supine position, (2) perform sport activity, and (3) run. In symptomatic patients, diagnostic latency (i.e. the time interval between clinical onset and diagnosis of LOPD) ranged from < 1 year (58%) to 2–12 years (42%).ConclusionsClinical diagnosis of LOPD in pediatrics is challenging in spite of its frequent presentation within 3 years of age. A selective screening by measuring GAA activity on dried blood spot in the two main clinical diagnostic contexts of LOPD in pediatrics – namely (1) age-related myopathic symptoms or (2) asymptomatic hyperCKemia (and hypertransaminasemia) – will likely ensure diagnostic anticipation for those patients not screened for Pompe’s disease in the neonatal period.

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive metabolic disorder resulting from mutations in the genes that encode the electron transfer flavoprotein (ETF) or its associated dehydrogenase (ETFDH), resulting in defects in mitochondrial fatty acid oxidation and a broad range of clinical presentations, most notably in the form of muscle weakness; exercise intolerance; and, in some cases, life-threatening metabolic crises. Late-onset MADD represents the most common form of lipid storage myopathy, but its diagnosis can be elusive due to its varied and often nonspecific clinical symptoms and may resemble other neuromuscular conditions, like inflammatory myopathies or other peripheral neuropathies, complicating the diagnostic process and delaying appropriate treatment. This case series aims to provide additional insights into the clinical presentation of MADD, highlighting diagnostic challenges in differentiating metabolic myopathies and emphasizing the role of muscle biopsy in diagnosing these conditions. We describe five clinical cases of patients who were diagnosed with MADD, their clinical manifestations, and the diagnostic processes undertaken to arrive at this diagnosis. Notably, three patients were initially misdiagnosed with inflammatory myopathy, and one was misdiagnosed with Guillain-Barré syndrome. The correct diagnosis was established following a muscle biopsy, which revealed characteristic findings consistent with lipid storage myopathy and prompted subsequent biochemical analyses and genetic testing that confirmed the diagnosis of MADD. MADD is an underdiagnosed condition, and the description of new patients with various clinical presentations could support the development of clinical tools to promptly recognize this disease and allow physicians to deliver the most appropriate and effective therapy protocol, with Riboflavin and Carnitine supplementations, avoiding inappropriate treatments. The muscle biopsy was essential for a correct diagnostic assessment.

McArdle disease (also known as glycogen storage disease type V) is a rare metabolic myopathy that is caused by myophosphorylase deficiency, leading to impaired glycogenolysis in skeletal muscles. This study explored the clinical, histopathological, and genetic landscape of McArdle disease in a regional cohort from Turkey, emphasizing diagnostic and management challenges. A retrospective analysis was conducted on 350 muscle biopsies performed between 2013 and 2024 in a tertiary care center. Seven patients (2.1 %) were diagnosed with McArdle disease. The clinical features included exercise intolerance (100 %), muscle pain (75 %), and the second wind phenomenon (62.5 %). Two patients presented with acute renal failure due to rhabdomyolysis with myoglobinuria, leading to metabolic acidosis. Histopathological findings revealed glycogen accumulation in subsarcolemmal vacuoles and absent myophosphorylase activity in all cases. Genetic analysis identified five distinct PYGM pathogenic variants, including c.808C>T (p.Arg270Ter) and c.2262del (p.Lys754fs). These findings highlight the phenotypic and genetic heterogeneity of McArdle disease. McArdle disease remains underdiagnosed due to its variable clinical presentation and limited access to advanced diagnostic tools. This study underscores the importance of a multidisciplinary approach that integrates clinical assessment, muscle biopsy, and molecular analysis. Increased awareness and training among healthcare providers are critical for early recognition and intervention. Future research should focus on expanding genetic databases and exploring targeted therapies to improve outcomes in this challenging condition.

ABSTRACTThanks to the rapid evolution of therapeutic strategies for muscular and neuromuscular diseases, the identification of quantitative biomarkers for disease identification and monitoring has become crucial. Magnetic resonance imaging (MRI) has been playing an important role by noninvasively assessing structural and functional muscular changes. This exploratory study investigated the potential of dynamic MRI during neuromuscular electrical stimulation (NMES) to detect differences between healthy controls (HCs) and patients with metabolic and myotonic myopathies. The study included 14 HCs and 10 patients with confirmed muscular diseases. All individuals were scanned with 3 T MRI with a protocol that included a multi‐echo gradient echo sequence for fat fraction quantification, multi‐echo spin‐echo for water T2 relaxation time calculation, and 3D phase contrast sequences during NMES. The strain tensor, buildup, and release rates were calculated from velocity datasets. Results showed that strain and strain buildup rate were reduced in the soleus muscle of patients compared to HCs, suggesting these parameters could serve as biomarkers of muscle dysfunction. Notably, there were no significant differences in fat fraction or water T2 measurements between patients and HCs, indicating that the observed changes reflect alterations in muscle contractile properties that are not reflected by structural changes. The findings provide preliminary evidence that dynamic muscle MRI during NMES can detect abnormalities in muscle contraction in patients with myotonia and metabolic myopathies, warranting further research with larger, more homogeneous patient cohorts.

Fatty acid beta-oxidation defects (FAOD) are a subgroup of lipid myopathies with heterogeneous presentations. Clinical presentation may manifest as muscular weakness, cramps, postexercise myalgias, and episodic rhabdomyolysis in children or adults. Our objective was to describe the clinical manifestations, biochemical, anatomopathological, and molecular results in a series of adult patients diagnosed with FAOD during adolescence or adulthood at five centers in Argentina. A total of seven patients with carnitine palmitoyltransferase-2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency were reported. The definite diagnosis of metabolic myopathies due to FAOD requires an understanding of clinical, biochemical, neurophysiological, and muscular imaging/biopsy patterns. All patients in this series consulted pediatricians, general practitioners, rheumatologists, and orthopedists for years, underscoring the need to disseminate these presentation patterns across various medical specialties. Early diagnosis and treatment using traditional diets and new pharmacological strategies not only enhance the quality of life, but also improve survival in these patients.

Myopathies are a heterogeneous group of disorders affecting the structure and metabolism of skeletal muscles. The causes of myopathies include hereditary factors (muscular dystrophy, distal myopathies, metabolic myopathies) and acquired factors (infections, endocrine abnormalities, drug-induced causes, idiopathic inflammatory myopathies). Recent advances have enabled clinicians to diagnose myopathies through genetic testing, highlighting the importance of differential diagnoses in clinical practice. Typical symptoms of myopathy include muscle weakness and atrophy. Recognizing symptom onset, progression, affected muscles, and associated symptoms (cataracts, skin rashes, lung issues, joint problems) facilitates accurate diagnosis. Myositis-specific autoantibodies and electromyography are valuable for diagnosing conditions such as dermatomyositis and myotonic dystrophy. Imaging, particularly muscle MRI, is crucial for diagnosis, optimal biopsy site selection, and assessment of disease activity. Muscle MRI allows identification of fat replacement, edema, and inflammatory changes. US and PET/CT offer additional diagnostic and evaluation benefits. Muscle pathologic analysis is essential for diagnosing muscular disorders and assessing structural changes, fiber size variation, necrosis, regeneration, fibrosis, and abnormal structures. Congenital myopathies such as RYR1- and NEB-related myopathies exhibit distinct MRI patterns. Muscular dystrophies, including dystrophinopathies and myotonic dystrophy type 1, display characteristic MRI findings. Limb-girdle muscular dystrophy subtypes reveal specific involvement patterns, leading to diagnosis. Metabolic and mitochondrial myopathies require biochemical testing, muscle biopsy, and genetic analysis. Idiopathic inflammatory and treatment-related myopathies also exhibit distinct imaging features. Continued research and enhanced diagnostic techniques will improve myopathy management. Radiologists must be knowledgeable about the clinical, pathologic, and imaging findings to ensure accurate diagnoses and optimal patient care. ©RSNA, 2025 Supplemental material is available for this article.

Abstract Introduction Progressive proximal muscle weakness with elevated creatine kinase poses a diagnostic challenge, often requiring exclusion of inflammatory, neurogenic, and metabolic myopathies. We present a 58-year-old woman with insidious onset of leg heaviness progressing to severe mobility impairment, bulbar symptoms, and elevated CK. Initial workup including autoantibodies, MRI spine, and EMG was inconclusive. Muscle biopsy ultimately revealed a lipid storage abnormality, highlighting a rare metabolic myopathy. This case underscores the importance of comprehensive neuromuscular evaluation in atypical presentations of muscle weakness. Case description A 58-year-old woman presented with a progressive history of lower limb heaviness and weakness starting in August 2024. Initially attributed to a possible lumbar spine pathology, she experienced gradual deterioration over several months, culminating in a fall and significant impairment of her mobility. Despite physiotherapy and analgesic treatment for a broad-based L4/5 disc bulge, her symptoms worsened, involving proximal muscle weakness, difficulty climbing stairs, and reliance on a wheelchair for ambulation. A few months later she developed bilateral shoulder pain and was commenced on corticosteroids for presumed polymyalgia rheumatica in primary care, but the treatment had no impact on symptoms. Around this time she commenced tirzepatide for weight loss and her symptoms progressed more rapidly. She noticed some bulbar symptoms including tongue numbness and her weakness worsened. She was referred to a general rheumatology clinic and initial assessment revealed no evidence of an inflammatory arthritis or connective tissue disease features. Family history included a sister who died due to cardiomyopathy. Baseline investigations revealed a raised creatine kinase of 1000 IU/L with negative autoantibody screen including myositis line blot, and MRI thigh showing mild STIR changes in adductor muscles. Electromyography suggested possible myopathic changes without definitive myositis. Muscle biopsy from the thigh revealed a lipid storage abnormality. The patient is undergoing further genetic testing under the care of the neuromuscular team. Discussion This case illustrates a diagnostic challenge in a middle-aged woman presenting with progressive proximal muscle weakness, bulbar symptoms, and elevated creatine kinase (CK), ultimately diagnosed with a lipid storage myopathy. The initial presentation with leg heaviness and gradual functional decline was initially attributed to lumbar spine pathology, supported by MRI findings of an L4/5 disc bulge. However, the lack of clinical improvement and progression to severe weakness, dysarthria, and impaired mobility suggested a primary neuromuscular disorder rather than purely mechanical nerve root compression. The differential diagnosis included inflammatory myopathies, motor neuron disease, metabolic myopathies, and neuropathies. Lack of connective tissue disease features, normal autoantibody screening and absence of myositis features on EMG reduced the likelihood of an inflammatory myopathy, while preserved reflexes and normal sensation argued against a large fibre neuropathy. The EMG showed mild myopathic features, but was non-specific. Importantly, muscle biopsy identified lipid storage abnormality, confirming a metabolic myopathy as the underlying cause. Lipid storage myopathies represent a heterogeneous group of inherited or acquired disorders characterised by abnormal lipid accumulation in muscle fibres, leading to muscle weakness and dysfunction. Presentation can be variable, often mimicking inflammatory or neurodegenerative conditions, which complicates early diagnosis. Bulbar symptoms and cranial nerve involvement, as seen in this patient, are less commonly described but may occur in advanced disease. Management of lipid storage myopathies is challenging and often requires multidisciplinary input. Early diagnosis is essential to guide specific therapy, such as dietary modification, supplementation, or targeted metabolic treatments where available. The patient’s poor response to corticosteroids reinforces the importance of accurate diagnosis before immunosuppressive therapy is initiated. This case emphasises the importance of considering metabolic myopathies in patients with unexplained progressive muscle weakness, especially when standard inflammatory and neurogenic workups are inconclusive. Comprehensive neuromuscular evaluation, including muscle biopsy, remains crucial for definitive diagnosis. Key learning points Atypical presentation of proximal muscle weakness: This case highlights the importance of considering a broad differential diagnosis when patients present with progressive proximal muscle weakness. Initial attribution to common causes such as lumbar spine pathology or polymyalgia rheumatica may delay accurate diagnosis and appropriate management. A detailed history and comprehensive clinical assessment is vital in these cases. Role of muscle biopsy in diagnosis: Muscle biopsy remains a critical diagnostic tool when non-invasive investigations are inconclusive. In this case, biopsy revealed a lipid storage abnormality, confirming a metabolic myopathy that would not be detected through standard inflammatory markers or imaging alone. Lipid storage myopathy as a rare but important cause of muscle weakness: Lipid storage myopathies can mimic inflammatory myopathies and neurodegenerative disorders. Recognition of this rare condition is essential, as management strategies differ significantly from those of inflammatory or mechanical causes. GLP-1 inhibitors like tirzepatide stimulate insulin secretion and reduce blood glucose. It is recognised that periods of fasting can lead to worsening metabolic abnormalities in those with an underlying lipid storage disorder. In this case, there is a likely association between tirzepatide usage and deterioration of her symptoms.

Abstract Introduction A patient was referred to the rheumatology team with suspected inflammatory myopathy. The investigations that ensued revealed unexpected findings including a large spinal mass with bone marrow signal changes on MRI, cavitating lung lesions on PET scan, and vacuolated myopathy on muscle biopsy. The time course, investigation and management of these findings are explored, elucidating the complex multi-system and multi-specialty nature of this presentation. Case description A 48-year-old male with a history of alcoholic liver disease presented with a three-week history of subacute, progressive weakness in both upper and lower limbs, resulting in recurrent falls. He also reported dysuria and offensive-smelling urine. Examination demonstrated reduced proximal limb power (4/5) in upper and lower limbs, sensory loss in the L4-S1 distribution, and absent ankle reflexes. Initial blood tests showed CK 4049, ALT 263, CRP 50, with normal white cell count and renal function. Urinalysis revealed pus cells, and culture was positive for S. aureus. MRI spine identified a soft tissue mass extending from C7 to T8, consisting of confluent extradural nodules causing spinal cord compression and bone marrow signal changes at T6-T7. Differentials included malignancy, abscess, and spinal vasculitis. Dexamethasone 8 mg BD was started. A CT TAP revealed no malignancy or lymphadenopathy. T-Spot and viral screens were negative. Echocardiography was performed to rule out a cardiac source of infection and was unremarkable. Neurosurgical input suggested the lesion was likely an abscess with septic arthritis; biopsy was deferred, and ceftriaxone with metronidazole was commenced. MRI thighs showed diffuse oedema in subcutaneous fat and within gluteus maximus and quadriceps bilaterally, and no fatty infiltration or soft tissue collections. Findings were confirmed by MSK radiologists. NCS and EMG revealed a moderate axonal sensorimotor peripheral neuropathy and features of a mild chronic proximal myopathy. These were thought to be related to chronic alcohol use and suspected infection. A diagnosis of myositis was made and the patient continued high-dose prednisolone alongside physiotherapy, with reported symptom improvement, normalisation of CK and ALT. Repeat MRI spine (showed partial improvement of the spinal lesion necessitating a restart of antibiotics. He developed steroid-induced hyperglycaemia and cushingoid facies, prompting a cautious steroid taper. PET scan demonstrated new bilateral cavitating pulmonary nodules and focal avidity in the T6/T7 facet joint with adjacent nodular thickening in the spinal canal. These were interpreted by the respiratory team as haematogenous spread of infection. Muscle biopsy ultimately revealed vacuolated myopathy suggestive of a metabolic myopathy, with no signs of inflammatory or necrotising myositis. Superadded acute-on-chronic neurogenic atrophy was also noted. Discussion A broad differential was considered, each purported by positive laboratory results and/or imaging findings, and included neoplasia, infection, vasculitis, sarcoidosis, IgG4-related disease, and myeloma—with sequential investigations guiding a systematic refinement of the working diagnosis. The patient’s progress was reviewed daily by medical, neurology and rheumatology teams. Ultimately, the diagnosis of a metabolic myopathy was confirmed only via targeted muscle biopsy—despite the patient lacking classical clinical features of such a disorder. This underscores the diagnostic value of tissue analysis, particularly in atypical or complex presentations. Metabolic myopathies are recognised mimics of idiopathic inflammatory myopathies. In this case, a concurrent infection not only unmasked a previously subclinical myopathy but also served as a major confounding factor, complicating the clinical picture and interpretation of investigations. Management of this patient was challenging, partly due to limitations inherent to a hospital without onsite PET scanning, neurosurgery, neurophysiology, or muscle histopathology services. Despite formal pathways for accessing these services, delays in coordination and approval processes negatively impacted diagnostic efficiency. The urgency of intervention, driven by the high-risk nature of the findings, and delays in obtaining essential investigations and results, created further challenge. Key learning points • This case highlights the significant diagnostic complexity and uncertainty involved, requiring input from both regional and national specialists to support the local multidisciplinary team. • In complex cases, differential diagnoses must be reviewed and refined based on investigation findings and collaborative discussions with all relevant parties. When life- or organ-threatening disease is suspected, treatment should not be delayed, and patients must be closely monitored to assess their response. • Metabolic myopathies are rare genetic conditions that can present at any age. Notably, adult presentations often lack the typical phenotypic features, increasing the risk of delayed or missed diagnosis.

McArdle disease, or glycogen storage disease type V, is a rare inherited metabolic myopathy caused by mutations in the PYGM gene, resulting in deficiency of the enzyme myophosphorylase. Patients usually present with lifelong exercise-induced fatigue, muscle pain, and sometimes rhabdomyolysis, but the condition is underdiagnosed due to its nonspecific manifestations. This case is distinctive because it documents molecularly confirmed McArdle disease in a woman with persistently elevated creatine kinase and a suggestive family history, underlining the importance of clinical suspicion, timely genetic testing, and appropriate counselling.A 35-year-old woman reported lifelong myalgia and easy fatigability. Her past history included recurrent migraines and use of a progestogen-only contraceptive. One sister, aged 21, had similar symptoms, while her other sister and parents were healthy. Physical examination was unremarkable. Laboratory tests showed an isolated elevation of creatine kinase (1,504 U/l). Genetic analysis revealed the PYGM c.148C>T, p.(Arg50*) variant in apparent homozygosity, a rare mutation transmitted in heterozygosity. At follow-up she was 30 weeks pregnant and was referred, along with her symptomatic sister, to a genetic consultation. Behavioural guidance focused on regular moderate exercise and symptom management.McArdle disease is underdiagnosed because its symptoms are often misinterpreted as poor physical fitness. This case highlights that early recognition, and molecular confirmation can avoid unnecessary invasive tests and provide clarity in patients with chronic exertional intolerance. The identification of a rare PYGM variant further emphasizes the importance of genetic counselling, which enables family screening and informed reproductive planning. Timely recognition and tailored management are essential for improving patient quality of life.LEARNING POINTSEarly recognition and diagnosis McArdle’s disease is underdiagnosed due to nonspecific symptoms. This case highlights the importance of maintaining clinical suspicion for timely diagnosis.Impact on quality of life Although no curative treatment exists, simple measures such as regular moderate exercise and carbohydrate intake can substantially improve symptoms and daily functioning.Value of genetic counselling Genetic confirmation allows family screening, clarifies prognosis, and supports individualized management strategies for patients and their relatives.

Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway.

Biallelic mutations in XPNPEP3 gene, encoding a mitochondrial peptidase, mainly cause nephronophthisis, but associated muscle involvement remains poorly described. We report here a 44-year-old male presenting since childhood with exercise intolerance and recurrent rhabdomyolysis. Electroneuromyography revealed a sensory axonal neuropathy and brain MRI showed white matter lesions in the posterior cranial fossa. Muscle biopsy revealed ragged-red fibers, COX negative fibers and abnormal mitochondria in electron microscopy. Whole genome sequencing identified a homozygous frameshift variant in the XPNPEP3 gene. Our results expand the spectrum associated with XPNPEP3 variants, including metabolic myopathy with subclinical central and peripheral nervous system involvement.

Neuromuscular diseases are often accompanied by various types of sleep-related breathing disorders, which can exacerbate the underlying condition and are associated with a poor prognosis. Early identification is essential, and interventions such as non-invasive ventilation, oxygen therapy, and respiratory rehabilitation should be initiated promptly to mitigate disease progression and improve outcomes. Nevertheless, the rates of missed and misdiagnosed cases remain common in clinical practice. Currently, there are no standardized guidelines for the diagnosis and treatment of sleep-disordered breathing related to neuromuscular diseases in China. Therefore, based on the latest domestic and international research progress, and combined with domestic clinical diagnosis and treatment experience, the Sleep Disorder Group of Chinese Thoracic Society has brought together multidisciplinary experts to develop this expert consensus. This consensus provides a comprehensive overview of the epidemiology, clinical manifestations, diagnostic approaches, assessment strategies, and treatment of sleep-disordered breathing related to neuromuscular diseases. It formulates evidence-based recommendations to guide clinical practice, with the aim of providing standardized recommendations for their diagnosis and management.Statement 1: The neuromuscular disorders that are most frequently associated with sleep-disordered breathing include: myasthenia gravis (1A), amyotrophic lateral sclerosis (2B), post-polio syndrome (2B), myotonic dystrophy (2B), peripheral neuropathies (2C), and metabolic myopathies, among other neuromuscular conditions.Statement 2: Patients with neuromuscular disorders frequently develop multiple types of sleep-disordered breathing concurrently or sequentially, with obstructive sleep apnea (OSA) being the most prevalent manifestation. Distinct clinical manifestations of OSA are observed across different neuromuscular disease subtypes (1A).Statement 3: Neuromuscular disorders predispose to central sleep apnea (CSA), with clinical manifestations varying significantly across disease subtypes, stages of progression, and severity levels (1A).Recommendation 1: In patients with neuromuscular disorders exhibiting progressive hypercapnia or worsening hypoxemia, clinicians should investigate potential comorbid nocturnal alveolar hypoventilation and/or sleep-associated hypoxemia (1A).Recommendation 2: When sleep-disordered breathing is suspected, patients with neuromuscular disorders should be evaluated for symptoms of sleep-disordered breathing. Meanwhile, sleep monitoring, non-invasive CO2 monitoring, and related examinations should be actively performed according to the actual situation (1A). A polysomnography should be performed when there is a high clinical suspicion of sleep-disordered breathing but a negative result on a portable sleep monitor (1A).Recommendation 3: (1) Noninvasive positive pressure ventilation (NPPV) titration under polysomnography is the standard method to determine the effective treatment parameters for neuromuscular diseases with sleep-disordered breathing (1A). (2) Positive airway pressure titration in OSA patients with neuromuscular diseases should follow American Academy of Sleep Medicine (AASM) guidelines (1A). (3) For neuromuscular disorders with CSA or Cheyne-Stokes respiration, bi-level positive airway pressure (BPAP) with ST pattern is recommended (1A); When BPAP is not tolerated or accompanied by severe Cheyne-Stokes respiratory and heart failure in patients, adaptive support ventilation (ASV) should be used (2B). (4) Patients with neuromuscular disease and sleep-related alveolar hypoventilation should be treated with BPAP or variable assurance pressure support (VAPS) (1A). (5) BPAP with alternate frequency is preferred for neuromuscular disorders with "pseudo-central events" (1A).Recommendation 4: Oxygen therapy alone is not recommended for neuromuscular disease patients combined with sleep-disordered breathing (2D). Oxygen therapy with monitoring of CO2 level is recommended when non-invasive ventilation therapy cannot effectively correct hypoxemia (2C). Diaphragmatic pacing should not be routinely used in amyotrophic lateral sclerosis patients with respiratory failure (2B). Transvenous phrenic nerve stimulation is not currently applied to CSA caused by neuromuscular disorders (2D). Respiratory rehabilitation may improve respiratory muscle strength in a subset of patients with neuromuscular disorders (2B). Protiline can be used for REM-associated alveolar hypoventilation, and daytime sleepiness could be addressed with methylphenidate and modafinil (2C).Recommendation 5: Neuromuscular disease combined with sleep-disordered breathing is a chronic disease requiring patient-centered, individualized education and long-term follow-up management (1A).