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Disease Models & Mechanisms Jun 2024Interpreting the wealth of rare genetic variants discovered in population-scale sequencing efforts and deciphering their associations with human health and disease... (Review)
Review
Interpreting the wealth of rare genetic variants discovered in population-scale sequencing efforts and deciphering their associations with human health and disease present a critical challenge due to the lack of sufficient clinical case reports. One promising avenue to overcome this problem is deep mutational scanning (DMS), a method of introducing and evaluating large-scale genetic variants in model cell lines. DMS allows unbiased investigation of variants, including those that are not found in clinical reports, thus improving rare disease diagnostics. Currently, the main obstacle limiting the full potential of DMS is the availability of functional assays that are specific to disease mechanisms. Thus, we explore high-throughput functional methodologies suitable to examine broad disease mechanisms. We specifically focus on methods that do not require robotics or automation but instead use well-designed molecular tools to transform biological mechanisms into easily detectable signals, such as cell survival rate, fluorescence or drug resistance. Here, we aim to bridge the gap between disease-relevant assays and their integration into the DMS framework.
Topics: Humans; High-Throughput Screening Assays; Disease; Mutation; Genetic Variation; Animals
PubMed: 38940340
DOI: 10.1242/dmm.050573 -
Cardiology Journal 2024
Topics: Humans; Muscular Dystrophy, Duchenne
PubMed: 38940257
DOI: 10.5603/cj.94330 -
Frontiers in Bioscience (Scholar... Jun 2024Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and... (Review)
Review
Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.
Topics: Humans; Muscular Diseases; Carnitine; Lipid Metabolism, Inborn Errors; Muscle, Skeletal; Muscular Dystrophies
PubMed: 38939976
DOI: 10.31083/j.fbs1602012 -
PloS One 2024
Topics: Muscular Dystrophy, Duchenne; Signal Transduction; Humans; Hippo Signaling Pathway; Protein Serine-Threonine Kinases
PubMed: 38935667
DOI: 10.1371/journal.pone.0306508 -
Cureus May 2024Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the...
Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.
PubMed: 38933611
DOI: 10.7759/cureus.61188 -
Medicina (Kaunas, Lithuania) Jun 2024: Although extracorporeal membrane oxygenation (ECMO) is an essential life-saving technique for patients with refractory cardiopulmonary shock, it can be fatal in... (Review)
Review
Critical Hemorrhage Caused by a Size-Mismatched Extracorporeal Membrane Oxygenation Cannula in a Patient with Myotonic Dystrophy Type 1: A Case Report and Literature Review.
: Although extracorporeal membrane oxygenation (ECMO) is an essential life-saving technique for patients with refractory cardiopulmonary shock, it can be fatal in certain cases. : A 19-year-old girl treated with ECMO presented with acute limb ischemia 2 days after cannula removal. The decannulation was performed percutaneously by an interventional cardiologist, and the vascular surgery department was consulted after the patient developed symptoms. The first suspected diagnosis was thrombosis due to incorrect use of the closure device. However, the artery had ruptured due to the insertion of a catheter with a cannula that was larger than the patient's artery. : Fortunately, excessive bleeding due to the size-mismatched cannula was prevented by an unintentional complication of the closing device, which saved the patient's life. She underwent a right common femoral artery thrombectomy and patch angioplasty. Hospital guidelines have changed regarding the surgical removal of ECMO cannulas. : This report aims to highlight the importance of two aspects that are critical to a successful outcome: individualized cannula selection followed by precise insertion and removal and postoperative evaluation of a patient's final status.
Topics: Humans; Extracorporeal Membrane Oxygenation; Female; Young Adult; Cannula; Hemorrhage; Myotonic Dystrophy; Femoral Artery; Thrombectomy; Adult
PubMed: 38929586
DOI: 10.3390/medicina60060969 -
Antioxidants (Basel, Switzerland) Jun 2024Redox modifications to the plasma protein albumin have the potential to be used as biomarkers of disease progression and treatment efficacy in pathologies associated...
Redox modifications to the plasma protein albumin have the potential to be used as biomarkers of disease progression and treatment efficacy in pathologies associated with inflammation and oxidative stress. One such pathology is Duchenne muscular dystrophy (DMD), a fatal childhood disease characterised by severe muscle wasting. We have previously shown in the mouse model of DMD that plasma albumin thiol oxidation is increased; therefore, the first aim of this paper was to establish that albumin thiol oxidation in plasma reflects levels within muscle tissue. We therefore developed a method to measure tissue albumin thiol oxidation. We show that albumin thiol oxidation was increased in both muscle and plasma, with levels correlated with measures of dystropathology. In dystrophic muscle, albumin content was associated with areas of myonecrosis. The second aim was to test the ability of plasma thiol oxidation to track acute changes in dystropathology: we therefore subjected mice to a single treadmill exercise session (known to increase myonecrosis) and took serial blood samples. This acute exercise caused a transient increase in total plasma albumin oxidation and measures of dystropathology. Together, these data support the use of plasma albumin thiol oxidation as a biomarker to track active myonecrosis in DMD.
PubMed: 38929159
DOI: 10.3390/antiox13060720 -
Antioxidants (Basel, Switzerland) May 2024Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely...
Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.
PubMed: 38929061
DOI: 10.3390/antiox13060622 -
International Journal of Environmental... Jun 2024Duchenne muscular dystrophy (DMD) is a disease that primarily affects males and causes a gradual loss of muscle strength. This results in a deterioration of motor skills...
Duchenne muscular dystrophy (DMD) is a disease that primarily affects males and causes a gradual loss of muscle strength. This results in a deterioration of motor skills and functional mobility, which can impact the performance of various occupations. Individuals with DMD often rely heavily on caregivers to assist with daily activities, which can lead to caregiver burden. A case study was conducted to explore and describe potential variations in the performance of a young adult diagnosed with DMD and his caregivers resulting from the integration of smart speakers (SS)-controlled Internet of Things (IoT) devices in the home environment. The study also examined the potential of SS as an environment control unit (ECU) and analysed variations in caregiver burden. Smart devices and SS were installed in the most frequently used spaces, namely, the bedroom and living room. The study employed WebQDA software to perform content analysis and Microsoft Excel to calculate the scores of the structured instruments. The implementation of the IoT-assisted environment compensated for previously physical tasks, resulting in a slight increase in independent performance and reduced demands on caregivers.
Topics: Muscular Dystrophy, Duchenne; Humans; Male; Young Adult; Activities of Daily Living; Adult; Caregivers
PubMed: 38929024
DOI: 10.3390/ijerph21060778 -
Bioengineering (Basel, Switzerland) Jun 2024Muscular dystrophies present diagnostic challenges, requiring accurate classification for effective diagnosis and treatment. This study investigates the efficacy of deep...
Muscular dystrophies present diagnostic challenges, requiring accurate classification for effective diagnosis and treatment. This study investigates the efficacy of deep learning methodologies in classifying these disorders using skeletal muscle MRI scans. Specifically, we assess the performance of the Swin Transformer (SwinT) architecture against traditional convolutional neural networks (CNNs) in distinguishing between healthy individuals, Becker muscular dystrophy (BMD), and limb-girdle muscular Dystrophy type 2 (LGMD2) patients. Moreover, 3T MRI scans from a retrospective dataset of 75 scans (from 54 subjects) were utilized, with multiparametric protocols capturing various MRI contrasts, including T1-weighted and Dixon sequences. The dataset included 17 scans from healthy volunteers, 27 from BMD patients, and 31 from LGMD2 patients. SwinT and CNNs were trained and validated using a subset of the dataset, with the performance evaluated based on accuracy and F-score. Results indicate the superior accuracy of SwinT (0.96), particularly when employing fat fraction (FF) images as input; it served as a valuable parameter for enhancing classification accuracy. Despite limitations, including a modest cohort size, this study provides valuable insights into the application of AI-driven approaches for precise neuromuscular disorder classification, with potential implications for improving patient care.
PubMed: 38927816
DOI: 10.3390/bioengineering11060580