Search Results (3,478)

Background/Objectives: Spinal Muscular Atrophy (SMA) is a genetic neurodegenerative disease characterized by severe muscle weakness and atrophy. Advances in disease-modifying therapies have dramatically changed the natural history of SMA and the outcome measures that are used to assess the clinical response to therapy. Standard assessment methods for SMA are limited in their ability to detect minor changes in fine motor abilities and in patients’ daily functions. The aim of this pilot study was to evaluate the feasibility and preliminary use of the Touchscreen-Assessment Tool (TATOO) alongside standardized tools to detect changes in upper extremity motor function among individuals with SMA receiving nusinersen therapy. Methods: Thirteen individuals with genetically-confirmed SMA, aged 6–23 years, eight with SMA type 2, and five with SMA type 3, participated. The patients continued the maintenance dosing of nusinersen during the study period. They were evaluated at the onset of the study, then twice more at intervals at least six months apart. Upper extremity functional assessments were performed via the TATOO and standardized tools: the Hand Grip Dynamometer (HGD), Pinch Dynamometer (PD), Revised Upper Limb Module (RULM), and Nine-Hole Peg Test (NHPT). Results: Significant changes in fine motor function were detected using the TATOO together with other standardized tools. Participants demonstrated notable improvements in hand grip strength and fine motor performance, as measured by the NHPT. The RULM results were not statistically significant for the total study group, particularly in ambulatory patients with SMA type 3. TATOO provided detailed metrics, and revealed enhancements in accuracy and speed across various tasks. However, given the small sample size, the lack of a control group, and the lack of baseline assessment before receiving therapy, these findings should be considered preliminary and exploratory. Conclusions: The findings suggest that the TATOO, alongside traditional assessment tools, offers a sensitive measure of fine motor function changes in patients with SMA. This study highlights the potential of touchscreen-based assessments to address gaps in current outcome measures and emphasizes the need for larger, multicenter studies that will include pre-treatment, baseline, and control data. Full article

Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune–muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context. Full article

MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity—enhancing oxidative metabolism—and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health. Full article

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately leading to pernicious anemia. Compensatory hypergastrinemia promotes enterochromaffin-like (ECL) cell hyperplasia and contributes to the development of type 1 gastric neuroendocrine neoplasms (gNENs). These clinical consequences are well recognized, yet the cellular and molecular mechanisms driving mucosal atrophy and neoplastic transformation remain incompletely defined. Recent advances highlight the role of endoplasmic reticulum stress, impaired autophagy, innate immune effectors, and dysbiosis in perpetuating inflammation and epithelial injury. The frequent coexistence of AIG with other autoimmune disorders further adds to its clinical complexity. Therapeutic options remain limited, spanning vitamin B12 replacement and endoscopic management to emerging targeted approaches. Netazepide, a gastrin/CCK2 receptor antagonist, is the only agent tested in clinical trials, whereas interventions targeting ER stress, autophagy, immune tolerance, or microbiome composition are still in the preclinical stage. Clarifying these mechanisms is crucial to improve biomarker development, optimize surveillance, and identify targeted therapies to prevent neoplastic transformation. Full article

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

Wild-type transthyretin amyloidosis is an underdiagnosed condition that significantly contributes to mortality in the elderly population. This histopathological study describes autopsy findings in patients with severe clinical course of COVID-19 and ATTR not identified during life. Autopsy findings in the myocardium were analyzed in 19 patients with pre-existing ATTR who died from severe COVID-19. RT PCR was used for pre- and post-mortem detection of SARS-CoV-2 RNA. Immunohistochemical typing was performed with a broad panel of antibodies against different amyloid types. Autopsy specimens from the myocardium and lungs were positive for SARS-CoV-2 RNA in 10 (53%) cases. Microscopic examination of the myocardium revealed focal cardiosclerosis and cardiomyocyte dissociation in 15 (68%) cases, hypertrophy and atrophy of cardiomyocytes in 17 (77%) and 7 (32%), respectively, and myocarditis in 4 (18%) cases. Immunohistochemical analysis determined ATTR amyloidosis in all cases. In patients with rapidly progressive heart failure, the postmortem examination revealed multiple sites of interstitial amyloid deposits and focal cardiosclerosis in the myocardium. Pre-existing cardiac amyloidosis contributes to the aggressive clinical course of COVID-19. Coupled with the toxic effect of the SARS-CoV-2 virus on the myocardium, the disease may lead to progressive heart failure and poor outcomes. Full article

Background/Objectives: The approval of disease-modifying therapies has significantly improved outcomes for patients with spinal muscular atrophy (SMA), yet their long-term safety profiles remain under continuous evaluation. This study aimed to assess trends in the reporting of suspected adverse drug reactions (ADRs) associated with nusinersen, onasemnogene abeparvovec, and risdiplam across the European Union. Methods: We conducted a secondary analysis of annual suspected ADR data reported to EudraVigilance from 2017 to 2024 for the three approved disease-modifying therapies for SMA. On top of general reporting trend, specific adverse reactions of interest included post-lumbar puncture syndrome for nusinersen, liver toxicity and elevated serum troponin for onasemnogene abeparvovec, and respiratory and gastrointestinal reactions for risdiplam. Joinpoint regression analysis was used to evaluate annual percent changes and identify statistically significant trend segments for each medicine. Results: The reporting of suspected ADRs for nusinersen showed an initial increase, followed by a significant decline after 2019. Onasemnogene abeparvovec exhibited a continued but decelerating increase in suspected ADRs, while risdiplam demonstrated a consistent upward trend across all reported reactions. Conclusions: Diverging patterns in adverse reaction reporting suggest a stabilizing safety profile for nusinersen and potential emerging safety signals for risdiplam and onasemnogene abeparvovec, underscoring the need for ongoing continued pharmacovigilance (e.g., post-authorization studies and spontaneous reporting). Full article

Background: Spinal Muscular Atrophy type 1 (SMA type 1) is a genetic neuromuscular disease that typically presents before 6 months of age and is characterized by profound hypotonia, progressive muscle weakness, and early involvement of respiratory and bulbar musculature. Swallowing impairment (dysphagia) is a hallmark of SMA type 1 and significantly contributes to morbidity. Despite the documented benefits of disease-modifying therapies (DMTs) in terms of enhanced survival and motor outcomes, their impact on swallowing remains understudied. Aim: This study aims to longitudinally characterize swallowing function in children with SMA type 1 treated with DMTs, while contextualizing these findings in relation to the patients’ current motor abilities and cognitive performance. Materials and Methods: A single-center, longitudinal, observational study was conducted at IRCCS Besta, Milan, Italy, from 2021 to 2025. Swallowing function was evaluated using four validated scales (MAS, OrSAT, FILS, and p-FOIS), while motor and cognitive functions were assessed using CHOP-INTEND and age-appropriate cognitive tests (DQ/IQ). Patients were stratified by baseline swallowing status, pharmacological therapy, and age at DMT administration. Non-parametric statistical tests were applied. Results: No statistically significant changes in swallowing function were observed over one year in the overall cohort or its subgroups, despite significant improvements in motor function. MAS/e, FILS, and p-FOIS showed moderate associations with CHOP-INTEND and DQ/IQ scores. Conclusions: Swallowing function in children with SMA type 1 remained largely stable, while motor function significantly improved over one year, regardless of baseline swallowing status, DMT type, and age at administration. These findings underscore the need for standardized, longitudinal assessments of swallowing, motor, and cognitive functions in the management of SMA type 1. Full article

Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington’s disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons. Full article

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation. Full article

Background/Objectives: Aging and metabolic disorders are associated with a decline in muscle function, referred to as age-related sarcopenia. The underlying mechanisms of sarcopenia include cellular senescence, imbalanced protein homeostasis, accumulation of oxidative and inflammatory stressors, and mitochondrial dysfunction. Probiotic supplementation improves the gut microbiome and enhances muscle function via the gut–muscle axis. However, details of molecular mechanisms and the development of an appropriate treatment are under active investigation. Methods: We have examined the effects of Lactiplantibacillus plantarum LM1001, a probiotic that reportedly improves the digestibility of branched-chain amino acids in myocyte cultures, but exactly how it contributes to muscle structure and function remains unclear. Results: We show that aged mice (male C57BL6/J) fed a high-fat diet (HFD) exhibit weak muscle strength, as reflected by a reduction in grip strength. LM1001 supplementation increases muscle strength and restores myofibril size, which has been altered by HFD in aged mice. Expression of myogenic proteins is increased, while protein markers for muscle atrophy are downregulated by LM1001 treatment via the IGF-1/Akt/FoxO3a pathway. LM1001 improves gut microbiota that are altered in aged HFD-fed mice, by increasing their abundance in beneficial bacteria, and efficiently maintains the epithelial lining integrity of the large intestine. Conclusions: We conclude that LM1001 supplementation serves a beneficial role in patients suffering from sarcopenia and metabolic disorders, improving their muscle function, gut microbiota, and intestinal integrity. Full article

Background/Objectives: This study was designed to investigate the potential clinical, biochemical, haematological, and pathological associations of carpal tunnel syndrome through a multidisciplinary approach encompassing the fields of internal medicine, gastroenterology, and neurology. Methods: The study group (CTS-positive) comprised 265 patients who presented with dyspeptic complaints and underwent upper gastrointestinal endoscopy, gastric antrum biopsy, electromyography, and comprehensive biochemical and haematological analyses. A control group of 265 patients with similar symptoms but without CTS was selected for comparison. A comparative analysis was conducted on clinical findings, gastric biopsy results, and biochemical and haematological parameters. Results: There were no significant differences in age, gender distribution, or gastric biopsy findings (Helicobacter pylori, intestinal metaplasia, atrophy, and dysplasia) between the CTS-positive and CTS-negative groups. However, significant biochemical differences were identified, including elevated calcium and reduced magnesium levels in CTS-positive patients. Haematological evaluations revealed higher lymphocyte, eosinophil, basophil, erythrocyte, haemoglobin, and haematocrit levels, along with reduced neutrophil-to-lymphocyte ratios and red blood cell distribution widths in the CTS-positive group. Further analysis in the form of correlation and logistic regression analyses provided further confirmation of the association of elevated calcium, haemoglobin, and lymphocyte levels with increased risk of CTS. Conclusions: This multidisciplinary study identifies significant associations between CTS and specific biochemical and haematological parameters, notably calcium-magnesium imbalance and erythrocyte indices. These findings suggest underlying biological interactions that may guide future diagnostic and therapeutic strategies for patients with carpal tunnel syndrome. Full article

Cancer-induced cardiac dysfunction has become a major clinical challenge as advances in cancer therapies continue to extend patient survival. Once regarded as a secondary concern, cardiotoxicity is now recognized as a leading contributor to morbidity and mortality among cancer patients and survivors. Its pathophysiology is multifactorial, involving systemic inflammation (e.g., TNF-α, IL-6), oxidative stress driven by reactive oxygen species (ROS), neurohormonal imbalances (e.g., angiotensin II, endothelin-1), and metabolic disturbances. These mechanisms collectively promote cardiomyocyte apoptosis, atrophy, mitochondrial dysfunction, and impaired cardiac output. Cardiac complications may arise directly from cancer itself or as adverse effects of oncologic therapies such as anthracyclines, trastuzumab, and immune checkpoint inhibitors. These agents have been linked to heart failure (HF), systolic dysfunction, and cardiac atrophy, often progressing insidiously and underscoring the importance of early detection and careful monitoring. Current preventive and therapeutic strategies include pharmacological interventions such as ACE inhibitors, beta-blockers, statins, dexrazoxane, and endothelin receptor antagonists like atrasentan. Emerging compounds, particularly Withaferin A (WFA), have shown potential through their anti-inflammatory and cardiac protective properties. In addition, antioxidants and lifestyle modifications may provide supplementary cardioprotective benefits, while interventional cardiology procedures are increasingly considered in selected patients. Despite encouraging progress, standardized treatment protocols and robust long-term outcome data remain limited. Given the heterogeneity of cancer types and cardiovascular responses, a personalized and multidisciplinary approach is essential. Continued research and close collaboration between oncologists, cardiologists, and basic scientists will be the key to advancing care, reducing treatment-related morbidity, and ensuring that improvements in cancer survival are matched by preservation of cardiovascular health. Full article

Background: Excessive scarring remains a frequent complication in plastic surgery, yet standardized preventive strategies are lacking. Type I collagen-based biomaterials may support regenerative processes and improve scar outcomes. Methods: This case series includes six female patients (ages 24–52) undergoing wound management after trauma and procedures including blepharoplasty, abdominoplasty, and revision mammaplasty. Native collagen type I (7% or 15%) was injected along wound margins or into hypertrophic scars at 3–4 week intervals. Outcomes were assessed through patient-reported symptoms and Antera 3D imaging (vascularity, pigmentation, surface topography). Results: Patients reported reduced tightness, pruritus, and scar stiffness after initial sessions. Antera 3D imaging showed decreased vascular and pigment indices, and a reduction in surface elevation over follow-up (up to 14 months). No adverse effects such as atrophy or infection were observed. Conclusions: Native type I collagen was well tolerated and may be a useful adjunct for wound healing and scar modulation following plastic surgery. Full article

Background: Multiple System Atrophy (MSA) is a rapidly progressing neurodegenerative movement disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. While its non-motor symptoms are well-documented, personality features in MSA remain underexplored. This study characterizes the personality traits of non-demented patients with MSA and explores their association with clinical variables. Methods: Twenty-six patients with MSA were assessed using the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). Dementia was excluded by Montreal Cognitive Assessment. Descriptive statistics and non-parametric analyses were conducted to examine clinical, demographic, and MMPI-2-RF variables. Results: Patients commonly showed elevated scores in somatic domains: Somatic Complaints (39%), Malaise (58%), and Neurological Complaints (85%), as well as in internalizing emotional traits: Low Positive Emotions (39%), Introversion (46%), Suicidal Ideation (46%), and Hopelessness (54%). Externalizing behavioral traits were absent, with only 4–8% of patients showing elevations in aggression or behavioral dysfunction. Strong correlations were found between somatic and emotional traits (r = 0.656, p < 0.001), and between Neurological Complaints and disease duration (r = 0.662, p < 0.001). Conclusions: This exploratory study reveals a distinct personality pattern in MSA, characterized by marked suicidal ideation, emotional vulnerability with internalizing coping, and absence of externalizing behaviors. These features highlight the need for suicide risk screening, interventions to alleviate psychological suffering, and tailored multidisciplinary care. Larger, longitudinal studies are warranted to confirm these preliminary results and clarify whether these traits reflect premorbid personality, early disease manifestations, or secondary responses, as well as their prognostic and clinical relevance. Full article