Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies DOI Creative Commons
Manuel Gónzalez-Sánchez, Marı́a Jesús Ramı́rez-Expósito, José Manuel Martı́nez-Martos

et al.

Life, Journal Year: 2025, Volume and Issue: 15(4), P. 647 - 647

Published: April 14, 2025

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, respiratory failure. This comprehensive review synthesizes current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, evolving therapeutic strategies. Mechanistically, arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), FUS) dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, prion-like propagation toxic aggregates. Phenotypic manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates rigorous application revised El Escorial criteria emerging biomarkers such neurofilament light chain. Clinically, intersects with frontotemporal dementia (FTD) up 50% cases, driven shared TDP-43 pathology C9orf72 hexanucleotide expansions. Epidemiological studies have revealed lifetime risk 1:350, male predominance (1.5:1) peak onset 50 70 years. Disease progression varies widely, median survival 2–4 years post-diagnosis, underscoring urgency for intervention. Approved therapies, riluzole (glutamate modulation), edaravone (antioxidant), tofersen (antisense oligonucleotide), offer modest benefits, while dextromethorphan/quinidine alleviates pseudobulbar affect. Non-pharmacological treatment advances, non-invasive ventilation (NIV), prolong 13 months improve quality life, particularly bulb-involved patients. Multidisciplinary care—integrating physical therapy, support, nutritional management, cognitive assessments—is critical addressing non-motor symptoms dysphagia, spasticity, sleep disturbances). Emerging therapies show promise preclinical models. However, challenges persist translating insights into universally effective treatments. Ethical considerations, euthanasia end-of-life decision-making, further highlight need patient-centered communication palliative

Language: Английский

Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies DOI Creative Commons
Manuel Gónzalez-Sánchez, Marı́a Jesús Ramı́rez-Expósito, José Manuel Martı́nez-Martos

et al.

Life, Journal Year: 2025, Volume and Issue: 15(4), P. 647 - 647

Published: April 14, 2025

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, respiratory failure. This comprehensive review synthesizes current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, evolving therapeutic strategies. Mechanistically, arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), FUS) dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, prion-like propagation toxic aggregates. Phenotypic manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates rigorous application revised El Escorial criteria emerging biomarkers such neurofilament light chain. Clinically, intersects with frontotemporal dementia (FTD) up 50% cases, driven shared TDP-43 pathology C9orf72 hexanucleotide expansions. Epidemiological studies have revealed lifetime risk 1:350, male predominance (1.5:1) peak onset 50 70 years. Disease progression varies widely, median survival 2–4 years post-diagnosis, underscoring urgency for intervention. Approved therapies, riluzole (glutamate modulation), edaravone (antioxidant), tofersen (antisense oligonucleotide), offer modest benefits, while dextromethorphan/quinidine alleviates pseudobulbar affect. Non-pharmacological treatment advances, non-invasive ventilation (NIV), prolong 13 months improve quality life, particularly bulb-involved patients. Multidisciplinary care—integrating physical therapy, support, nutritional management, cognitive assessments—is critical addressing non-motor symptoms dysphagia, spasticity, sleep disturbances). Emerging therapies show promise preclinical models. However, challenges persist translating insights into universally effective treatments. Ethical considerations, euthanasia end-of-life decision-making, further highlight need patient-centered communication palliative

Language: Английский

Citations

0