Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies

Abstract

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

Keywords: C9orf72 expansion; SOD1 mutations; TDP-43 proteinopathy; amyotrophic lateral sclerosis; frontotemporal dementia; multidisciplinary care; neurodegenerative disease; neurofilament light chain; non-invasive ventilation; riluzole.

Figure 1

Spatial organization of nucleoporins in the nuclear pore complex.

Figure 2

Poly(PR) and poly(GR) enhance FUS aggregation and phase separation.

Figure 3

ALS-related mechanisms, associated or not with PSLL. Schematic illustration of the most important ALS-related pathological process that depends on or is influenced by the functioning of PSLL in motor neurons.

Figure 4

Graphic summary of prion transmission between cells.

Figure 5

Importance of ALS biomarkers.

Figure 6

Temporal trajectory of the effects of neurofilament NfL expression and its utility as a biomarker through the course of pre-symptomatic and symptomatic ALS.

Figure 7

Neuroimaging biomarkers in cognitively normal older adults. Cognitively normal older adults can present with varying amounts of amyloid and tau positivity.

Figure 8

Diagnostic algorithm for amyotrophic lateral sclerosis (ALS) diagnosis. The flowchart illustrates the stepwise diagnostic process for ALS, starting with the assessment of clinical history (1) that includes family history and the identification of the initial symptoms. Electrophysiological tests (2), such as nerve conduction studies and needle electromyography, are indicated, along with laboratory tests (3) to rule out other conditions. Magnetic resonance imaging (MRI) (4) of the spinal cord is crucial to exclude differential diagnoses like a herniated disc or spinal cord compression. The revised El Escorial criteria (5) are fundamental to confirm the presence (A) or absence (B) of specific signs of upper and lower motor neuron dysfunction, evaluated during the neurological examination (6). The figure summarizes the diagnostic categories ranging from “clinically definite” to “clinically possible,” based on the combination of clinical signs, electrodiagnostic findings, and neuroimaging results. Additional symptoms include unexplained weight loss, cognitive dysfunction, and pseudobulbar affect.