Amyotrophic Lateral Sclerosis: A Review of Aetiopathogenetic Insights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by damage to motor neurons, manifested as the development of mixed (spastic-atrophic) paresis in conjunction with symptoms of corticonuclear pathway damage, ultimately leading to immobility and death due to progressive respiratory failure and accompanying pathological conditions.A genetic factor is present in 10% of cases, whereas the remaining manifestations of the disease are sporadic.Genetic research has identified approximately 50 genes associated with a high risk of developing the disease and has highlighted genetic heterogeneity, indicating the complex pathological mechanisms underlying the development of this pathology.Protein homeostasis disruptions, caused by variants in the nucleotide sequence of genes, contribute to abnormal protein aggregation and cellular stress, leading to motor neuron degradation.Additionally, RNA metabolism disorders, particularly those associated with mRNA processing, are key points in the pathogenesis of ALS.Variants in the nucleotide sequences of genes encoding RNA-binding proteins lead to toxic conformations and cellular dysfunction.Other mechanisms, such as excitotoxicity, oxidative stress, impaired DNA repair and neuroinflammation, are also associated with the pathogenesis of ALS.This complex molecular landscape of the disease demonstrates the convergence of multiple pathogenetic pathways, complicating its study and treatment.The current research study focuses on analysing up-to-date information on the etiopathogenesis underlying both the foundations of diagnostic search and the development of new therapeutic strategies.Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of both upper and lower motor neurons, which ultimately leads to muscle weakness, atrophy, spasticity and contractures. 1ALS typically manifests in the 50-60 years age range, although familial cases may present in late adolescence or early adulthood. 2The time from the first symptom to diagnosis is approximately 10-16 months, underscoring the difficulty of timely initiation of therapeutic intervention at an early stage. 3The relentless progression of the disease eventually leads to respiratory muscle dysfunction and limits survival to 3-5 years after the onset of the disease. 4proximately 10% of ALS cases are hereditary with an autosomal dominant pattern of inheritance, and the known genes associated with ALS, including SOD1, C9ORF72, FUS and TARDBP, collectively account for approximately 40-55% of all familial forms. 5,6In fact, approximately 50 genes that influence the course of ALS have been identified. 4,6In total, 90% of cases are sporadic and do not present with a familial history.The aetiology of these instances remains undetermined in the majority of cases. 7The incidence of sporadic ALS (sALS) is greater in men than in women, with a ratio of 2:1, whereas the incidence of familial ALS (fALS) is comparable between the sexes. 8e epidemiology of ALS involves variations in disease prevalence, which are influenced by genetic inheritance factors, leading to differences in morbidity levels across various regions.For example, in Europe and North America, where the population primarily has European ancestry, the incidence of ALS is somewhat higher than the global average, ranging from 1.71 to 1.89 per 100,000 people per year. 9These findings suggest that genetic or environmental factors specific to these populations may contribute to a higher frequency of ALS occurrence.In contrast, Asian countries, particularly South Asia and West Asia, have lower ALS incidence rates, with frequencies ranging from 0.73 to 0.94 cases per 100,000 people per year. 10Oceania, which includes countries such as Australia and New Zealand, has some of the highest ALS incidence rates in the world, at 4.42 per 100,000 people per year, indicating a pronounced prevalence of the disease in this region, which may be linked to a combination of genetic predispositions and environmental factors unique to Oceania. 10,11 Aetiology and pathogenesisThe onset and progression of ALS are facilitated by multiple factors.