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Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons in the cerebral cortex, brainstem, and spinal cord. It involves both upper and lower motor neurons, leading to clinical manifestations such as progressive skeletal muscle weakness, atrophy, fasciculations, bulbar palsy, and pyramidal tract signs.While sensory systems and sphincter control are typically preserved, nearly 50% of patients may experience cognitive or behavioral impairments, and approximately 10–15% meet diagnostic criteria for frontotemporal degeneration. Additionally, 30–60% of ALS patients may develop hypermetabolic syndrome, characterized by increased resting energy expenditure, weight loss, and an accelerated decline in motor function and survival [1].

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ALS is classified as a rare disease, with an annual incidence of 2–3 per 100,000 and a prevalence of 3–5 per 100,000 in Europe and North America. The peak age of onset is between 50 and 75 years, and the male-to-female ratio ranges from 1.2 to 1.5:1. Approximately 10% of ALS cases are familial (fALS), while the remaining 90% are sporadic (sALS).In China, the incidence is approximately 0.6 per 100,000, with a prevalence of 3.1 per 100,000. The peak onset age is around 50 years, with a trend toward younger onset in recent years. Notably, familial ALS cases tend to have an earlier onset than sporadic cases. In China, 22.8% of ALS cases present with bulbar-onset symptoms. The median survival for most patients is 2–4 years, although significant individual variability exists [2–3].

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Pathogenesis and Therapeutic AdvancesThe pathogenesis of ALS remains incompletely understood, with approximately 90% of cases having unknown causes. Current research suggests that ALS results from a combination of genetic and environmental factors. The most commonly implicated genes include C9orf72, SOD1, FUS, and TARDBP.In 2023, the FDA approved the first gene-targeted therapy—Tofersen (Qalsody)—specifically for patients with SOD1-mutant ALS. Multiple cellular and molecular mechanisms have been identified in disease progression, including mitochondrial dysfunction, axonal transport deficits, toxic protein aggregation, impaired protein degradation, and prion-like propagation. Abnormal accumulation of TDP-43 is observed in the vast majority of ALS patients, underscoring its central role in ALS pathogenesis [4–5].

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ALS research and treatment are increasingly moving toward the era of precision medicine. Integrative multi-omics approaches, including deep phenotyping, imaging, and genomic analysis, are expected to improve understanding of disease heterogeneity and help identify more homogeneous patient subgroups, enabling the development of targeted therapies.Gene therapy, especially approaches aimed at specific mutations, is an active area of exploration. The first ALS prevention trial is currently underway, assessing Qalsody in asymptomatic SOD1 mutation carriers. For sporadic ALS, further research is needed to investigate the impact of environmental risk factors and lifestyle in order to inform effective prevention strategies. Moreover, the development and validation of biomarkers will be essential for early diagnosis and prognostic assessment.

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[1]   Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400(10360): 1363-1380.

[2]  Van Es MA,Hardiman O,Chio A,et al. Amyotrophic lateral sclerosis[J].Lancet,2017,390 (10107):2084-2098.

[3]  NORRIS S P, LIKANJE M N, ANDREWS J A. Amyotrophic lateral sclerosis: update onclinicalmanageme nt[J]. Curr Opin Neurol. 2020; 33(5):641- 648.

[4] The ALS Association, https://www.als.org/research/als-research-topics/als-risk-factors   

[5] Bozzoni V, Pansarasa O, Diamanti L, Nosari G, Cereda C, Ceroni M. Amyotrophic lateral sclerosis and environmental factors. *Funct Neurol*. 2016;31(1):7-19.

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