Amyotrophic lateral sclerosis (ALS) was initially described as a pure motor neuron disorder in 1869 by the eminent French neurologist Jean-Martin Charcot, who was also the first to use the term “amyotrophic lateral sclerosis” (Rowland, 2001; Chakraborty and Diwan, 2022). In honor of Jean-Martin Charcot, ALS is also referred to as Charcot’s disease (Akçimen et al., 2023). ALS is currently recognized as a fatal multisystem neurodegenerative disorder characterized by progressive degeneration of both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord, which leads to muscle weakness, dysphagia, dysarthria, spasticity, paralysis, and ultimately respiratory failure (Root et al., 2021; Feldman et al., 2022; Goutman et al., 2022). Neuropathologically, ALS is marked by axonal retraction, loss of neuromuscular junction, motor neuron death, astrocyte and microglia proliferation, and ubiquitin-positive cytoplasmic inclusions in surviving neurons (Masrori and Van Damme, 2020). The variability and atypicality of the initial symptoms in ALS pose a challenge to the early diagnosis. ALS manifests as insidiously focal muscle weakness that progresses to widespread involvement, including respiratory muscles such as the diaphragm (Brown et al., 2017). Respiratory muscle paralysis is the proximate cause of death, typically occurring within 2–4 years post-diagnosis (Masrori and Van Damme, 2020; Goutman et al., 2022). ALS is one of the most frequent intractable neurodegenerative diseases with adult onset (Nowicka et al., 2019). The crude prevalence is 4.42/100,000, and the estimated incidence is 1.59/100,000 per year worldwide, but the accumulated lifetime disease risk is approximately 1/800–2/800 (Xu et al., 2019; Martier and Konstantinova, 2020). Worldwide epidemiological studies demonstrated geographical heterogeneity in the incidence of ALS, with higher incidence rates in Europe and America compared to those in Africa and Asia (Chiò et al., 2013; Marin et al., 2017).

Approximately 10% of ALS cases are classified as familial ALS (FALS) due to the presence of a positive family history, which typically manifests a Mendelian pattern of inheritance (Zou et al., 2013; Li et al., 2023). The remaining cases without prior family history are classified as sporadic ALS (SALS) (Lanznaster et al., 2020). Some FALS cases may be misclassified as sporadic due to factors including short disease duration, phenotypic heterogeneity, incomplete penetrance, small family size, and incomplete family history information (Udine et al., 2023). Over the past 30 years, with the significant advancement of molecular genetic technology, substantial progress has been made in identifying causative and susceptibility genes associated with ALS. Genetic factors are widely recognized to play a significant role in the pathogenesis of ALS, and pathogenic variants in known genes are responsible for approximately 70% of FALS cases and 15% of SALS cases (Yuan et al., 2024). Variants occurring in crucial regions of ALS-related genes may result in FALS, whereas variants in non-essential regions of genes might confer disease susceptibility or cause SALS, modified by other genetic, epigenetic, and environmental factors (Deng et al., 2016). To date, at least 34 disease-causing loci and 32 genes associated with ALS have been identified according to the Online Mendelian Inheritance in Man database (Table 1). These include 4 genes with dual inheritance patterns (autosomal dominant and recessive), 24 autosomal dominant genes, 3 autosomal recessive genes, and an X-linked inheritance gene. The inheritance pattern related to the gene variants generally reflects the underlying molecular disease mechanisms. Autosomal dominant phenotypes typically result from variants exhibiting gain-of-function, dominant-negative, or loss-of-function (haploinsufficiency) effects, whereas autosomal recessive phenotypes are often associated with loss-of-function variants (Holtes et al., 2025). The pathophysiological processes of ALS can be broadly categorized into several categories (Fig. 1): aberrant RNA metabolism, impaired DNA repair, toxic protein aggregation, vesicular transport defects, altered autophagy, proteostasis defects, cytoskeletal disturbances, axonal transport defects, mitochondrial dysfunction, excitotoxicity, oxidative stress, prion-like spreading, dysfunction of non-neuronal cells, and neuroinflammation, which are related to various genes (Taylor et al., 2016; Bagyinszky et al., 2023). In this review, we systematically summarize the findings regarding the clinical characteristics, neuropathological features, and causative or susceptibility loci/genes associated with ALS. The focus is on the significant genetic findings and how these findings provide us with a better understanding of potential pathogenic pathways and mechanisms underlying the monogenic forms of ALS.