Advances in ALS genetics and emerging precision therapies

Amyotrophic lateral sclerosis (ALS) is characterized by devastating degeneration of upper and lower motor neurons, leading to weakness, bulbar dysfunction, respiratory failure, and a mean survival of 3–5 years. Pathogenic variants are detected in about 70 % of familial and 10–20 % of sporadic cases, with more than 50 disease-associated genes identified. The most common ones are C9ORF72 , SOD1 , TARDBP , and FUS . In Taiwan, SOD1 and C9ORF72 mutations occur at similar frequencies, contrasting with the predominance of C9ORF72 in Europe and North America, underscoring ethnic differences. These findings highlight that ALS pathogenesis is complex, with mechanisms increasingly understood as multistep and oligogenic. Beyond conventional mutations, short tandem repeat (STR) expansions represent another important category of pathogenic variants. In addition to C9ORF72 hexanucleotide expansion, intermediate ATXN2 CAG expansions increase ALS risk, while expansions in HTT , ATXN1 , TBP , and NOTCH2NLC have also been implicated. Genetically targeted therapies are advancing. The antisense oligonucleotide (ASO) tofersen, which degrades SOD1 mRNA, received FDA approval in 2023 as the first precision therapy for SOD1 -ALS. Other approaches, such as ulefnersen (ION363) for FUS -ALS, RNAi therapy for SOD1 (ALN-SOD), are in development. Genetic insights are reshaping ALS nosology and accelerating precision medicine in clinical care and therapeutic development.