Clinical and genetic characteristics of 536 young-onset amyotrophic lateral sclerosis in China: a single-center retrospective study.

Objective: Young-onset amyotrophic lateral sclerosis (ALS), defined as symptom onset at or before 45 years, remains poorly characterized in Chinese patients. We aimed to describe its clinical and genetic features and compare them with adult-onset ALS. Methods: We retrospectively analyzed 536 young-onset ALS patients registered at Peking Union Medical College Hospital (2014-2022) alongside 1136 adult-onset patients (onset >45 years). Whole exome sequencing targeting 41 established ALS-related genes was performed in all young-onset patients. Results: Young-onset ALS accounted for 32.0% of the cohort, with a median onset age of 39.5 years (IQR 34.25-44.0). Compared with adult-onset patients, young-onset cases had less bulbar onset (14.2% vs. 19.5%, p = 0.008), more frequent predominant upper motor neuron phenotype (25.9% vs. 15.4%, p < 0.001), higher baseline ALSFRS-R scores (p < 0.001), slower progression (p = 0.001), and longer median survival (36 vs. 30 months, p = 0.009). Familial ALS was more common in the young-onset group (8.4% vs. 3.8%, p < 0.001). Rare variants were identified in 20.0% of young-onset patients across 32 genes; pathogenic or likely pathogenic variants were predominantly in SOD1 and FUS. Compared with adult-onset patients, SOD1 was proportionally more common in adult-onset disease, whereas FUS variants were markedly enriched among young-onset cases, suggesting age-dependent differences in genetic architecture. Conclusion: Young-onset ALS in China is characterized by a slower clinical course and a distinct genetic profile dominated by SOD1 and FUS, with near-absent C9orf72 expansions. Routine genetic testing and age-stratified trial design are warranted in this population.