ATXN2 Spectrum Disorders: Genetic Complexity Beyond Dominant Inheritance

The genetic complexity of ATXN2 challenges conventional paradigms in neurodegeneration. While initially linked to autosomal dominant spinocerebellar ataxia type 2, ATXN2 CAG expansions have emerged as a major risk factor for amyotrophic lateral sclerosis. In a recent article, Saucier et al. describe an Acadian family with a recessive inheritance pattern of ATXN2-related disease, challenging the long-held assumption of a predominantly autosomal dominant, gain-of-function-driven mechanism. Here, we analyze how ATXN2's inheritance mode may shift based on repeat interruptions, somatic mosaicism, and gene dosage, suggesting that loss-of-function mechanisms contribute to pathogenesis in certain contexts. We discuss implications for disease classification, genetic counseling, and therapeutic strategies, emphasizing the need for genetic stratification.