Insights into X-linked Dystonia-Parkinsonism and Spinocerebellar Ataxia type 36 Through the Lens of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.

The abnormal expansion of repetitive DNA sequences falls within the spectrum of neurological conditions driven by dual pathogenic pathways of RNA toxicity and protein toxicity. Within this spectrum, hexanucleotide repeat disorders (HRDs) represent a rare but important subgroup: C9orf72-amyotrophic lateral sclerosis/frontotemporal dementia (C9orf72-ALS/FTD), X-linked dystonia-parkinsonism (XDP) and spinocerebellar ataxia type 36 (SCA36), unified by the presence of expanded intronic repeats capable of forming non-canonical nucleic acid structures. Despite this shared repeat architecture, they differ in critical molecular and genetic respects: C9orf72-ALS/FTD is hallmarked by TDP-43 aggregation and prominent proteinopathy; SCA36 lacks TDP-43 pathology entirely; and XDP uniquely harbors a SINE-VNTR-Alu (SVA) retrotransposon insertion within the expanded locus and follows an X-linked recessive inheritance pattern. Among these, C9orf72-ALS/FTD is relatively well characterized, with established pathogenic mechanisms including G-quadruplex (G4) formation, dipeptide repeat (DPR) protein toxicity, RNA foci formation, and downstream cellular disruptions. The molecular mechanism underlying SCA36 and XDP remains comparatively less characterized. Given the mechanistic overlap with ALS/FTD, downstream disruptions such as RNA toxicity, mitochondrial dysfunction, impaired DNA repair and proteasomal dysfunction could similarly result from these core molecular processes. However, direct experimental evidence supporting these mechanisms in SCA36 and XDP remains limited. This review compares established, emerging and hypothetical mechanisms across HRDs to distinguish shared pathogenic pathways from disease-specific molecular features. Through horizontal comparison, this review identifies opportunities and limitations for translating ALS/FTD therapeutics to XDP and SCA36, establishing a unified analytical framework for mechanistic research and clinical intervention in rare repeat expansion disorders.