Genetic architecture of hereditary spastic paraplegia: from monogenic to oligogenic models

Hereditary spastic paraplegia (HSP) encompasses a clinically and genetically heterogeneous group of neurodegenerative disorders, characterized by progressive lower limb spasticity due to corticospinal tract degeneration. While traditionally regarded as monogenic, recent genomic advances have revealed more complex inheritance models, including oligogenic and polygenic contributions. This mini-review examines the evolving genetic landscape of HSP, integrating established monogenic forms with emerging evidence of cumulative variant burden. Importantly, current evidence remains insufficient to establish oligogenic inheritance as a validated or broadly applicable pathogenic mechanism in HSP, and most available data should be considered exploratory and hypothesis-generating rather than conclusive. Monogenic subtypes such as SPG4, SPG7, and SPG11 remain central to current understanding, but analyses of large sequencing cohorts show that up to 40% of cases lack a single-gene explanation. Both statistical analyses and illustrative reports, such as ultra-rare variant enrichment involving SYNE1, CAPN1, and PGAP1, suggest that oligogenic inheritance may operate in a subset of unresolved cases, although current evidence remains preliminary and not yet broadly validated. Pathogenic mechanisms converge on shared molecular pathways including microtubule dynamics, endoplasmic reticulum shaping, lipid metabolism, mitochondrial maintenance, and vesicular trafficking. Recognition of these multilayered mechanisms informs diagnostic strategies, favoring whole-exome or genome sequencing, variant burden analysis, and refined genetic counselling. Functional studies in cellular and animal models, coupled with biomarker discovery, are crucial to unravel gene-gene interactions and identify therapeutic targets. HSP exemplifies a genetic continuum ranging from high-penetrance monogenic forms to genetically unresolved phenocopies and putative oligogenic cases influenced by cumulative variant burden. Accordingly, diagnosis should incorporate multi-locus models as a hypothesis-testing framework in selected unresolved cases rather than as an established default explanation, counselling must address probabilistic inheritance, and therapeutic development should prioritize pathway-based interventions. Multidisciplinary integration of genomic, mechanistic, and clinical insights is essential to achieve precise diagnoses and personalized therapies.