Double trouble in hereditary spastic paraplegia: revisiting the classical inheritance model

Hereditary spastic paraplegia (HSP) comprises a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower-limb spasticity and weakness. Although HSP genes have traditionally been classified according to a single mode of inheritance, increasing evidence indicates that several genes can cause disease through both autosomal dominant and autosomal recessive inheritance, complicating molecular diagnosis, variant interpretation, and genetic counseling. Here, we present the first comprehensive review of dual inheritance in HSP by systematically evaluating the published literature through June 2026. Patients carrying monoallelic or biallelic pathogenic variants were identified, and classically dominant HSP genes were further assessed for evidence supporting recessive disease. Six genes (ALDH18A1, ERLIN2, KIF1A, REEP2, UCHL1, and SPTSSA) were confirmed as established dual-inheritance HSP genes, while supporting evidence for recessive inheritance was identified for ATL1, SPAST, RTN2, BSCL2, and SPTAN1. Dual inheritance was shown to arise through diverse molecular mechanisms, including haploinsufficiency, dominant-negative effects, gene dosage, and allele-specific functional consequences. Although biallelic variants generally resulted in earlier onset and more severe phenotypes, genotype-phenotype correlations varied considerably among genes. Comparative analyses also identified gene-specific patterns of variant distribution, recurrent mutational hotspots, and domain enrichment. Together, these findings provide a unified framework for understanding dual inheritance in HSP and highlight the evolving nature of inheritance patterns as genomic evidence continues to expand. Recognizing dual inheritance has important implications for molecular diagnosis, variant interpretation, and genetic counseling and supports considering biallelic pathogenic variants even in genes traditionally regarded as exclusively autosomal dominant, particularly in patients with early-onset or unusually severe disease.