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

Dual inheritance, dominant and recessive, of the same gene through haploinsufficiency, dominant-negative effects, gene dosage or allele-specific functional consequences

This review, presented as the first comprehensive synthesis of dual inheritance in hereditary spastic paraplegia (HSP), evaluates the literature published up to June 2026, identifying patients with monoallelic or biallelic pathogenic variants and assessing classically dominant genes for evidence of recessive disease. Six genes (ALDH18A1, ERLIN2, KIF1A, REEP2, UCHL1, SPTSSA) are confirmed as established dual-inheritance genes, and supporting evidence for recessive inheritance is found for ATL1, SPAST, RTN2, BSCL2 and SPTAN1. Dual inheritance arises through diverse mechanisms: haploinsufficiency, dominant-negative effects, gene dosage and allele-specific functional consequences. Biallelic variants generally lead to earlier onset and more severe phenotypes, but genotype-phenotype correlations vary considerably between genes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A useful reminder for interpretation: in a gene considered dominant such as SPAST or ATL1, a second variant should not be dismissed outright, especially with early onset or unusually severe disease, and genetic counselling (recurrence risk, parental status) depends directly on it. The method is not detailed in the abstract (databases searched, inclusion criteria, number of studies), which limits assessment of its completeness. For SPAST and ATL1, recessive inheritance remains at the stage of supporting evidence, not an established mode.

Analysis by Dr Thibaut Benquey