SPG4 and Dementia: Expanding the Clinical Spectrum

Objective: Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/SPAST being the most common cause. Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4/SPAST gene in patients with HSP. Methods: The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4/SPAST variants were identified using direct and next-generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis. Results: Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4/SPAST mutations in 284 patients, including four novel variants. Several mutations were population-specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP-SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4/SPAST mutations presented with thin corpus callosum and intellectual disability. Interpretation: In this study, we investigated pathogenic SPG4/SPAST variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP-SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype-phenotype relationships offers insights into patient counseling and future research planning.