SPG4 and Dementia: Expanding the Clinical Spectrum

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.

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.

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.

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.