SPG4 and Dementia: Expanding the Clinical Spectrum.

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders.
• Mutations in the SPG4/SPAST gene are the most frequent cause of HSP.
• Limited comparative studies exist on the clinical and molecular aspects of SPG4/SPAST mutations across diverse populations.

Purpose of the Study:

• To investigate the clinical, pathological, and genetic spectrum of SPG4/SPAST gene mutations in HSP patients.
• To compare SPG4/SPAST mutation characteristics across different ethnic populations.
• To identify novel SPG4/SPAST variants and understand their pathogenicity.

Main Methods:

• Recruitment of 726 HSP patients from Italy, Brazil, and Japan (2001-2025).
• Identification of SPG4/SPAST variants using direct and next-generation sequencing.
• Confirmation of variant pathogenicity via familial segregation and in silico analysis.

Main Results:

• Observed clinical and epidemiological variations in phenotype, age at onset, and disability across populations.
• Identified 52 pathogenic SPG4/SPAST mutations in 284 patients, including four novel variants.
• Found population-specific mutations and a potential founder effect in Italy; noted dementia in 44 patients, with atypical pathology in four autopsied cases; identified thin corpus callosum and intellectual disability in 18 patients.

Conclusions:

• Pathogenic SPG4/SPAST variants were analyzed in an international HSP cohort.
• The study expands the clinical spectrum of HSP-SPG4, including a novel atypical dementia presentation.
• Genotype-phenotype correlations provide insights for patient counseling and research.