Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that impacts movement and cognition,caused by abnormal tau protein accumulation in the brain. It involves tau aggregation with 4-repeat domains in various brain regions and cell types. PSP is associated with the tau gene (MAPT),which contains recurrent genomic inversion. Evaluate the distribution and clinical impact of MAPT haplotypes on both motor and non-motor features among Tunisian PSP cohort. We conducted a cross-sectional study where we retrospectively review the medical records of all patients diagnosed with PSP, reclassifying them into phenotypes based on the MDS-2017 criteria. The phenotypes were categorized into three subgroups: Richardson’s syndrome (PSP-RS), PSP-cortical and PSP-subcortical. We collected data on clinical and neuropsychological assessments, and genotyping for MAPT haplotypes were performed using classic PCR methods, with validation by Sanger sequencing. We included 118 patients, stratifying them into three groups: 44.06% patients with PSP-RS, 31.35% with cortical PSP, and 24.57% with subcortical PSP. Regarding the MAPT genotype, female predominance was observed among H1/H1 carriers (p = 0.0096). For motor features, homozygous H1 carriers developed parkinsonism earlier (p = 0.041), more frequent Freezing of gait (p = 0.028) and vertical supranuclear gaze palsy (p = 0.041),with earlier development of oculomotor signs associated (p = 0.034). In terms of non-motor features, the homozygo0us MAPT genotype was more associated with cognitive impairment than the heterozygous profile (p = 0.0234). Memory impairment as inaugural symptom was more common in homozygous MAPT patients (p = 0.025), as was language impairment (p = 0.011). These findings suggest that PSP is linked to haplotype-dependent increases in 4-repeat (4R) tau mRNA, which may contribute to the pathogenesis of PSP and influence its clinical phenotype.