Neurogenetics. 2025 Aug 9;26(1):58. doi: 10.1007/s10048-025-00841-8.
ABSTRACT
Hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Autosomal recessive HSPs (AR HSPs) are rare and account for approximately 30% of cases, with a higher prevalence in populations with increased consanguinity rates. In this study, we investigated 10 patients diagnosed with AR HSPs and identified pathogenic variants in SPART, FA2H, AP4B1, SPG7, SPG11, CYP2U1, and CYP7B1, with three cases harboring novel variants. Clinical presentations ranged from pure spastic paraplegia to complex phenotypes involving intellectual disability, ataxia, dysarthria, joint abnormalities, and systemic features. Exome sequencing and detailed bioinformatics analyses were employed to identify causative variants, which were classified based on ACMG criteria. The study expands the known genetic spectrum of AR HSPs by reporting previously undescribed variants and providing insight into their potential pathogenic mechanisms. The presence of distinct clinical features in patients with the same genetic variant emphasizes the complexity of genotype-phenotype correlations in HSP. Our findings highlight the importance of genetic testing in early diagnosis and clinical management of HSP, enabling more precise prognostic evaluations and potential therapeutic interventions. Given the high consanguinity rates in certain populations, targeted genetic screening may facilitate early detection and personalized treatment strategies. Further functional studies are needed to elucidate the molecular impact of these novel variants and their role in disease progression, potentially paving the way for future gene-based therapies.
PMID:40782215 | DOI:10.1007/s10048-025-00841-8
