Objective: To describe the epidemiological, clinical, and genetic features of patients affected by hereditary spastic paraplegia (HSP) in an international cohort of affected individuals.To describe the epidemiological, clinical, and genetic features of patients affected by hereditary spastic paraplegia (HSP) in an international cohort of affected individuals.

Background: HSP represents a clinical and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The gene found most often mutated in this group of disease is SPG4/SPAST. Nevertheless, data about the incidence of mutations in this gene in HSP patients from different populations is unknown.

Method: The study includes the evaluation of a comprehensive spectrum of neurological features, and the mutational screening of the SPG4/SPAST gene in a large cohort of patients, recruited from worldwide populations in a period from 2008 to 2023.

Results: Clinical assessment and genetic analysis on the SPG4/SPAST gene were performed. Mutational screening was carried out by next generation sequencing and Sanger sequencing, or investigation of large rearrangements by using multiplex ligation dependent probe amplification. Novel variants were confirmed and pathogenetic effect was determined by co-segregation with the disease, population studies, and in silico analysis. Haplotype study was performed on some recurrent variants and suggested the founder effect for one mutation in the Italian population.

Conclusion: In this multicenter international work, we present the genetic analysis of the SPG4/SPAST gene and the clinical and epidemiological results of the screening in a large cohort of HSP patients from worldwide. The analysis broadens the spectrum of the clinical presentations associated with SPG4 mutations and confirms a predominantly pure form of HSP with mild-to-moderate disability in many cases.

References: 1. Panza E, Meyyazhagan A, Orlacchio A: Hereditary spastic paraplegia: Genetic heterogeneity and common pathways. Experimental Neurology 2022, 357: 114203. 2. Meyyazhagan A, Kuchi Bhotla H, Pappuswamy M, Orlacchio A: The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences 2002, 23(14), 7665.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-spastic-paraplegia-type-4-spg4-an-international-multicenter-clinical-and-genetic-study/