Objective: To determine the clinical and genetic differences in hereditary spastic paraplegia SPG4 patients across various countries.

Background: SPG4/SPAST gene account for approximately 40% of cases involving autosomal dominant hereditary spastic paraplegia (HSP) and contribute to around 20% of sporadic instances. SPAST is inactivated by point mutations and deletions that can include most of the gene. Individuals affected by these genetic variations typically exhibit pyramidal signs in their lower limbs, often accompanied by additional features. Late-onset forms of HSPs commonly manifest cognitive impairment in affected individuals.

Method: A cohort of 726 SPG4 patients, consisting of 628 cases with family history and 98 sporadic cases without family history, were recruited from Italian, Brazilian, and Japanese populations in a period from 2001 to 2024. In this study, novel variants were identified by direct gene sequencing or next-generation sequencing and their pathogenetic effect was settled by co-segregation with the disease, population studies, and in silico analysis. Haplotype analysis was also performed. Additionally, neuroimaging and pathological evaluations were carried out.

Results: Genetic analysis reveals a total of 52 different pathogenic DNA changes in 284 patients. We found 20 missense mutations, and among all four variants were novel. The analysis revealed a great portion of private mutations across the populations studied and confirmed the founder effect for one recurrent variant in the Italian population. Remarkably, in our study we found four SPG4 patients with features typical of Alzheimer’s disease and eighteen with thin corpus callosum in addition to mental retardation.

Conclusion: This study aimed to investigate the SPG4/SPAST on an international cohort of HSP patients from three different continents. Epidemiological and clinical results broaden the spectrum of the clinical presentations of SPG4 suggesting new clinical associations.

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: 7665. [3] Martinello C, Panza E, Orlacchio A: Hereditary spastic paraplegias proteome: common pathways and pathogenetic mechanisms. Expert Review of Proteomics 2023, 20: 171-188.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/new-pathological-findings-in-an-international-cohort-of-hereditary-spastic-paraplegia-4-patients/