Hereditary spastic paraplegia: new insights into clinical variability and spasticity-ataxia phenotype, and novel mutations

Introduction Hereditary spastic paraplegias (HSPs), a genetically heterogeneous group of neurodegenerative diseases, have an incidence of around 3 to 9 individuals every 100,000. Due to the broad clinical and genetic variability of HSPs, it is challenging to diagnose the disorder quickly and precisely. Hereditary spastic ataxias (HSAs) and HSPs are overlapping diseases, and their intersection has been gradually identified by next-generation sequencing. The idea of the spasticity-ataxia phenotype (SAP) spectrum is further substantiated by the similarities in phenotypes and underlying genes in ataxias and inherited spastic paraplegias and the related cellular processes and disease mechanisms these disorders exhibit. Methods Whole-exome sequencing was performed on the 25 spastic or spastic-ataxic gait patients. Results Twenty-two specific HSPs-HSAs-SAP mutations, including 14 novel mutations, were found in 25 cases from 18 Turkish and 2 Syrian families. This research discovers many novel hereditary spastic paraplegia (HSP) mutations and shows a robust genotype-phenotype heterogeneity in the disease. Conclusions This research helped expand the clinical and molecular scope of HSP and clarified the concept of the spasticity-ataxia phenotype, further enhancing our understanding of the complicated form of HSP and its association with ataxia. Our data broadens the spectrum of HSPs and HSAs related gene mutations and provides insights for genotype-phenotype correlations for HSPs and HSAs.

Automated summary

This study identified 22 specific HSPs-HSAs-SAP mutations, including 14 novel mutations, in 25 patients with spastic or spastic-ataxic gait, expanding the clinical and molecular scope of HSP and clarifying the concept of the spasticity-ataxia phenotype. The research reveals a robust genotype-phenotype heterogeneity in the disease, broadening the spectrum of HSPs and HSAs related gene mutations and providing insights for genotype-phenotype correlations for HSPs and HSAs.