Expanding the genotypic and phenotypic spectrum of AP5Z1-related spastic paraplegia: a novel variant and comprehensive literature review

Abstract

Background: Hereditary spastic paraplegias are a diverse group of neurodegenerative diseases, clinically divided into pure and complex types. Spastic paraplegia 48 is caused by pathogenic biallelic variants in the AP5Z1 gene. Our study aims to expand the phenotypic and genotypic spectrum in this very rare syndrome. Materials and Methods: Case files, detailed anamnesis, radiological imaging, physical examination findings, ophthalmological examination and genetic results were evaluated as part of the clinical assessment. Whole-exome sequencing was performed for the proband. Sanger sequencing and next-generation sequencing were performed for confirmation of the variants and segregation analysis. Results: We identified two disease-causing variants in the AP5Z1 (NM_014855.3) gene, including a pathogenic nonsense variant (c.1322G>A, p.(Trp441Ter)) and a pathogenic frameshift variant (c.857_866del, p.(Leu286ProfsTer25)). Segregation analysis showed compound heterozygosity of the variants. Conclusion: In this report, we present a patient from Turkey with spasticity, who has compound heterozygous variants in the AP5Z1 gene, representing the 17th case described in the literature. This report expands the phenotypic spectrum of the AP5Z1- related spastic paraplegia type 48, which has only rarely been reported in the literature. It underscores the importance of comprehensive genetic testing and variant interpretation in achieving an accurate diagnosis and providing genetic counselling for affected families with spastic paraplegia.