Unraveling SPG46: Clinical, Genetic, and Neuroimaging Features.
TL;DR
The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant suggests a potential founder effect and expands the phenotypic spectrum of SPG46 in Brazil.
Abstract
Background
SPG46 is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic GBA2 mutations. As a rare and still poorly understood condition, information about its clinical and genetic spectrum is scarce.
Objective
This study aimed to delineate the clinical, neuroimaging, and genetic characteristics of a Brazilian SPG46 cohort.
Methods
We conducted a retrospective cross-sectional study at two referral centers, identifying nine patients from six unrelated families harboring pathogenic GBA2 variants through whole-exome sequencing. Demographic, clinical, neuroimaging, and genetic data were systematically analyzed.
Results
The cohort (4 males, 5 females) presented disease onset between 6 and 24 years (mean, 10.7). All exhibited progressive spastic paraplegia associated with cerebellar ataxia, dysarthria, and cognitive impairment. Psychiatric manifestations, sleep disturbances, skeletal deformities, and dystonia were frequent. Cerebellar atrophy was observed in four cases, whereas corpus callosum thinning, cataracts, and hearing impairment were absent.
Conclusion
The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant suggests a potential founder effect and expands the phenotypic spectrum of SPG46 in Brazil.