Unraveling SPG46: Clinical, Genetic, and Neuroimaging Features
Raphael Pinheiro Camurugy da Hora1, Victor Rebelo Procaci1, Júlian Letícia Freitas1
1Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, São Paulo, Brazil.
Movement Disorders Clinical Practice
|July 23, 2026
Summary
This study details the clinical and genetic features of Hereditary Spastic Paraplegia type 46 (SPG46) in Brazil. Findings reveal a consistent phenotype and suggest a founder effect for a specific GBA2 mutation.
Area of Science:
- Genetics
- Neurology
- Rare Diseases
Background:
- Hereditary Spastic Paraplegia type 46 (SPG46) is a rare autosomal recessive disorder.
- It is caused by mutations in the GBA2 gene and is poorly understood.
- Clinical and genetic data for SPG46 are scarce.
Purpose of the Study:
- To characterize the clinical, neuroimaging, and genetic profile of SPG46 patients in Brazil.
- To expand the understanding of the SPG46 phenotype.
- To investigate potential founder effects in the Brazilian cohort.
Main Methods:
- Retrospective cross-sectional study at two Brazilian referral centers.
- Whole-exome sequencing identified pathogenic GBA2 variants in nine patients from six families.
- Systematic analysis of demographic, clinical, neuroimaging, and genetic data.
Main Results:
- Nine patients (4 males, 5 females) with SPG46, onset 6-24 years (mean 10.7).
- Consistent progressive spastic paraplegia with cerebellar ataxia, dysarthria, and cognitive impairment.
- Frequent psychiatric issues, sleep disturbances, skeletal deformities, dystonia; cerebellar atrophy noted; no corpus callosum thinning, cataracts, or hearing loss.
Conclusions:
- The recurrent GBA2 c.1365G>C;p.(Trp455Cys) variant indicates a possible founder effect in Brazil.
- This study expands the known phenotypic spectrum of SPG46.
- Highlights the importance of genetic and clinical characterization for rare diseases.
