No association of GBA mutations and multiple system atrophy

Background: Multiple system atrophy (MSA) is a synucleinopathy characterized by oligodendroglial and neuronal α-synuclein inclusions. Heterozygous mutations in the glucocerebrosidase (GBA) gene represent the most common genetic risk factor for Parkinson’s disease and have been associated with atypical clinical features overlapping with MSA. This study investigated whether GBA mutations are also associated with MSA.

Methods: A total of 344 European patients with probable MSA were analyzed. Two hundred and ninety-five patients were screened for the common GBA mutations N370S and L444P using restriction enzyme digest, high-resolution melting curve analysis, or Sanger sequencing. An additional 49 patients underwent full sequencing of all coding exons of GBA. Mutation frequencies were compared with previously analyzed healthy controls.

Results: Two N370S mutations were identified among 295 screened patients, yielding a mutation frequency of 0.58%. No L444P mutations or additional pathogenic GBA variants were detected. Four patients carried the non-pathogenic T369M polymorphism. No GBA mutations were found in healthy controls. The observed mutation frequency is comparable to that of the general population.

Conclusions: GBA mutations are not common in patients with MSA and do not represent a major genetic risk factor for the disease. Despite clinical overlap between GBA-associated Parkinson’s disease and MSA, these findings support the view that MSA is largely a sporadic disorder with distinct genetic underpinnings.