Frequency of GBA Variants in Autopsy-proven Multiple System Atrophy

Abstract

Background: Multiple system atrophy (MSA) is marked by abnormal inclusions of α-synuclein in oligodendrogliocytes, and its etiology remains unknown. Variants in the glucocerebrosidase (GBA) gene have been associated with the other synucleinopathies, dementia with Lewy bodies, and Parkinson's disease. It is unclear whether glucocerebrosidase variants are associated with MSA. The objective of this study was to analyze the frequency of GBA variants among patients who had autopsy-proven MSA at a brain bank in New York City. Methods: GBA was fully sequenced in brain tissues from 17 patients with autopsy-proven MSA for whom there was extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test whether brains from patients with MSA were enriched for GBA variants, the frequency of GBA variants in the MSA brains was compared with that of variants in all brains from patients with pure Alzheimer's disease (AD) at Columbia University for which GBA genotype was available (n = 82). Results: Of 17 MSA brains, 4 carried GBA variants (23.5%), including 1 that was homozygous for N370S and 1 each that carried heterozygous N370S, T369M, and R496H variants. Among the comparator brains with pure AD, 3 of 82 (3.7%) carried GBA variants (P = 0.0127; Fisher exact test), including 1 each with an N370S homozygous variant, an R496H heterozygous variant, and a T369M heterozygous variant. Conclusion: A higher frequency of GBA variants was observed among brains from patients who had pathologically diagnosed MSA compared with the frequency of variants in brains from patients who had AD. The results indicate a need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.