GLUCOCEREBROSIDASE MUTATIONS IN 108 NEUROPATHOLOGICALLY CONFIRMED CASES OF MULTIPLE SYSTEM ATROPHY

Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA) are synucleinopathies whose primary pathogenic event is the deposition of inclusions composed of aberrantly fibrillized α-synuclein.¹ In PD and LBD, Lewy bodies are the key aggregate, whereas in MSA, α-synuclein accumulates in the form of oligodendroglial and neuronal cytoplasmic inclusions (GCIs and NCIs).^2,3

Parkinsonian manifestations have been noted in a subset of patients with Gaucher disease and there is evidence that parkinsonism is more frequent among carrier relatives of patients with Gaucher disease.⁴ In a remarkable study, the glucocerebrosidase (GBA) gene was sequenced in an American PD brain bank series where GBA mutations were detected at a much higher frequently than in controls (PD 21% vs control 4.5%).⁵ These findings have since been replicated, mainly in Ashkenazi patient groups who have a higher mutation frequency but also in patients with clinically and pathologically diagnosed PD and LBD in a number of studies in different populations.⁴ In a study of 75 neuropathologically confirmed synucleinopathies, GBA mutations were found in 23% of the cases with Lewy bodies.⁶ The frequency of GBA mutations around the world between 2.3 and 31% (depending on population) indicates …