Progressive Supranuclear Palsy-Like Phenotype in a GBA E326K Mutation Carrier

Mutations in the beta‐glucocerebrosidase gene (GBA ), encoding the lysosomal enzyme that is deficient in Gaucher's disease (GD), are important and common risk factors for Parkinson's disease (PD) and Lewy body dementia (LBD; i.e., α‐synucleinopathies). PD patients with GBA mutations have younger age at onset and are more likely to develop cognitive dysfunction. There are approximately 300 known GBA mutations and determining accurate exact genotype‐phenotype correlations is challenging. In general, GBA mutations were found to variably influence PD risk according to their impact on the protein function. The GBA variant, E326K, has long been considered a polymorphism, given that homozygous individuals do not develop GD. However, this variant was found to reduce GBA enzymatic activity in vitro and mildly increase the risk to develop PD (OR:1.7), with frequent development of associated dementia. The impact of GBA mutations on the risk to develop tauopathies is less defined, given that previous studies failed to report a significant association with PSP and corticobasal degeneration. Yet, more recent data suggest that the clinical phenotype of GBA‐associated neurodegeneration is more heterogeneous than previously assumed, including phenotypes distinct from α‐synucleinopathies. Herein, we report on a patient with an unusual phenotype characterized by supranuclear vertical gaze palsy at onset with late emergence of postural instability carrier of the GBA E326K variant.