The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant.
We conducted a longitudinal analysis of Parkinson's disease (PD) patients carrying mutations in the GBA gene to better characterize genotype-phenotype correlations.
Recent evidence suggests that glucosidase beta acid (GBA) mutations predispose Parkinson's disease (PD) patients to a greater burden of cognitive impairment and non-motor symptoms.
We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates.
The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.
The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates.
In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD.