Decreased Penetrance of Parkinson's Disease in Elderly Carriers of Glucocerebrosidase Gene L444P/R Mutations: A Community-Based 10-Year Longitudinal Study

Background: Heterozygous mutations in the glucocerebrosidase gene (GBA) have been shown to be an important genetic risk factor for Parkinson's disease (PD) worldwide. However, the penetrance of GBA heterozygote for L444P, the common mutation for Asian population, is not known in older Chinese people.

Objectives: To assess the conversion rate to PD in identified carriers of GBA L444P/R mutations in Chinese community-dwelling older adults.

Methods: The GBA gene was sequenced for mutations at position 444 in 8405 people older than 55 years who participated in the Beijing Longitudinal Study on Aging II cohort. Nine subjects were identified as heterozygous carriers of GBA L444P or L444R mutations at baseline and clinically followed up from 2009 to 2019 to investigate their PD conversion, motor and nonmotor symptoms, and change of vesicular monoamine transporter type 2 using tracer of [¹⁸ F]9-fluoropropyl-(+)-dihydrotetrabenazine (¹⁸ F-DTBZ, also known as ¹⁸ F-AV-133).

Results: Eight heterozygous GBA L444P and 1 L444R mutation carriers were identified without PD at baseline, and none of them developed clinical parkinsonism after a 10-year follow-up.

Conclusions: Although GBA mutations may lead to an earlier onset PD, the majority of GBA L444P heterozygotes in older adults may not convert to PD. Further studies are warranted to identify factors that modify the risk of conversion. © 2020 International Parkinson and Movement Disorder Society.