A study of glucocerebrosidase gene variants and enzyme activity in Parkinson's disease

Abstract

Mutations in the glucocerebrosidase gene (GBA) are one of the most common genetic risk factors for Parkinson’s disease (PD). PD patients with GBA mutations appear to have an earlier age of onset and higher prevalence of non-motor symptoms (NMS). GBA mutations may confer PD risk by reducing glucocerebrosidase (GCase) activity. The frequency and clinical features of GBA- associated PD in Hong Kong are unknown. Whether reduced GCase activity is correlated with worse clinical features of PD is not well established. Hence, the aims of this study were 1) to explore the prevalence of GBA variants in Hong Kong PD patients; 2) to compare GCase activity between PD patients and healthy controls and 3) study the association among GBA variants, GCase activity and their clinical features.

A total of 311 PD patients and 99 age- and gender-matched healthy controls were recruited from two hospitals in Hong Kong. GCase activity was measured in dried blood spots for all participants and sequencing for GBA variants was performed in PD patients. Each patient was assessed for motor and non-motor features with clinical rating scales. A database containing whole exome sequencing results of 699 healthy individuals in Hong Kong was used to compare the frequency of GBA variants between patients and controls.

Fourteen GBA variants were found in 15 PD patients. More PD patients than healthy controls carried GBA variants (4.82% vs 1.29%, p < 0.001). Most GBA carriers were female (73.3%). Blood GCase activity was lower in GBA carriers than both idiopathic PD (iPD) and healthy controls (24.31 vs 38.50 vs 40.69 nmol/h/ug, p < 0.001). GBA carriers had worse bradykinesia (unstandardised difference (β) = 5.97, p = 0.026) than iPD patients, after adjusting for age, disease duration, and levodopa dosage. They also had increased risks of apathy (odds ratio (OR) = 3.02, p = 0.042), problems with concentration (OR = 5.03, p = 0.004), daytime somnolence (OR = 4.19, p = 0.017), and leg swelling (OR = 3.24, p = 0.032) compared with iPD. Furthermore, even among iPD patients with no GBA mutations, lower GCase activity was associated with increased motor fluctuations (β = 0.02, p = 0.048), increased risks of developing dysphagia (OR = 0.98, p = 0.048), sleep-related problems including intense and vivid dreams (OR = 0.97, p = 0.017) and rapid eye movement sleep behaviour disorder (OR = 0.97, p = 0.017).

This study represents one of the first investigations into the prevalence of GBA variants in Hong Kong PD patients and their role in PD. GBA variants are more frequently found in PD patients than in healthy controls and reduce GCase activity. Furthermore, low GCase activity, regardless of GBA mutation status, is associated with worse motor and non-motor features. These findings provide the basis for future studies to examine the mechanisms by which GBA genotype and activity affect clinical outcome. If the pathogenic role of reduced GCase activity in PD is confirmed, its modulation may be a viable strategy for disease modification not only in GBA-PD but also idiopathic PD.