Patients with Parkinson disease (PD) with glucocerebrosidase (GBA) gene variants experience faster progression of motor impairment in the early stages of PD, according to study results published in Neurology. Additionally, a GBA mutation led to faster decline in activities of daily living (ADL) and motor examination scores compared with a GBA polymorphism.
This is the first study to evaluate the association of GBA variants and motor impairment as measured by Unified Parkinson Disease Rating Scale (UPDRS) in the disease’s early stages.
The study researchers examined longitudinal data from 3 prospective population-based studies of patients with PD in Northern Europe: the Norwegian ParkWest study, the Swedish NYPUM study, and the Scottish PINE study. At baseline, they performed genomic DNA extraction, medical and neurologic exams, and interviews to obtain medical, drug, and family history of the disease. They used the Hoehn and Yahr, the UPDRS sections II (ADL) and III (motor examination), and the Mini-Mental State Examination in conducting regular clinical follow-up with 440 patients (men, 267) for a median of 7 years from the time of diagnosis. A study neurologist prescribed antiparkinsonian treatment.
The patients’ mean age at baseline was 69.9 (Standard Deviation [SD], 9.6) years. A total of 25 patients withdrew from the study and 117 patients died during the study. The study researchers identified 53 patients with GBA variants: 29 E326K, 16 T369M, 6 L444P, 1 Y135C, 1 N370S, and 1 V460L variant.
Carriers of GBA variants experienced the first motor symptoms of PD earlier than noncarriers did (P =.022) and were younger at age of diagnosis (P =.014). The 2 groups did not differ at the time of diagnosis in severity of overall motor or ADL function, tremor, rigidity, bradykinesia, or axial impairment (all P >.1).
Using mixed linear models and adjusting for age, sex, study cohort, and duration of motor symptoms at baseline, the study researchers found a 69 percent more rapid motor decline per year in GBA-carriers than in noncarriers. Carriers experienced an annual increase in UPDRS motor score of 2.2 (95% CI, 1.3-3.1) points, while noncarriers experienced an annual increase of 1.3 (95% CI, 1.1-1.6) points. The difference was significant (0.9-point difference per year; 95% CI, 0.2-1.5; P =.007). Carriers were also predicted to display an annual increase in UDPRS ADL score of 1.5 (95% CI, 1.1-2) points compared with a 1-point annual increase in noncarriers (95% CI, 0.9-1.1).
The deleterious mutation carrier group had the highest predicted change in annual UPDRS ADL score compared with noncarriers (0.9-point difference per year; 95% CI, 0.1-1.7; P =.029) than for the polymorphism carrier group (0.4-point difference per year; 95% CI, 0.1-0.8; P =.016). UPDRS motor score declined more steeply for carriers of a GBA mutation (1.2-point difference per year; 95% CI, -0.3 to 2.7; P =.11) than for carriers of a polymorphism (0.8-point difference per year; 95% CI, 0.1-1.5; P =.022).
Bradykinesia score was predicted to increase by 0.5 points per year more in carriers of a GBA variant compared with noncarriers (95% CI, 0.2-0.8; P =.002). The annual change in bradykinesia was greater in carriers of a GBA mutation (0.85; 95% CI, 0.13-1.58; P =.021) than carriers of a GBA polymorphism (0.41; 95% CI, 0.08-0.75; P =.014). Rigidity increased more quickly in GBA carriers than in noncarriers (0.2-point difference per year; 95% CI, 0-0.3; P =.038).
Limitations of the study included the sample size of genotype groups and the use of a linear model to estimate disease progression.
Based on their findings, study researchers concluded that “GBA variants are linked to a more aggressive motor disease course over seven years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.”
Disclosure: A few study authors declared affiliations with the industry. Please see the original reference for a full list of authors’ disclosures.
Maple-Grødem J, Dalen I, Tysnes O, et al. Association of GBA Genotype with Motor and Functional Decline in Newly Diagnosed Patients with Parkinsons Disease. Neurology. Published online December 21, 2020. doi:10.1212/WNL.0000000000011411