Objective: To study differences in disease characteristics in PD associated with 1 or 2 mutations in the most common PD-associated genes in the Ashkenazi Jewish (AJ) population, GBA and LRRK2.

Background: About 30% of patients with sporadic PD and more than 40% of patients with familial PD of AJ descent carry the LRRK2 p.G2019S mutation, a GBA mutation, or both.

Methods: GBA and LRRK2 were fully sequenced using DNA samples of AJ PD patients (n=566) attending the Movement Disorders Institute between 2008 and 2017.4 study populations were compared regarding age at symptom onset (AAO) and clinical characteristics obtained from patient files: patients with a GBA mutation negative for the LRRK2 G2019S mutation (GBA+/LRRK2-), patients with the G2019S mutation but negative for GBA mutations (GBA-/LRRK2+), patients with both (GBA+/LRRK2+) and patients with neither mutation (GBA-/LRRK2-). Comparisons among the groups was performed by non-parametric Kruskal-Wallis and chi-square tests.

Results: 11 GBA+/LRRK2+carriers (36.4% males, AAO 53.9±10.9 years), 64 GBA-/LRRK2+ carriers (57.8% males, AAO 57.9±10.9 years), 67 GBA+/LRRK2- carriers (61.2% males, AAO 57.7±11.0 years), and 81 GBA-/LRRK2- PD patients (selected using a random list generator, 66.7% males, AAO 61.8±11.8 years) were identified. AAO was significantly younger for the double mutation group (p=0.02). PD duration at last follow up was similar among the 4 groups (p=0.35). Levodopa-induced dyskinesia was most common for GBA+/LRRK2+ PD group (73%), followed by GBA-/LRRK2+ carriers (62%), GBA+/LRRK2- carriers (53%) and GBA-/LRRK2- (32%, p=0.001). A significantly higher proportion of patients with GBA+/LRRK2- had dementia, RBD and psychosis (37%, 49%, 48%) comparing to the other groups, GBA-/LRRK2+ (6%, 17%, 17%), GBA+/LRRK2+ (9%, o%, 9%) and GBA-/LRRK2- (14%, 33%, 18%), (p≤0.001). Prevalence of FOG and time from onset to H & Y 3 did not differ significantly among groups.

Conclusions: In this retrospective cross sectional study of AJ PD patients, differences in disease course were found between mutation groups reflecting genotype-phenotype impact. GBA mutation was associated with more prevalent non-motor/neuropsychiatric symptoms. Patients carrying both a GBA mutation and LRRK2 mutation exhibited the youngest age of onset but less neuropsychiatric complications, similar to LRRK2 mutation carriers without GBA mutations, probably suggesting differential distribution of neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pd-associated-with-gba-and-lrrk2-mutations-genotype-phenotype-correlation/