Parkinson disease phenotype in Ashkenazi jews with and without LRRK2 G2019S mutations

Abstract

Background The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking. Objective To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. Methods We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. Results LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status. Conclusion PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers

“…[1][2][3][4][5] The most prevalent known genetic cause of neurodegeneration, the G2019S mutation in the LRRK2 kinase domain, has an incomplete lifetime penetrance that varies between 30% and 80% depending on the study. 6,7 A recent fMRI study demonstrated that asymptomatic G2019S mutation carriers may have abnormalities in corticostriatal circuitry.…”

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

“…2 Select PD populations, e.g., Ashkenazi Jews (AJ) (14.3%-18.8%) [3][4][5][6] and North African Berbers (39.3%), 7 have much higher frequencies of G2019S mutations. The frequency of LRRK2 G2019S is estimated at 2% among AJ population controls.…”

“…Four-hundred seventy-four AJ PD probands including 415 newly genotyped and 59 previously genotyped participants were recruited at 3 sites: Beth Israel Medical Center (n 5 136), Columbia University Medical Center (n 5 146), both in New York, and Tel Aviv Medical Center in Tel Aviv, Israel (n 5 192). 6 Standard protocol approvals, registrations, and patient consents. Institutional review boards at each site approved the protocol and each participant signed a written informed consent.…”

“…10 Probands and relatives were genotyped for LRRK2 G2019S and glucocerebrosidase (GBA) mutations (8 mutations plus 2 variants in New York, and 7 mutations in Israel). 6 Probands who carried GBA mutations were excluded. 6 Family history interview.…”

“…6 Probands who carried GBA mutations were excluded. 6 Family history interview. We have used the FHI since 1998 to study familial aggregation of PD and more specifically to study the penetrance of parkin, 11 LRRK2 G2019S, 4 and GBA.…”