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.

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What are the novel findings of this work?In this study of 114 cases that underwent termination of pregnancy following the detection of a major central nervous system anomaly, chromosomal microarray analysis (CMA) detected causative copy-number variants (CNVs) in 10% of fetuses. Among 86 CMA-negative cases, exome sequencing (ES) detected causative sequence variants in 44%. The ES bioinformatics pipeline also detected 13 of the causative and previously known non-causative CNVs. What are the clinical implications of this work?Our data suggest that ES could be considered as a first-tier clinical diagnostic test in the prenatal diagnosis of fetuses with major CNS anomalies, as it can detect both sequence variants and CNVs.

On the basis of these results, it may be possible to detect triploid pregnancies in the first trimester and determine their origin using combined first-trimester screening.

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