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.
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.
We have previously identified risk factors for acute fetal demise (<24 hours after procedure) after fetoscopic laser procedure (FLP) for twin twin transfusion syndrome (TTTS). There is a gap in knowledge in perinatal outcomes between FLP and selective reduction (SR). We aim to compare procedure-to-delivery interval and perinatal survival between patients with single fetal survival following FLP to planned SR in complicated monochorionic twin pregnancies. STUDY DESIGN: This was a secondary analysis of prospectively collected data in complicated monochorionic twin pregnancies from two fetal centers from 2008-2015. The selection of procedure was dependent upon provider and patient preference. Group 1 was defined as women undergoing FLP for TTTS with an idiopathic single fetal demise within 24 hours of the procedure. Group 2 consisted of women undergoing planned SR for TTTS, and Group 3 was SR for indications other than TTTS, such as discordant anomalies, twin reverse arterial perfusion (TRAP), and selective IUGR. Baseline demographics and perinatal outcomes were compared among the three groups using comparative statistics. Kaplan-Meier survival analysis and Cox-proportional hazard model was performed to compare gestational age (GA) at delivery and procedure to delivery time. RESULTS: In Group 1, 77/1043 (7%) had a single fetal demise within 24 hours of FLP, of which 59 (76%) were donor fetal demise and 18 (24%) were recipient demise. Group 2 included 15 patients, of which 13 (87%) donor fetuses and 2 (13%) recipient fetuses were selectively reduced. Relevant outcomes among the three groups are illustrated in Table below. Survival of the co-twin was highest in the Group 1 (p¼0.04). Although no differences were found in the mean GA at delivery and procedure to delivery time among the groups, on K-M plot with Cox-proportional hazard model, there was significant difference among groups (Figure 1; p¼0.01). On multivariate analysis with cox-proportional hazard model, GA at procedure (Hazard ratio [HR]: 1.1; p¼0.04) and FLP for TTTS (HR: 2.1; p¼0.04) were the only factors found independently associated with GA at delivery. CONCLUSION: When single fetal demise occurs following fetoscopic laser photocoagulation, the other twin is more likely to survive to delivery, but more likely to deliver at an earlier GA compared to selective reduction for TTTS.
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