Objective: To determine frequency and determinants of resting tremor in the leg as first motor symptom in Parkinson Disease (PD), especially as related to age at onset (AAO), genetic etiology, and sex.

Background: Leg tremor is an infrequent first motor symptom of PD. It is often associated with early onset disease, but the degree to which this is attributable to genetic etiology is not clear. Understanding the association between leg tremor at onset and genetic status may help direct genetic testing regardless of patient age.

Method: 878 patients with iPD, LRRK2 G2019S, and carriers of the 11 most common GBA variants in the Ashkenazi Jewish population (N370S, L444P, 84GG, IVS2+1, V394L, D409G, A456P, R496H, RecNciI, E326K, T369M) were recruited at Mount Sinai Beth Israel, New York City. Initial motor symptoms were self-reported by patients and reviewed by movement disorders neurologists. Demographics, disease characteristics, and prevalence of initial motor symptoms were compared between genetic groups using chi-square tests, Fisher’s exact, and Student’s t-tests. Regression models were constructed to test the association between genetic status and leg tremor.

Results: Among 123 LRRK2-PD, 150 GBA-PD, and 605 iPD, iPD were more likely to be men (62%) versus LRRK2-PD (50%) and GBA-PD (55%). GBA-PD had a lower mean [SD] AAO of 57.2 [11.4] years (LRRK2-PD: 59.9 [11.6], iPD: 60.9 [11.4], p = 0.002). LRRK2-PD were also more likely to report a family history of PD (72% versus GBA-PD 62% and iPD 45%). Prevalence of rest tremor as an initial motor symptom did not differ between groups, however, when stratified by onset site, rest tremor in the leg was more prevalent among LRRK2-PD (29/123, 24% vs. GBA-PD: 9/148, 6.1% vs. iPD: 42/597 7%, p < 0.001). Those with leg tremor vs. no leg tremor had a younger AAO (57.9 years [8.65] vs. 60.4 [11.7]), although this difference was not significant (p = 0.069). In logistic models adjusted for AAO, sex, and family PD history, LRRK2-PD had a 4.38 (95% CI: 2.50–7.64) greater odds of having leg tremor as an onset symptom, relative to iPD.

Conclusion: Resting leg tremor as an initial motor symptom is highly associated with LRRK2-PD. Although genetic testing is often prioritized for early onset disease, leg tremor at onset should prompt genetic testing regardless of the patient’s age as LRRK2 genetic status may have important implications, as targeted therapies develop.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/contribution-of-genetics-to-onset-of-pd-with-leg-tremor/