Objective: Our study aims to describe the clinical features and genetic profile of patients of PD carrying LRRK2 variants and draw correlation with genetic variants.

Background: Parkinson’s disease (PD) related to LRRK2 is one of the common causes of genetic autosomal-dominant PD. PARK-LRRK2 presents with idiopathic-PD phenotype but phenotypic and genotypic profile vary based on the population studied.

Method: Retrospective study,  patients with PD carrying LRRK2 variants were identified,selected from our database of 250 patients with PD who underwent exome sequencing. Detailed demographic, clinical data and genetic details of these patients were extracted.

Results: Twelve patients, 6 males with mean age at onset 49.7±11.6 years ,duration of 4.6±3.5 years were recruited.Early-onset was observed in 6 patients. Symptoms onset: upperlimb in 66.7% and lowerlimb in 33.3%. Hyposmia was most frequent non-motor symptom.Family history of parkinsonism was present in 5 patients.All patients were on treatment with motor fluctuation in 7 patients (58.3%) . On examination, 5 patients -41.7% had hypometric saccades, and 1 patient 8.3% had cognitive impairment.Ten -83.3% patients had tremor predominant PD and 2 patients- 16.7% had akinetic rigid subtype. The mean  UPDRS-III-OFF score  and ON score -50.9±25.1 and 27.6±22.3 respectively with mean improvement of 48.3±22.9%.Two underwent DBS. Exome sequencing revealed  12 unique heterozygous LRRK2 variants (11 missense, 1 exon-34 deletions).Two are reported to be pathogenic (G2019S and I1371V), 2  to be likely pathogenic (R1067Q and R1325Q), and 4 reported to be variants of uncertain significance (S784R, C353Y, S2525P and T1024M). The remaining 4 variants were novel and could only be classified as variants of uncertain significance (R1957G, S2213C, F160L, and Exon-34 deletion). MRI was non-contributory in  majority of cases.

Conclusion: LRRK2-PARK closely simulates IPD with tremor dominant PD subtype in the majority and good levodopa responsiveness. Hyposmia was  most frequent NMS. Majority had motor fluctuation and peak dose dyskinesia. Twelve unique variants identified with only one  having the common G2019S mutation. Majority  variants were of uncertain significance. A large-scale multicentric study across India from different ethnicity would help in identifying the variants common to our population and that are frequent in patients with PD compared to control.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-analysis-of-patients-with-parkinsons-disease-lrrk2-variants-from-a-referral-centre-in-india/