Comparative study of Parkinson's disease phenotypes in homozygous and heterozygous LRRK2-G2019S mutation carriers

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is a common genetic cause of Parkinson's disease (PD) and a founder variant in the Tunisian population. However, the clinical impact of the homozygous form remains unclear.

Assess the clinical impact of both homozygous and heterozygous LRRK2-G2019S mutations in Tunisian PD-patients.

A retrospective longitudinal study was carried out in the Neurology Department of Razi-University-Hospital, Tunisia. All participants were genotyped for the LRRK2-G2019S mutation through direct sequencing of exon-41 of the LRRK2 using Sanger sequencing. In addition, all cases were screened for the most common GBA1 variants (p.E326K, p.T369M, p.N370S, and p.L444P) using the appropriate laboratory techniques. Patients were evaluated based on baseline clinical features and disease progression using validated motor and non-motor assessment tools.

We included 22 homozygous and 44 heterozygous LRRK2-G2019S PD patients, matched for age at onset, gender, and disease course. We identified two carriers of the GBA-L444P mutation and one carrier of the N370S mutation, all in the heterozygous state, distributed across both the homozygous and heterozygous LRRK2-G2019S subgroups.Our results demonstrate that significant motor differences emerge between the two groups between 3 and 8 years (p = 0.0019 at 3-5 years of disease duration and p = 0.007 at 6-8 years of disease evolution). However, as PD progresses beyond this period, the clinical trajectories of both groups meet, resulting in a similarly presentation at later stages after 9-years.

Significant divergence in motor impairment emerged mid-course in homozygous patients but diminished in later stages, with both groups converging in motor outcomes during the final phase of the disease.