Objective: To evaluate the mutation frequency in recessive genes and the associated phenotype in a large series of French and North African cases with Parkinson’s disease (PD).

Background: Mutations in recessive (AR) PD account for about 13% of patients with onset <40. Results from the largest multi-center study of PD cases systematically sampled by age at onset (AO), family history and ethnic origins have not been reported.

Method: Clinical data from 510 AR PD and 1,098 isolated cases were collected. All the recessive genes were screened by Sanger and/or NGS target sequencing and gene dosage analysis. Clinical features wee compared between cases with no mutations (PD-NM; n=1,362) and those with PRKN mutations (PRKN-PD; n=241) using regression analyses adjusted for gender, age at onset, disease duration and levodopa medication.

Results: Of the 1,608 PD index cases, 199 had PRKN mutations (12.4%) followed by PINK1 in 23 (1.8%) and DJ-1 in two (0.2%). Overall, PRKN and PINK1 mutations were more frequent in EO than in late-onset (LO) PD and particularly in familial when compared to isolated cases. The prevalence of PRKN mutations in the whole 1,664 PD cases declined with AO from 39.3% in cases ≤20 years to 5.7% in those with AO 41-60 but no mutations were found above 60. PRKN mutations were more frequent in PD Caucasians (15.6%) than in North Africans (8.6%). In contrast, PINK1 mutations predominated in the North African group (6.8%). For genotype/phenotype correlations, in both unadjusted and adjusted models, PRKN cases had earlier age at onset (31.3±10.7 years vs 39.8±12.3 years, p<0.001) and longer disease duration (14.1±10.4 years vs 9.7±8.6 years, p<0.001) than PD-NM. PRKN-PD had more tremor than PD-NM (68.8% vs 59.7%, pc=0.03), less asymmetry (91.4% vs 96.7%, pc=0.008), akinesia (48.1% vs 61.9%, pc=0.001) and micrographia (21.1% vs 33.1%, pc=0.002). There was no difference in the rate of the 3 cardinal signs between groups. Lower UPDRS score was noted for PRKN-PD (mean score 15.8±11.9) than for NM-PD (mean score 19.4±13.8, pc=0.008), less dysautonomia rate (18.8% for PRKN-PD vs 54.7% for NM-PD, p<0.001) and less motor complications (dyskinesia: 54.8% vs 68.9%, p=0.002; motor fluctuations: 46.6% vs 73.2%, p<0.001).

Conclusion: This is the first largest study that shows an increase likelihood of mutations in recessive genes in cases with lower AO, family history, ethnic origin and less severe clinical features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetics-and-phenotypes-of-recessive-parkinsonism-in-french-and-north-african-populations/