Characterization of Recessive Parkinson Disease in a Large Multicenter Study

Abstract

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.

FIGURE 1:

Schematic representation of the (A) PRKN and (B) PINK1 genes and respective proteins and associated disease-linked mutations. Exonic deletions (in red), duplications (in green), or triplications (in blue) are shown in the upper panel, and point mutations (missense, frameshift, nonsense, and splice) are shown in the lower panel. Newly identified mutations are shown in bold. Numbers in brackets indicate the number of mutation carriers. PRKN cDNA numbering: NM_004562.2; PINK1 cDNA numbering: NM_032409.2. IBR, in-between RING; MTS, mitochondrial targeting sequence; RING, really interesting new gene; TM, transmembrane helix; UBL, ubiquitin-like.

FIGURE 2:

Distribution of PRKN and PINK1 mutation carriers by age at onset, pattern of disease presentation, and ethnicity. (A) Proportion of probands by age at onset for PRKN (199 carriers among 1,587 probands). (B) Proportion of PRKN mutation carriers from 497 cases with autosomal recessive Parkinson disease (PD; in blue) versus 1,090 isolated cases (in orange) by age at onset and pattern of presentation of PD. (C) Proportion of probands by age at onset for PINK1 (23 carriers among 1,223 probands). (D) Proportion of PINK1 mutation carriers from 386 cases with autosomal recessive PD (in blue) versus 837 isolated cases (in orange) by age at onset and pattern of presentation of PD. (E) Proportion of PRKN and PINK1 mutation carriers, according to their ethnicity: Caucasians (n = 1,324, in blue) or Arab-Berbers (n = 213, in orange).