Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Abstract

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were Lesage et al. Characterization of Dominant Parkinson's Disease screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

“…It appears to be important in neuronal transport to dendrites [ 46 ] and neuronal cells from humans with the p.D620N variant show disrupted endosomal transport and abnormal accumulation of α-synuclein and reactive oxygen species [ 47 , 48 ]. Although pathogenic variants in VPS35 are particularly rare, comprising only 0.2% of European patients with suspected autosomal dominant PD, patients manifest typical PD symptoms with a good response to L-DOPA [ 49 , 50 ]. It is reasonable to consider that the gene function, particularly with its association with α-synuclein and mitochondrial function, is also implicated in sporadic PD.…”

Single‐Molecule Counting Coupled to Rapid Amplification Enables Detection of α‐Synuclein Aggregates in Cerebrospinal Fluid of Parkinson's Disease Patients

“…Earlier studies have established that αSyn was the main component of the Lewy bodies [3] . Furthermore, links between familial forms of PD and αSyn mutations [3b, 4] or duplications of gene encoding αSyn [5] were soon identified, leading to the hypothesis that αSyn aggregation played an important role in disease genesis and progression.…”

Alpha-Synuclein and Lipids: The Elephant in the Room?

“…Further studies are needed to confirm the roles of transcript, epigenetic, and mosaicism variants in the pathogenesis of PD. Overall, the SNCA gene is one of the most important genetic determinants involved in the pathogenesis of PD [ 25 , 26 ].…”

“…Further studies are needed to confirm the roles of transcript, epigenetic, and mosaicism variants in the pathogenesis of PD. Overall, the SNCA gene is one of the most important genetic determinants involved in the pathogenesis of PD [25,26]. The α-syn is composed of three domains: the N-terminal domain (green), the NAC domain (orange) and the C-terminal domain (blue).…”