Genotype‐phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review

Abstract

This comprehensive MDSGene review is devoted to the three autosomal‐dominant PD forms: PARK‐SNCA, PARK‐LRRK2, and PARK‐VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (http://www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P < 0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l‐dopa. © 2018 International Parkinson and Movement Disorder Society

α‐synuclein RT‐QuIC in cerebrospinal fluid of LRRK2‐linked Parkinson's disease

“…Pathogenic mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are one of the most frequent causes of inherited Parkinson's disease (PD) . Among the different mutations in this gene, p.G2019S is the most frequently found in the population worldwide accounting for 1% of sporadic and 4% of familial PD patients .…”

Using global team science to identify genetic parkinson's disease worldwide

“…Even for cognition, published information is available only for about one‐third of the cases with monogenic PD (http://www.mdsgene.org). In contrast, our present approach indicates the availability of nonmotor signs in general for two‐thirds of the reported cases (Table).…”

“…However, individual clinical information for patients with genetic PD is only reported for a fraction of cases (n = 1,769; Movement Disorder Society Genetic mutation database [MDSGene]; http://www.mdsgene.org) in the international medical literature, and publications are often biased toward unusual presentations of gene mutations. Both clinical expression and penetrance of gene mutations may vary considerably across different populations and ethnicities, further challenging pooling of data and their interpretation. Finally, given the growing availability of diagnostic genetic testing and the increasing difficulty of publishing case reports of mutation carriers in peer‐reviewed journals, we expect the proportion of published versus unpublished cases to rapidly shift toward the latter.…”

“…Employing novel methods of team science, electronic databases, and global communication, we performed a worldwide survey of genetic PD with an emphasis on the availability of demographic, clinical, omics, and imaging data as well as of biomaterials, to both foster and exploit global collaboration. To identify possible participants for our survey, we compiled the names of corresponding authors from articles included in the MDSGene database covering the following PD genes: SNCA , LRRK2 , VPS35, Parkin , PINK1 , and DJ1 . For GBA , we screened the literature according to MDSGene criteria to identify corresponding authors of eligible articles (articles published in English with clinical information available).…”

“…To fill these knowledge gaps, a new collaborative mindset is indispensable. Our worldwide collaborative effort revealed an unprecedented level of data completeness, a paramount prerequisite when aiming to perform meaningful genotype–phenotype correlations and when selecting patients for clinical studies and trials . Team science of clinicians and researchers in the field of rare neurological diseases will facilitate sharing of expertise, promote new research opportunities, offer a network to foster new training opportunities for young researchers, and advance development of individualized therapies.…”