Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Abstract

Background As gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited. Objective The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods We conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

“…47,48 In fact, recognizing this is an area that deserves additional attention (the MDS established a task force dedicated to this topic) to better define EOPD. 47,49…”

Parkinson’s Disease is Predominantly a Genetic Disease

“…Indeed, the discovery of SNCA , the first gene implicated in PD, was prompted when clinicians who were initially convinced that genetics played “no significant role in the etiology of PD” and “must be considered to be acquired” [ 10 ], encountered a very large kindred with an autosomal dominant pattern of PD transmission [ 11, 12 ]. Supportive evidence for the strong role of genetics in familial PD has been repeatedly demonstrated over the past three decades (e.g., references [ 13, 14 ], and in all regions of the world where this has been studied (http://www.mdsgene.org and [ 15 ]; Fig. 1 ).…”

“…Remarkably, in some populations, these monogenic forms may even account for the majority of PD patients (e.g., >50% of PD patients attending a tertiary-care neurology clinic in the Malaysian state of Sabah are EOPD, of whom >50% have homozygous or compound-heterozygous PRKN exon deletions) [ 30 ]. Very high rates (sometimes exceeding 40%) of monogenic PD, or involving the strongest known risk factor gene GBA1 , are also seen in selected populations such as the North African Arab-Berbers, Ashkenazi Jews, and Spanish Basques, especially involving LRRK2 and GBA1 [ 31–34 ], which have more variable (and age-related) penetrance and overall late age of onset [ 15 ].…”

Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

“…Monogenic PD represents a minority of cases—estimated to be about 1 in 10, with some variation depending on the population studied [ 62 , 63 ]. The overwhelming majority (>90%) of people living with Parkinson's do not have a single genetic cause of their disease, and the overlap between the functional biology of monogenic and idiopathic disease has only recently begun to emerge [ 12 ].…”