LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort.

Tatiana Usnich,Norbert Brüggemann,Kathrin Reetz,Nathalie Schell,Hanaa Gaber,Jens Volkmann,Simone Zittel,Xenia Bogdanovic,Joanne Trinh,Franco Valzania,Andrea A Kühn,Enza Maria Valente,Anne Grünewald,Andreas Heuer,Toni M Förster,Brit Mollenhauer,Doreen Gruber,Christine Klein,Meike Kasten,Sibel Ertan,Daniela Berg,Volha Skrahina,Natalia Koleva-Alazeh,David J Pedrosa,Arndt Rolfs,Susen Schaake,Emma L Schymanski,Katja Lohmann,Péter Bauer ,Ilona Csóti ,A Nazlı Başak ,Gencer Genç ,Eva‐Juliane Vollstedt ,Stuart Isaacson ,Esther Sammler

doi:10.3389/fneur.2021.710572

Abstract

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions.Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants.Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021).Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivityClinical Trial Registration:ClinicalTrials.gov, NCT04214509.

Highlights

Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson’s disease (PD)
LRRK2-linked PD is inherited in an autosomal dominant fashion with reduced, age-dependent penetrance and variable expressivity that differ across ethnicities and geographic regions, indicating that ancestral background or environmental factors contribute to the manifestation and expressivity of pathogenic LRRK2 variants
LRRK2-linked PD is clinically indistinguishable from idiopathic PD, i.e., PD of unknown cause, the disease course appears to be milder with regard to motor and cognitive functions [8]

Summary

Introduction

Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson’s disease (PD). First identified in 2004, LRRK2 pathogenic variants account for up to ∼40% of all PD cases in selected populations, e.g., North African Berber [1]. In the PD phenotype-genotype database MDSGene (www.mdsgene.org), ∼700 individual LRRK2 pathogenic variant carriers are listed, but clinical information apart from cardinal signs of PD is overall scarce [1]. The majority of the reported LRRK2 pathogenic variantpositive PD patients are of European descent (63%), whereas all other ethnicities comprise ∼10% or fewer patients of described pathogenic variant carriers despite clusters in the Ashkenazi Jewish (AJ) and Arab Berber populations [1, 2]. Pathogenic variants identified in LRRK2 include p.G2019S, p.R1441C/G/H, p.N1437H, p.Y1699C, and, p.I2020T. LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions

Methods

Results

Conclusion