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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 expressivity Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.
RESUMEN
BACKGROUND: Although diarrhea has been reported as a side effect of L-3,4- dihydroxyphenylalanine (L-DOPA)/benserazide, it is largely unknown and unrecognized, presumably because it is very rare. There is almost no literature on benserazide-induced diarrhea (BID), no pharmacological explanation and, crucially, no treatment recommendation. This can lead to physicians misdiagnosing BID, for example as colitis, and initiating misguided and ultimately ineffective drug treatments. Or it can lead to erroneous assumptions about a general intolerance and subsequent discontinuation of L-DOPA medication - for lack of a better solution - at the high price of living with the recurring symptoms of Parkinson's disease. Thus, our study aims to fill these gaps, beginning with a treatment recommendation: A simple switch to LDOPA/ carbidopa has proven to be an effective solution in virtually all cases of BID, usually leading to full remission within days. Finding a possible pharmacological explanation was the next objective of this study. METHODS: We retrospectively analyzed 50 case files of patients with BID, searching for patterns that could potentially explain this intolerance. RESULTS: The most frequent concomitant disease was hypertension, likely due to high average age. Beta-blockers and acetylsalicylic acid were the most frequent concomitant medications. Otherwise, no conspicuous pattern emerged in this seemingly rather heterogeneous sample. CONCLUSIONS: Plasma protein binding (PPB) was suspected as a key difference between benserazide and carbidopa that might potentially explain why some patients can tolerate carbidopa but not benserazide. However, reports on PPB of carbidopa and benserazide vary wildly from one source to another, making definitive conclusions impossible.
RESUMEN
BACKGROUND: Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants. METHODS: Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing. RESULTS: Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers. CONCLUSIONS: The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
