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

in Frontiers in Neurology (2021), 12

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 ... [more ▼]

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. [less ▲]

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

in Nature genetics (2018), 50(4), 524-537

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454 ... [more ▼]

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. [less ▲]

An unusual neurological syndrome of crawling gait, dystonia, pyramidal signs, and limited speech.

in Movement Disorders (2011), 26(12), 2279-83

BACKGROUND: The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family. METHODS: Five patients, their 2 siblings, and their parents ... [more ▼]

BACKGROUND: The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family. METHODS: Five patients, their 2 siblings, and their parents were clinically examined. DNA from all 7 siblings was genotyped with Affymetrix SNP arrays and sequencing of selected candidate genes. RESULTS: An unusual neurological syndrome of crawling gait, predominant leg dystonia, pyramidal signs, microcephaly, and suspected deafness segregated in the family. Three patients ambulated on hands and knees, either by hopping and crossing their legs, or by dragging the legs behind them. Two patients have acquired the ability to walk bipedally with a dystonic gait. Unexpectedly, no chromosomal region was homozygous in patients only. Under different disease models, we localized 7 chromosomal regions in the genome common to all patients. No pathogenic mutations were identified in selected candidate genes or the mitochondrial genome. CONCLUSION: We describe an unusual movement disorder syndrome reminiscent of but distinct from Uner Tan syndrome. [less ▲]