Movement Disorders

BackgroundParkinsons disease (PD) involves environmental risk and protective factors as well as genetic variance. Most of the research in genomics has been done in subjects of European ancestry leading to sampling bias and leaving Latin American populations underrepresented. ObjectiveWe sought to phenotype and genotype Costa Rican PD cases and controls. MethodsWe enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective fa...

BackgroundA recent study identified a mutation in the SH3GL Interacting Endocytic Adaptor 1 (SGIP1) gene, located at 1p31.3, linked to early-onset Parkinsonism in 2 sisters in an Arab family with a history of young-onset Parkinson symptoms. SGIP1 had not been previously associated with Parkinsonism, a group of disorders including Parkinsons disease (PD), characterized by motor dysfunction and cognitive decline. SGIP1 plays a role in endocytosis, particularly clathrin-mediated synaptic vesicle re...

BackgroundPRKN biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinsons disease (PD). However, the variants responsible for suspected PRKN-PD individuals are not always identified with standard genetic testing. ObjectivesIdentify the genetic cause in two siblings with a PRKN-PD phenotype using long-read sequencing (LRS). MethodsThe genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger...

The frequency and clinical impact of LRRK2 p.G2385R and p.R1628P risk variants in Parkinsons disease (PD) remain uncertain, particularly across different Asian populations. We genotyped 3,058 multi-ethnic Malaysian PD patients, performed detailed phenotyping in 185, and analyzed disease progression in 635 using longitudinal Clinical Impression of Severity Index for PD scores. p.G2385R was largely confined to Chinese (8.2%), while p.R1628P occurred in mixed ancestry (11.0%), Chinese (8.3%), Malay...

BackgroundPathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene are the most common cause of familial Parkinsons disease (PD). LRRK2 shows incomplete penetrance, yet the biological factors influencing disease expression remain unknown. ObjectivesTo investigate whether genetic variants in aquaporin-4 (AQP4), key in glymphatic system functioning, are associated with the penetrance of PD in LRRK2 carriers. MethodsWe analyzed baseline data from 302 LRRK2 carriers from the Parkinson...

ImportanceParkinsons disease (PD) is a neurodegenerative disorder with complex aetiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. ObjectiveThe aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures/phenotypic traits in the 23andMe, Inc. research dataset. DesignNested cross-sectional case-control study. SettingPopulation-based cohort. ParticipantsPD subjects were r...

BackgroundKnowledge of genetic determinants in Parkinsons disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach has been exploited in this study. MethodsInformative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of PD were used for whole exome sequencing. Variant data analysis and in vitro functional characteris...

BackgroundVariants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype- phenotype correlations exist but with conflicting data, particularly in the cognitive domain. ObjectivesComparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients. MethodsPatients underwent a comprehensive assessment of motor and non-motor functions. Two-group (GBA- PD vs iPD) and multiple-group comparisons (iPD, risk, m...

Variants in GBA1 are important genetic risk factors in Parkinsons disease (PD). GBA1 T369M has been linked to an [~]80% increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the...

BackgroundAlthough levodopa remains the gold standard treatment for Parkinsons disease (PD), its chronic use is associated with levodopa-induced dyskinesia (LID), a motor complication that impacts prognosis, quality of life, and treatment costs. Most known LID-associated factors have been identified in European-descendant populations. ObjectivesTo describe the epidemiology of LID in Latin American and Caribbean (LATAM) countries and assess the relevance of known and novel LID-associated factors...

BackgroundSeveral lysosomal genes are associated with Parkinsons disease (PD), yet the association between PD and ARSA, which encodes for the enzyme arylsulfatase A, remains controversial. ObjectivesTo evaluate the association between rare ARSA variants and PD. MethodsTo study possible association of rare variants (minor allele frequency<0.01) in ARSA with PD, we performed burden analyses in six independent cohorts with a total of 5,801 PD patients and 20,475 controls, using optimized sequence...

BackgroundApolipoprotein E-{varepsilon}4 (APOE {varepsilon}4) genotype may be associated with the development of cognitive decline in idiopathic Parkinsons disease i(PD), however its effect in genetic PD is understudied. ObjectivesIn the current work we aimed to assess the impact of APOE genotype on cognition in iPD as well as in genetic PD with mutations in the Alpha-synuclein (SNCA) and Glycocerebrosidase (GBA1) genes. MethodsTwo independent PD cohorts were analyzed: The first cohort (Athens...

ImportanceCurrent recommendations for genetic testing in Parkinsons disease (PD) prioritize groups of patients based on age at onset (AAO) and family history (FH). The increasing importance of identifying genetic PD for personalized counseling and potential gene-specific therapies calls for a data-driven evaluation of these recommendations. ObjectiveTo estimate the diagnostic accuracy, specifically the sensitivity, specificity, and positive predictive value (PPV), of genetic testing in PD based...

BackgroundMelanocortin 1 receptor (MC1R) is a key regulator of pigmentation. Previous studies have linked MC1R loss-of-function variants to increased risk for Parkinsons disease (PD); however, whether they are associated with PD progression remains unknown. Using data from the Parkinsons Progression Markers Initiative (PPMI) cohort, we aimed to test whether MC1R loss-of-function variants, especially those previously associated with an increased risk of PD, are associated with PD progression and ...

Background and objectivesThe LRRK2 p.G2019S Parkinsons disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of other LRRK2 variants with PD and its association with GCase activity. MethodsLRRK2 and GBA were fully sequenced in 1,123 PD patients and 576 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry. Re...

ObjectiveTo investigate the genetic etiology of dystonia-parkinsonism among individuals with parkinsonism who have dopamine transporter (DAT) SPECT scans without evidence of dopaminergic deficits (SWEDD). MethodsData for this case-control study were from the Parkinsons Progression Markers Initiative (PPMI) cohort, a multisite observational study. The sample analyzed included participants with whole genome sequencing (WGS) who were diagnosed as Parkinsons disease (PD, n=421), SWEDD (n=64) or hea...

Background and ObjectiveHeterozygous variants in the glucocerebrosidase gene (GBA1) are the major genetic risk factor for Parkinsons Disease (PD). GBA-PD has been associated with worse progression and higher risk of cognitive decline. Here we took advantage of the Parkinsons Progression Markers Initiative (PPMI) to investigate whether sex could interact with GBA1 carrier status in determining the clinical phenotype, with a special focus on cognitive decline. MethodsWe evaluated 118 PD subjects ...

BackgroundProgress in Parkinsons disease (PD) is hampered by two critical obstacles: the lack of disease-modifying drugs and the difficulty of identify individuals at early, prodromal disease stages for clinical trials. MethodsWe conducted a retrospective, multi-cohort study using data from the Mass General Brigham (MGB) Biobank for discovery and the Accelerating Medicines Partnership Parkinsons Disease (AMP-PD) program for replication. Logistic regression was used to estimate the associations ...

BackgroundRecent evidence indicates that sex and genetic status significantly influence serum metabolic profiles in idiopathic Parkinsons disease (iPD) and in patients carrying at least a mutation in GBA1, LRRK2, TMEM175, PARK2, PINK1, or PARK7 genes. However, Parkinsons disease patients (PD) may also carry rare genetic variants of uncertain significance, whose effects on systemic metabolism have yet to be studied. MethodsWe combined untargeted 1H-NMR-based metabolomics to characterize serum me...

ImportanceLRRK2 kinase inhibition is one of the most promising therapeutic strategies in Parkinsons disease (PD), yet understanding of kinase activity in the Asian-prevalent p.G2385R and p.R1628P variants, each affecting 5-10% of PD patients, remains limited. Development of patient stratification and target engagement markers applicable across global cohorts is an urgent priority. ObjectiveTo investigate pRab10Thr73 phosphorylation and pLRRK2Ser935 dephosphorylation as markers of in vivo LRRK2 ...