A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease.

Background: Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD.

Objective: Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.

Alpha-synuclein misfolding as fluid biomarker for Parkinson's disease measured with the iRS platform.

Misfolding and aggregation of alpha-synuclein (αSyn) play a key role in the pathophysiology of Parkinson's disease (PD). Despite considerable advances in diagnostics, an early and differential diagnosis of PD still represents a major challenge. We innovated the immuno-infrared sensor (iRS) platform for measuring αSyn misfolding.

Development of a simplified smell test to identify Parkinson's disease using multiple cohorts, machine learning and item response theory.

To develop a simplified smell test for identifying patients with Parkinson's disease (PD), we reevaluated the Sniffin'-Sticks-Identification-Test (SST-ID) and University-of-Pennsylvania-Smell-Identification-Test (UPSIT), using three case-control studies. These included 301 patients with PD or dementia with Lewy bodies (DLB), 68 subjects with multiple-system atrophy (MSA) or progressive supranuclear palsy (PSP), and 281 healthy controls (HC). Scents were ranked by area-under-the-curve values for group classification and results leveraged by 8 published studies with 5853 individuals.

Anosmia and Upper Limb Rigidity-A Potential Phenotype of Idiopathic Normal Pressure Hydrocephalus with Cerebrospinal Fluid α-Synuclein Seeds.

Background: The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) and its association with neurodegenerative disorders is poorly understood.

Objectives: The aim was to determine the prevalence of α-synuclein pathology in iNPH and its associations with clinical characteristics.

Methods: We used α-synuclein seed amplification assay (synSAA) to retrospectively analyze cerebrospinal fluid (CSF) from a large single-center iNPH cohort (n = 144).

A novel alpha-synuclein K58N missense variant in a patient with Parkinson's disease.

Mutations and multiplications in the SNCA , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report the identification of a novel missense mutation (NM_000345.4, cDNA 174G>C; protein K58N) in a PD patient using whole exome sequencing, and describe comprehensive molecular and cellular analysss of the effects of this novel mutation.

Plasma proteomics identify biomarkers predicting Parkinson's disease up to 7 years before symptom onset.

Parkinson's disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process.

Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson's disease.

Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson's disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-naïve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD.

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta-Analysis.

Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development.

Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort.

Background: Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD).

Objectives: The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline.

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease.

Background: Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression.

Objective: The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high-throughput sandwich immune multiplex panels in deeply phenotyped PD.

Methods: Proximity Extension Assay technology on 273 markers was applied in plasma of 109 drug-naive at baseline (BL) patients with PD (BL, 2-, 4-, and 6-year follow-up [FU]) and 96 healthy control patients (HCs; 2- and 4-year FU) from the de novo Parkinson's cohort.

Evidence for immune system alterations in peripheral biological fluids in Parkinson's disease.

Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well.

Longitudinal Change and Progression Indicators Using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale in Two Independent Cohorts with Early Parkinson's Disease.

Background: The MDS-Unified Parkinson's disease (PD) Rating Scale (MDS-UPDRS) is the most used scale in clinical trials. Little is known about the predictive potential of its single items.

Objective: To systematically dissect MDS-UPDRS to predict PD progression.

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs.

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia.

Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement).

Monogenic variants in dystonia: an exome-wide sequencing study.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

A novel pathogenic variant in MYO18B associating early-onset muscular hypotonia, and characteristic dysmorphic features, delineation of the phenotypic spectrum of MYO18B-related conditions.

Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing.

Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes.

Background: The genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE.

A unique de novo gain-of-function variant in associated with intellectual disability and hyperkinetic movement disorder.

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing.

Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up.

Background: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation.

Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.

Background: An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts.