Common Variants Near <scp>ZIC1</scp> and <scp>ZIC4</scp> in Autopsy‐Confirmed Multiple System Atrophy

Hopfner, Franziska; Tietz, Anja K.; Ruf, Viktoria; Ross, Owen A.; Koga, Shunsuke; Dickson, Dennis W.; Aguzzi, Adriano; Attems, Johannes; Beach, Thomas G.; Beller, Allison; Cheshire, William P.; Deerlin, Vivianna M. Van; Desplats, Paula; Deuschl, Günther; Duyckaerts, Charles; Ellinghaus, David; Evsyukov, Valentin; Flanagan, Margaret E.; Franke, André; Frosch, Matthew P.; Gearing, Marla; Gelpí, Ellen; Gerpen, Jay A. van; Ghetti, Bernardino; Glass, Jonathan D.; Grinberg, Lea T.; Halliday, Glenda M.; Helbig, Ingo; Höllerhage, Matthias; Huitinga, Inge; Irwin, David J.; Keene, Dirk; Kovács, Gábor G.; Lee, Edward B.; Levin, Johannes; Martı́, Marı́a José; McKeith, Ian; McLean, Catriona; Mollenhauer, Brit; Neumann, Manuela; Newell, Kathy L.; Pantelyat, Alexander; Pendziwiat, Manuela; Peters, Annette; Porcel, Laura; Rábano, Alberto; Matěj, Radoslav; Rajput, Alex; Rajput, Ali H.; Reimann, Regina; Scott, William K.; Seeley, William W.; Selvackadunco, Sashika; Simuni, Tanya; Stadelmann, Christine; Svenningsson, Per; Thomas, Alan; Trenkwalder, Claudia; Troakes, Claire; Trojanowski, John Q.; Uitti, Ryan J.; White, Charles L.; Wszołek, Zbigniew K.; Xie, Tao; Ximelis, Teresa; Yebenes, Justo; Müller, Ulrich; Schellenberg, Gerard D.; Herms, Jochen; Kuhlenbäumer, Gregor; Höglinger, Günter U.

doi:10.1002/mds.29164

Cited by 12 publications

(2 citation statements)

References 48 publications

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“…Heterozygous deletions encompassing the ZIC4 locus are associated with a rare congenital cerebellar malformation known as the Dandy–Walker malformation 26 . Notably, mutations in proximity to the ZIC4 loci are implicated in multiple system atrophy, a rare neurodegenerative disease 27 . Large scale GWAS study of brain morphology has also identified associations with ZIC4 , underscoring its significance in diverse neurological processes 28 .…”

Section: Resultsmentioning

confidence: 99%

Prioritizing disease-related rare variants by integrating gene expression data

Guo,

Urban,

Wong

2024

Preprint

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Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.

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Section: Resultsmentioning

confidence: 99%

Prioritizing disease-related rare variants by integrating gene expression data

Guo,

Urban,

Wong

2024

Preprint

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“…Another recent GWAS study in postmortem confirmed MSA cases identified a variant in close proximity of ZIC1 and ZIC4 which encode transcription factors critical for cerebellum development. Further immunohistochemical analysis showed reduced ZIC4 -immunoreactive neurons in patients with olivopontocerebellar atrophy suggesting ZIC4 -mediated neuronal vulnerability in MSA [8].…”

Section: Geneticsmentioning

confidence: 91%

An update on multiple system atrophy

Stankovic,

Kuijpers,

Kaufmann

2024

Current Opinion in Neurology

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Purpose of review Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein's role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials. Recent findings A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression. Summary New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression.

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Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria

Jensen,

Heine,

Ruf

et al. 2024

Movement Disorders

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BackgroundMultiple system atrophy is a neurodegenerative disease with α‐synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia.ObjectiveThe aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers.MethodsDiagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy‐confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration.ResultsWe identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%–100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%–9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%–100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%–100% throughout).ConclusionsThe International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Common Variants Near ZIC1 and ZIC4 in Autopsy‐Confirmed Multiple System Atrophy

Cited by 12 publications

References 48 publications

Prioritizing disease-related rare variants by integrating gene expression data

Prioritizing disease-related rare variants by integrating gene expression data

An update on multiple system atrophy

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria

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