The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes.
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ABSTRACT:
SUBMITTER: Diez-Fairen M
PROVIDER: S-EPMC8347917 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 × 10-30; ε2: OR: 0.21, 95% CI: 0.13-0.34; p = 5.39 × 10-10) and LBD (ε4: OR: 2.94, 95% CI: 2.34-3.71, p = 6.60 × 10-20; ε2: OR = OR: 0.39, 95% CI: 0.26-0.59; p = 6.88 × 10-6). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE ε4 decreases survival in a dose-dependent manner in Alzheimer's disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE ε4 allele with increased risk for LBD, and importantly demonstrate that APOE ε2 reduces risk of this disease.
| S-EPMC6588472 | biostudies-literature
Project description:Objective: Parkinson's disease (PD) has significant clinical overlaps with atypical parkinsonism syndromes (APS), which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS. Methods: Plasma samples (n = 204) were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB), multiple system atrophy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or frontotemporal dementia (FTD) with parkinsonism (FTD-P) or without parkinsonism. We measured plasma levels of α-synuclein, total tau, p-Tau181, and amyloid beta 42 (Aβ42) by immunomagnetic reduction-based immunoassay. Results: Plasma α-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01). Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01). A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Aβ42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml)2, with an area under the curve (AUC) of 0.932. An α-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947). In patients with predominant parkinsonism, an α-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87). Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P).
| S-EPMC5934438 | biostudies-literature
Project description:Background and purposeAccurate diagnosis of Atypical Parkinsonian Syndromes (APS) is important due to differences in prognosis and management, but remains a challenge in the clinical setting. The purpose of our meta-analysis was to identify characteristic patterns of gray matter atrophy in Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Multisystem-Atrophy Parkinsonian type (MSA-P), and Idiopathic Parkinson's Disease (IPD).Materials and methodsWhole-brain meta-analysis was performed on 39 published voxel-based morphometry (VBM) articles (consisting of 404 IPD, 87 MSA-P, 165 CBD, and 176 PSP subjects) using the modified Anatomic Likelihood Estimation method. Based on these results, contrast analyses were then utilized to determine areas of atrophy shared by as well as unique to each disorder.ResultsCBD was characterized by asymmetric gray matter atrophy in multiple cortical regions, while the thalamus-midbrain and insula were predominantly involved in PSP. The striatum and superior cerebellum were affected in MSA-P, while IPD demonstrated an anterior cerebral pattern. Although there was a mild overlap among PSP, CBD, and MSA-P, significant regions of atrophy unique to each disorder were identified, including (1) the superior parietal lobule in CBD (2) putamen in MSA-P (3) insula and medial dorsal nucleus in PSP.ConclusionOur results suggest that there are characteristic patterns of atrophy in APS. Guided by these findings, future studies on the individual subject level may lead to the development of robust imaging biomarkers.
| S-EPMC4467770 | biostudies-literature
Project description:Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions.
| S-EPMC4632769 | biostudies-other
Project description:Transdermal rotigotine (RTG) is a non-ergot dopamine agonist (D3>D2>D1), and is indicated for use in early and advanced Parkinson's disease (PD). RTG patch has many potential advantages due to the immediacy of onset of the therapeutic effect. Of note, intestinal absorption is not necessary and drug delivery is constant, thereby avoiding drug peaks and helping patient compliance. In turn, transdermal RTG seems a suitable candidate in the treatment of atypical Parkinsonian disorders (APS). Fifty-one subjects with a diagnosis of APS were treated with transdermal RTG. The diagnoses were: Parkinson's disease with dementia, multiple system atrophy Parkinsonian type, multiple system atrophy cerebellar type, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, and frontotemporal dementia with Parkinsonism. Patients were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS; part III), Neuropsychiatric Inventory (NPI), and mini-mental state examination (MMSE) and all adverse events (AEs) were recorded. Patients treated with RTG showed an overall decrease of UPDRS III scores without increasing behavioral disturbances. Main AEs were hypotension, nausea, vomiting, drowsiness, tachycardia, and dystonia. On the whole, 15 patients were affected by AEs and seven patients suspended RTG treatment due to AEs. The results show that transdermal RTG is effective with a good tolerability profile. RTG patch could be a good therapeutic tool in patients with APS.
| S-EPMC4051815 | biostudies-literature
Project description:This update discusses novel aspects on genetics, diagnosis, and treatments of atypical parkinsonism published over the past 2 years.A genome-wide association study identified new genetic risk factors for progressive supranuclear palsy and new genetic conditions presenting with atypical parkinsonism have been described. The clinical criteria for diagnosis of corticobasal degeneration have been revised, and for progressive supranuclear palsy are under revision. Novel molecular techniques to identify possible biomarkers, as in other neurodegenerative disorders, have started being studied on atypical parkinsonian conditions, and although preliminary results seem promising, further studies are urgently warranted. Therapeutic trials based on disease-specific targets have shown no clinical improvement.The knowledge obtained recently on atypical parkinsonian conditions points out the major deficits in this field. With the expanding phenotypical spectrum of atypical parkinsonian conditions, the early identification of patients has become difficult. The inability of conventional methods to identify these disorders earlier and better than clinicians, and the recent failure of promising therapeutic compounds, highlight the fact that the lack of biomarkers is probably the greatest limitation for developing treatments for these disorders. Thus, current and future research in this direction will be crucial.
| S-EPMC4196800 | biostudies-literature
Project description:High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.
| S-EPMC3918868 | biostudies-other
Project description:Objective:To identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations. Methods:Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here. Results:We identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases. Conclusions:This large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.
| S-EPMC7073457 | biostudies-literature
Project description:PURPOSE OF REVIEW:Atypical parkinsonian disorders (APDs) comprise a heterogenous group of disorders including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Based on literature published in 2010, we here review recent advances in the APD field. RECENT FINDINGS:Genome-wide association studies have provided robust evidence of increased disease risk conferred by synuclein and tau gene variants in MSA and PSP. Furthermore, advanced imaging tools have been established in the differential diagnosis and as surrogate markers of disease activity in patients with APDs. Finally, although therapeutic options are still disappointing, translational research into disease-modifying strategies has accelerated with the increasing availability of transgenic animal models, particularly for MSA. SUMMARY:Remarkable progress has been achieved in the field of APDs, and advances in the genetics, molecular biology and neuroimaging of these disorders will continue to facilitate intensified clinical trial activity.
| S-EPMC6200126 | biostudies-literature
Project description:Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting and repetitive movements and abnormal postures. Several causative genes have been identified, but their genetic bases still remain elusive. Primary Torsion Dystonias (PTDs), in which dystonia is the only clinical sign, can be inherited in a monogenic fashion, and many genes and loci have been identified for autosomal dominant (DYT1/TOR1A; DYT6/THAP1; DYT4/TUBB4a; DYT7; DYT13; DYT21; DYT23/CIZ1; DYT24/ANO3; DYT25/GNAL) and recessive (DYT2; DYT17) forms. However most sporadic cases, especially those with late-onset, are likely multifactorial, with genetic and environmental factors interplaying to reach a threshold of disease. At present, genetic counseling of dystonia patients remains a difficult task. Recently non-motor clinical findings in dystonias, new highlights in the pathophysiology of the disease, and the availability of high-throughput genome-wide techniques are proving useful tools to better understand the complexity of PTD genetics. We briefly review the genetic basis of the most common forms of hereditary PTDs, and discuss relevant issues related to molecular diagnosis and genetic counseling.
| S-EPMC3622056 | biostudies-literature