Investigation of Phase Shifts Using AUC Diagrams: Application to Differential Diagnosis of Parkinson's Disease and Essential Tremor.

This study was motivated by the well-known problem of the differential diagnosis of Parkinson's disease and essential tremor using the phase shift between the tremor signals in the antagonist muscles of patients. Different phase shifts are typical for different diseases; however, it remains unclear how this parameter can be used for clinical diagnosis. Neurophysiological papers have reported different estimations of the accuracy of this parameter, which varies from insufficient to 100%. To address this issue, we developed special types of area under the ROC curve (AUC) diagrams and used them to analyze the phase shift. Different phase estimations, including the Hilbert instantaneous phase and the cross-wavelet spectrum mean phase, were applied. The results of the investigation of the clinical data revealed several regularities with opposite directions in the phase shift of the electromyographic signals in patients with Parkinson's disease and essential tremor. The detected regularities provide insights into the contradictory results reported in the literature. Moreover, the developed AUC diagrams show the potential for the investigation of neurodegenerative diseases related to the hyperkinetic movements of the extremities and the creation of high-accuracy methods of clinical diagnosis.

Analysis of PARK2 gene exon rearrangements in Russian patients with sporadic Parkinson's disease.

BACKGROUND: Deletions and duplications of single exons or exon groups account for a large proportion of the PARK2 gene mutations described in juvenile autosomal recessive Parkinson's disease (PD). METHODS: We analyzed rearrangements in exons 1 to 12 of the PARK2 gene in Russian sporadic patients with early-onset PD (EOPD) and late-onset PD (LOPD). RESULTS: The frequency of EOPD and LOPD patients carrying these mutations was 12.4% and 3.8%, respectively. The most frequent rearrangements were detected in exons 3 and 4. The odds ratio for EOPD in individuals carrying PARK2 exon deletions and duplications was 13.95 (95% confidence interval [CI], 1.846-105.46; P = .0022). In addition, we found a correlation between exon rearrangements in PARK2 and the age at onset of PD, presence of dystonia, and symmetrical course of the disease. CONCLUSIONS: Exon rearrangements in the PARK2 gene play a significant role in the pathogenesis of sporadic PD in Russian patients.

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson's Disease.

Background: Parkinson's disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated. Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas. Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database. Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant. Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.

Effective quantitative real-time polymerase chain reaction analysis of the parkin gene (PARK2) exon 1-12 dosage.

BACKGROUND: One of the causes of Parkinson's disease is mutations in the PARK2 gene. Deletions and duplications of single exons or exon groups account for a large proportion of the gene mutations. Direct detection of these mutations can be used for the diagnosis of Parkinson's disease. METHODS: To detect these mutations, we developed an effective technique based on the real-time TaqMan PCR system, which allows us to evaluate the copynumbers of the PARK2 gene exons by comparing the intensity of the amplification signals from some exon of this gene with that of the beta-globin gene (the internal control). RESULTS: We analyzed rearrangements in exons 1-12 of the PARK2 gene in 64 patients from Russia with early-onset Parkinson's disease. The frequency of these mutations in our patients was 14%. CONCLUSION: We have developed a simple, accurate, and reproducible method applicable to the rapid detection of exon rearrangements in the PARK2 gene. It is suitable for the analysis of large patient groups, and it may become the basis for a diagnostic test.

Mutation analysis of the parkin gene in Russian families with autosomal recessive juvenile parkinsonism.

Autosomal recessive juvenile parkinsonism (AR-JP) is a form of hereditary parkinsonism characterized by variable clinical presentations and caused by mutations in a novel gene, parkin, on chromosome 6q25.2-27. Until now, no Russian cases of parkin-associated AR-JP have been reported on. We recruited 16 patients from 11 Russian families with dopa-responsive movement disorders according to the following criteria: 1) family history compatible with autosomal recessive inheritance; 2) onset of symptoms at A). The majority of our parkin-associated cases were characterized by early-onset dopa-responsive parkinsonism with benign course and slow progression (5 patients from two families have been followed for as long as 18-36 years), and 1 patient had a phenotype of dopa-responsive dystonia. This first description of Russian patients with AR-JP and molecularly proven parkin mutations confirms the widespread occurrence of this polymorphic hereditary extrapyramidal disorder.