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Objective To examine the genetic variability of Estonian Parkinson's disease (PD) patients using an ongoing epidemiological study in combination with a genetic analysis. Methods This study was a community‐based genetic screening study of 189 PD patients, and 158 age‐ and sex‐matched controls screened for potential mutations in 9 PD genes using next‐generation sequencing and multiplex ligation‐dependent probe amplification method. Different clinimetric scales and questionnaires were used to examine PD patients and assess clinical characteristics and severity of the disease. Results The overall frequency of pathogenic PD‐causing variants was 1.1% (2/189), and any rare genetic variant was present in 21.2% (40/189) of the patients and in 8.2% (13/158) of the controls (P < .05). Variants of unknown significance accounted for 10.6% (20/189). Frequency of any GBA variant among PD patients was 10.1% (19/189) and in controls 3.8% (6/158). The frequency of any GBA variant in PD compared to controls was significantly higher (P = .035; OR 2.82; CI 95% 1.05‐8.87). Burden of rare variants was not different between patients and controls. Also, a novel GBA pathogenic variant p.E10X was detected. Conclusion Among different genetic variants identified in Estonian PD patients, GBA variants are the most common, while an overall pathogenic variant frequency was 1.1%.

Objective To examine the genetic variability of Estonian Parkinson's disease (PD) patients using an ongoing epidemiological study in combination with a genetic analysis. Methods This study was a community‐based genetic screening study of 189 PD patients, and 158 age‐ and sex‐matched controls screened for potential mutations in 9 PD genes using next‐generation sequencing and multiplex ligation‐dependent probe amplification method. Different clinimetric scales and questionnaires were used to examine PD patients and assess clinical characteristics and severity of the disease. Results The overall frequency of pathogenic PD‐causing variants was 1.1% (2/189), and any rare genetic variant was present in 21.2% (40/189) of the patients and in 8.2% (13/158) of the controls (P < .05). Variants of unknown significance accounted for 10.6% (20/189). Frequency of any GBA variant among PD patients was 10.1% (19/189) and in controls 3.8% (6/158). The frequency of any GBA variant in PD compared to controls was significantly higher (P = .035; OR 2.82; CI 95% 1.05‐8.87). Burden of rare variants was not different between patients and controls. Also, a novel GBA pathogenic variant p.E10X was detected. Conclusion Among different genetic variants identified in Estonian PD patients, GBA variants are the most common, while an overall pathogenic variant frequency was 1.1%.

Background and purpose Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. Methods During 20062012 we studied 38 methcathinone abusers with a mean age of 33years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 970 (20 +/- 15)months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. Results The average total UPDRS score was 43 +/- 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 +/- 3.8ppm) than controls (0.82 +/- 1.02ppm), P=0.02. Plasma Mn concentrations were higher (11.5 +/- 6.2ppb) in active than in former users (5.6 +/- 1.8ppb), P=0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. Conclusion Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We used microarrays to analyze whole-genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data were analyzed by Bayesian modeling and functional annotation. Of 28,869 genes on the microarrays, 326 showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative real-time PCR confirmed differential expression for the most of the genes selected for validation. Functional annotation and network analysis indicated activation of a gene network that included immunological disease, cellular movement, and cardiovascular disease functions (enrichment score 42). As HIV and HCV infections were confounding factors, we performed additional stratification of subjects. A similar functional activation of the “immunological disease” category was evident when we compared subjects according to injection status (past versus current users, balanced for HIV and HCV infection). However, this difference was not large therefore the major effect was related to the HIV status of the subjects. Mn–methcathinone abusers have blood RNA expression patterns that mostly reflect their HIV and HCV infections.

Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We used microarrays to analyze whole-genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data were analyzed by Bayesian modeling and functional annotation. Of 28,869 genes on the microarrays, 326 showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative real-time PCR confirmed differential expression for the most of the genes selected for validation. Functional annotation and network analysis indicated activation of a gene network that included immunological disease, cellular movement, and cardiovascular disease functions (enrichment score 42). As HIV and HCV infections were confounding factors, we performed additional stratification of subjects. A similar functional activation of the “immunological disease” category was evident when we compared subjects according to injection status (past versus current users, balanced for HIV and HCV infection). However, this difference was not large therefore the major effect was related to the HIV status of the subjects. Mn–methcathinone abusers have blood RNA expression patterns that mostly reflect their HIV and HCV infections.

Objective - To identify biomarkers supporting the clinical diagnosis of manganism in patients several years after exposure to manganese (Mn). Methods - Neurophysiological examinations, magnetic resonance imaging (MRI), single-photon emission computed tomography and fluorodeoxyglycose (FDG) positron emission tomography were performed in four former ephedrone addicts with extrapyramidal symptoms. Results - Peripheral nervous system was not affected. No patients had reduced uptake of (123)I Ioflupane in the striatum. MRI signal intensities were slightly changed in the basal ganglia. All patients showed a widespread, but not uniform, pathological pattern of FDG uptake with changes mainly located to the central part of the brain including the basal ganglia and the surrounding white matter. Conclusions - Presynaptic neurons in the nigrostriatal pathway are intact in Mn-induced parkinsonism after prolonged abstinence from ephedrone. The diagnosis is principally based on clinical signs and the history of drug abuse.