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See detailThe Levodopa Response Trial and the Parkinson Disease Digital Biomarker Challenge: Monitoring symptoms of Parkinson’s disease in the lab and home using wearable sensors
Daneault, J.; Vergara-Diaz, G.; Costante, G. et al

in Movement Disorders : Official Journal of the Movement Disorder Society (2018, October 03), 33(S2), 525

Objective: To leverage a community of researchers and shared wearable data to develop algorithms to estimate the severity of PD specific symptoms. Background: People with Parkinson’s disease (PwPD) often ... [more ▼]

Objective: To leverage a community of researchers and shared wearable data to develop algorithms to estimate the severity of PD specific symptoms. Background: People with Parkinson’s disease (PwPD) often experience fluctuations in motor symptom severity. Wearable sensors have the potential to help clinicians monitor symptoms over time, outside the clinic. However, to gather accurate and clinically-relevant measures, there is a need to develop robust algorithms based on clinically- labelled data. Methods: The Levodopa Response Trial captured three-axis acceleration from two wrist-worn sensors and a smartphone located at the waist from 29 PwPD continuously over 4 days. On day 1, in an in-clinic visit, participants performed clinical assessments and motor tasks on their regular medication regimen. During these visits, a clinician also provided symptom severity scores for tremor, bradykinesia, and dyskinesia. On days 2 & 3, sensor data was collected while participants were at home. On day 4, participants returned to the clinic for the same assessments as day 1, but arrived without having taken their medication for at least 10 hours. Leveraging this dataset, Sage Bionetworks, the Michael J Fox Foundation and the Robert Wood Johnson Foundation launched the PD Digital Biomarker DREAM Challenge which made a subset of the data available to researchers to develop robust and accurate algorithms for the estimation of specific symptoms’ severity. Results: Teams participating in the challenge used several technical approaches, from signal processing to deep learning. 35 submissions were received for the estimation of action tremor severity. Teams achieved an area under the precision-recall curve (AUPR) of 0.444 to 0.75. As for dyskinesia during movement, 37 submissions were received and the teams achieved an AUPR of 0.175 to 0.477. Finally, 39 submissions were received for the estimation of bradykinesia and the teams achieved an AUPR of 0.413 to 0.95. Null expectations for the testing datasets were 0.432, 0.195, and 0.266, respectively. Conclusions: Making datasets available to the community leverages the creativity of different groups to develop robust and accurate algorithms for the estimation of PD symptom severity. This will lead to better quality and interpretability of data collected in unsupervised settings within the community. [less ▲]

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See detailRare variant analysis of the PPMI dataset to uncover the complex genetic architecture of Parkinson’s disease
Bobbili, Dheeraj Reddy UL; May, Patrick UL; Krüger, Rejko UL

in Movement Disorders : Official Journal of the Movement Disorder Society (2017, June 02), 322(Supplement S2), 405

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s ... [more ▼]

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s disease (PD) is a complex disease. Besides variants in high-risk genes such as LRRK2 and PARK2, multiple genes associated to sporadic PD were discovered via genome-wide association studies. Yet, there is a large number of genetic factors that need to be deciphered. Methods: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). The dataset comprised of 435 PD cases and 162 ethnically matched controls, respectively. We performed burden tests at single variant, gene and geneset levels on common and rare exonic and splice-variants. We also looked for severity of rare highly deleterious variants (CADD phred score>30) using the CADD score as well as singleton (variants seen in only one individual across cases and controls) rare variants. Additionally, we performed the functional enrichment analysis with the genes harboring rare highly deleterious variants (case uniq genes) that are only present in cases. Results: We observed an increased mutational burden of singleton variants in PD cases compared to the controls in nonsynonymous+LOF variants (empirical P-value 0.005) but not in the synonymous variants (empirical P-value 0.09). We observed a higher significant burden (P-value 0.028) as well as higher significant severity (empirical P-value 0.027) of rare, highly deleterious nonsynonymous variants, but not in the synonymous variants of the candidate genes (P-value 0.686, empirical P-value 0.556 for burden and severity respectively). The network analysis of genes having deleterious variants only present in cases (Case uniq) showed a significant increase in connectivity compared to random networks (P-value 0.0002). Pathway analysis of those genes showed a significant enrichment of pathways and biological process implicated in the nervous system functioning and the etiology of PD. Conclusions: Our study supports the complex disease notion of PD by highlighting the convoluted architecture of PD where case uniq genes including LRRK2 are implicated in several biological processes and pathways related to PD. The main finding of this study is to discover the complex genetics of PD at an exome wide level. [less ▲]

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See detailThe nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder.
Heintz-Buschart, Anna UL; Pandey, Urvashi; Wicke, Tamara et al

in Movement disorders : official journal of the Movement Disorder Society (2017)

BACKGROUND: Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD ... [more ▼]

BACKGROUND: Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD patients. It is, however, unknown whether these differences can be observed in individuals at high risk, for example, with idiopathic rapid eye movement sleep behavior disorder, a prodromal condition of alpha-synuclein aggregation disorders including PD. OBJECTIVES: To compare microbiota in carefully preserved nasal wash and stool samples of subjects with idiopathic rapid eye movement sleep behavior disorder, manifest PD, and healthy individuals. METHODS: Microbiota of flash-frozen stool and nasal wash samples from 76 PD patients, 21 idiopathic rapid eye movement sleep behavior disorder patients, and 78 healthy controls were assessed by 16S and 18S ribosomal RNA amplicon sequencing. Seventy variables, related to demographics, clinical parameters including nonmotor symptoms, and sample processing, were analyzed in relation to microbiome variability and controlled differential analyses were performed. RESULTS: Differentially abundant gut microbes, such as Akkermansia, were observed in PD, but no strong differences in nasal microbiota. Eighty percent of the differential gut microbes in PD versus healthy controls showed similar trends in idiopathic rapid eye movement sleep behavior disorder, for example, Anaerotruncus and several Bacteroides spp., and correlated with nonmotor symptoms. Metagenomic sequencing of select samples enabled the reconstruction of genomes of so far uncharacterized differentially abundant organisms. CONCLUSION: Our study reveals differential abundances of gut microbial taxa in PD and its prodrome idiopathic rapid eye movement sleep behavior disorder in comparison to the healthy controls, and highlights the potential of metagenomics to identify and characterize microbial taxa, which are enriched or depleted in PD and/or idiopathic rapid eye movement sleep behavior disorder. (c) 2017 International Parkinson and Movement Disorder Society. [less ▲]

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See detailCost-Effectiveness of Neurostimulation in Parkinson's Disease With Early Motor Complications
Dams, J; Balzer-Geldsetzer, M; Siebert, U et al

in Movement Disorders : Official Journal of the Movement Disorder Society (2016), 31(8), 1183-1191

Background: Recent research efforts have focused on the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) for selected patients with mild-to-moderate PD experiencing motor ... [more ▼]

Background: Recent research efforts have focused on the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) for selected patients with mild-to-moderate PD experiencing motor complications. Objectives: We assessed the cost utility of subthalamic DBS compared with the best medical treatment for German patients below the age of 61 with early motor complications of PD. Methods: We applied a previously published Markov model that integrated health utilities based on EuroQoL and direct costs over patients’ lifetime adjusted to the German health care payer perspective (year of costing: 2013). Effectiveness was evaluated using the Parkinson’s Disease Questionnaire 39 summary index. We performed sensitivity analyses to assess uncertainty. Results: In the base-case analysis, the incremental cost-utility ratio for STN DBS compared to best medical treatment was 22,700 Euros per quality-adjusted life year gained. The time to, and costs for, battery exchange had a major effect on the incremental cost-utility ratios, but never exceeded a threshold of 50,000Euros per quality-adjusted life year. Conclusions: Our decision analysis supports the fact that STN DBS at earlier stages of the disease is cost-effective in patients below the age of 61 when compared with the best medical treatment in the German health care system. This finding was supported by detailed sensitivity analyses reporting robust results. Whereas the EARLYSTIM study has shown STN DBS to be superior to medical therapy with respect to quality of life for patients with early motor complications, this further analysis has shown its cost-effectiveness. [less ▲]

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See detailAlpha-synuclein gene variants may predict neurostimulation outcome.
Weiss, D.; Herrmann, S.; Wang, Lin UL et al

in Movement disorders : official journal of the Movement Disorder Society (2016)

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See detailFailing as Doorman and Disc Jockey at the Same Time: Amygdalar Dysfunction in Parkinson’s Disease
Diederich, Nico UL; Goldman, Jennifer; Stebbins, Glenn et al

in Movement Disorders : Official Journal of the Movement Disorder Society (2015), 00(00),

In Braak’s model of ascending degeneration in Parkinson’s disease (PD), involvement of the amygdala occurs simultaneously with substantia nigra degeneration. However, the clinical manifestations of ... [more ▼]

In Braak’s model of ascending degeneration in Parkinson’s disease (PD), involvement of the amygdala occurs simultaneously with substantia nigra degeneration. However, the clinical manifestations of amygdalar involvement in PD have not been fully delineated. Considered a multitask manager, the amygdala is a densely connected “hub,” coordinating and integrating tasks ranging from prompt, multisensorial emotion recognition to adequate emotional responses and emotional tuning of memories. Although phylogenetically predisposed to handle fear, the amygdala handles both aversive and positive emotional inputs. In PD, neuropathological and in vivo studies suggest primarily amygdalar hypofunction. However, as dopamine acts as an inverted U-shaped amygdalar modulator, medicationinduced hyperactivity of the amygdala can occur.We propose that amygdalar (network) dysfunction contributes to reduced recognition of negative emotional face expressions, impaired theory of mind, reactive hypomimia, and impaired decision making. Similarly, impulse control disorders in predisposed individuals, hallucinations, anxiety, and panic attacks may be related to amygdalar dysfunction. When available, we discuss amygdala-independent trigger mechanisms of these symptoms. Although dopaminergic agents have mostly an activation effect on amygdalar function, adaptive and compensatory network changes may occur as well, but these have not been sufficiently explored. In conclusion, our model of amygdalar involvement brings together several elements of Parkinson’s disease phenomenology heretofore left unexplained and provides a framework for testable hypotheses in patients during life and in autopsy analyses. VC 2015 International Parkinson and Movement Disorder Society [less ▲]

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See detailAlpha-synuclein repeat variants and survival in Parkinson's disease.
Chung, Sun Ju; Biernacka, Joanna M.; Armasu, Sebastian M. et al

in Movement disorders : official journal of the Movement Disorder Society (2014)

OBJECTIVES: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of ... [more ▼]

OBJECTIVES: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in PD. Further studies of alpha-synuclein's role in disease progression and long-term outcomes are needed. (c) 2014 International Parkinson and Movement Disorder Society. [less ▲]

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See detailGenome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?
Lohmann, Katja; Schmidt, Alexander; Schillert, Arne et al

in Movement disorders : official journal of the Movement Disorder Society (2014), 29(7), 921-7

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument ... [more ▼]

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 x 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 x 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 x 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (lambda = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients. [less ▲]

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See detailPopulation-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.
Heckman, Michael G.; Soto-Ortolaza, Alexandra I.; Aasly, Jan O. et al

in Movement disorders : official journal of the Movement Disorder Society (2013), 28(12), 1740-4

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease ... [more ▼]

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. [less ▲]

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See detailLack of Polysomnographic Non-REM Sleep Changes in Early Parkinson’s Disease
Diederich, Nico UL; Rufra, Olivier; Pieri, Vannina et al

in Movement Disorders : Official Journal of the Movement Disorder Society (2013)

Background: Polysomnography (PSG) data are rare in patients who have early stage idiopathic Parkinson’s disease (IPD). Methods: Thirty-three patients who had IPD with a disease duration 3 years and 37 age ... [more ▼]

Background: Polysomnography (PSG) data are rare in patients who have early stage idiopathic Parkinson’s disease (IPD). Methods: Thirty-three patients who had IPD with a disease duration 3 years and 37 age-matched controls were recruited. PSG analysis was performed on current medication. Results: Patients with IPD had a reduced mean percentage of muscle atonia during rapid eye movement (REM) sleep (80% vs 93%; P < 0.05). Total sleep time, sleep efficiency, indices/hour of arousals, awakenings, apnea/hypopnea, and periodic leg movements were similar in both groups. Age, but not dopaminergic medication, had a negative impact on sleep architecture in patients with IPD. There was no correlation between sleep efficiency assessed by PSG and sleep quality assessed by questionnaire. Conclusions: The results confirmed a reduction in muscle atonia during REM sleep as a characteristic finding in early IPD. However, there were no further disease-inherent or medication-induced changes in sleep architecture. Although sleep disturbances are considered to be an integral part of IPD, PSG cannot yet identify them objectively at an early stage. VC 2013 International Parkinson and Movement Disorder Society [less ▲]

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See detailLRRK2: Understanding the role of common and rare variants in Parkinson's disease.
Sharma, Manu; Krüger, Rejko UL; Gasser, Thomas

in Movement disorders : official journal of the Movement Disorder Society (2012), 27(4), 475

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See detailCentral oscillators in a patient with neuropathic tremor: evidence from intraoperative local field potential recordings.
Weiss, Daniel; Govindan, Rathinaswamy B.; Rilk, Albrecht et al

in Movement disorders : official journal of the Movement Disorder Society (2011), 26(2), 323-7

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct ... [more ▼]

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct evidence of central tremor processing in a 76-year-old female who underwent bilateral deep brain stimulation of the ventral intermedial nucleus of the thalamus (Vim-DBS) because of neuropathic tremor associated with IgM paraproteinemia. Electrophysiological recordings of EEG and EMG were performed in three perioperative sessions: (1) preoperatively, (2) intraoperatively, and (3) 4 days after surgery in both rest and postural tremor conditions. Tremor-related synchronization (coherence) between motor cortex (M1) and muscles (M. extensor digitorum, M. flexor digitorum) was assessed, and additional intraoperative local field potential (LFP) recordings from Vim allowed comprehensive coherence mapping in thalamo-cortico-muscular networks. Directionality of information flow was determined by directed transfer function (DTF) and phase analyses. Stimulation effects on tremor and corticomuscular coherence were assessed and the patient was followed for 12 months on clinical outcome measures (Tremor Rating Scale, CADET-Score). Vim-DBS reduced tremor (59%) and improved motor functionality in daily activities (31%, CADET-A) after 12 months. Intraoperative recordings demonstrated significant coherence in the tremor frequency (4 Hz) between M1 and contralateral muscle, Vim and ipsilateral M1, Vim and contralateral muscle, but not between Vim and contralateral M1. Information flow was directed from M1 to Vim and bidirectional between M1 and muscle and between Vim and muscle, respectively. Corticomuscular coherence at tremor frequency was completely suppressed by Vim-DBS. Our case study demonstrates central oscillators underlying neuropathic tremor and implies a strong pathophysiological rationale for Vim-DBS. [less ▲]

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See detailAn unusual neurological syndrome of crawling gait, dystonia, pyramidal signs, and limited speech.
Arif, Beenish; Grünewald, Anne UL; Fatima, Amara et al

in Movement disorders : official journal of the Movement Disorder Society (2011), 26(12), 2279-83

BACKGROUND: The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family. METHODS: Five patients, their 2 siblings, and their parents ... [more ▼]

BACKGROUND: The purpose of the study was to identify and molecularly characterize a neurological syndrome in a consanguineous Pakistani family. METHODS: Five patients, their 2 siblings, and their parents were clinically examined. DNA from all 7 siblings was genotyped with Affymetrix SNP arrays and sequencing of selected candidate genes. RESULTS: An unusual neurological syndrome of crawling gait, predominant leg dystonia, pyramidal signs, microcephaly, and suspected deafness segregated in the family. Three patients ambulated on hands and knees, either by hopping and crossing their legs, or by dragging the legs behind them. Two patients have acquired the ability to walk bipedally with a dystonic gait. Unexpectedly, no chromosomal region was homozygous in patients only. Under different disease models, we localized 7 chromosomal regions in the genome common to all patients. No pathogenic mutations were identified in selected candidate genes or the mitochondrial genome. CONCLUSION: We describe an unusual movement disorder syndrome reminiscent of but distinct from Uner Tan syndrome. [less ▲]

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See detailComplex hyperkinetic movement disorders associated with POLG mutations.
Synofzik, Matthis; Schule, Rebecca; Schulte, Claudia et al

in Movement disorders : official journal of the Movement Disorder Society (2010), 25(14), 2472-5

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See detailDiscriminative power of different nonmotor signs in early Parkinson's disease. A case-control study
Diederich, Nico UL; Pieri, Vannina; Hipp, Geraldine et al

in Movement Disorders : Official Journal of the Movement Disorder Society (2010), 25(7), 882-887

The objective of this study was to evaluate the discriminative power of different nonmotor signs for early diagnosis of Parkinson's disease (PD). Thirty patients with PD with <or=3 years of disease ... [more ▼]

The objective of this study was to evaluate the discriminative power of different nonmotor signs for early diagnosis of Parkinson's disease (PD). Thirty patients with PD with <or=3 years of disease duration were compared with 30 healthy controls. Six deficit domains (DD) were defined: hyposmia, sleep abnormalities, dysautonomia, visual deficits, executive dysfunction, and depression. Plotting of Receiver operating characteristic (ROC) curves and exact conditional logistic modeling, followed by manual stepwise descending procedure were used to identify a model for nonmotor signs that detects early PD. Patients with PD and controls did not differ in terms of age, gender, and educational level. Several DD discriminated patients with PD from healthy controls. Visual deficits showed the largest area under the ROC curve (0.83), followed by hyposmia (0.81) and dysautonomia (0.80). When combining the DD visual deficits and dysautonomia, the best residual model was obtained; it maximized both sensitivity and specificity for PD at a level of 0.77. At an early disease stage, several nonmotor domains were already able to discriminate patients with PD from healthy controls. Visual deficits had the best discriminatory power. Being brief and inexpensive, visual tests should be further investigated in larger cohorts as potential screening tool for early PD. [less ▲]

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See detailSevere muscular fasciculations as an uncommon side-effect due to microdefect of an extension wire in deep brain stimulation.
Wachter, Tobias; Weiss, Daniel; Breit, Sorin et al

in Movement disorders : official journal of the Movement Disorder Society (2009), 24(14), 2161-2

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See detailThe DRD2 TaqIA polymorphism and demand of dopaminergic medication in Parkinson's disease.
Paus, Sebastian; Grünewald, Anne UL; Klein, Christine UL et al

in Movement disorders : official journal of the Movement Disorder Society (2008), 23(4), 599-602

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD ... [more ▼]

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD) and schizophrenia, respectively. We tested whether the TaqIA genotype in PD is responsible for demand of dopaminergic medication, measured in total dopaminergic load per year of disease, in a large scale association study based on the gene bank of the German Competence Network on Parkinson's disease. Regression analysis yielded no significant differences between the TaqIA genotypes. We conclude that the DRD2 TaqIA polymorphism alone has no pivotal role for interindividual variability of dopaminergic requirement in PD. We propose a practicable system of measuring dopaminergic treatment for future pharmacogenetic studies in PD. [less ▲]

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See detailRapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification.
Djarmati, Ana; Guzvic, Miodrag; Grünewald, Anne UL et al

in Movement disorders : official journal of the Movement Disorder Society (2007), 22(12), 1708-14

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening ... [more ▼]

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening for small sequence changes and for large exonic rearrangements in disease-associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real-time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation-dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M-D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large-scale and cost-effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype-genotype correlations. [less ▲]

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See detailAutosomal dominant myoclonus-dystonia and Tourette syndrome in a family without linkage to the SGCE gene.
Orth, Michael; Djarmati, Ana; Baumer, Tobias et al

in Movement disorders : official journal of the Movement Disorder Society (2007), 22(14), 2090-6

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to ... [more ▼]

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to the DYT15, DYT1, and DRD2 gene loci in a family with autosomal dominant myoclonus-dystonia (M-D) and Gilles de la Tourette syndrome (GTS). Fourteen family members, from three generations, underwent a detailed clinical assessment and donated DNA samples. The SGCE and the SLITRK1 gene were sequenced and investigated by gene dosage analysis in selected family members. Linkage to the SGCE, DYT15, DYT1, DRD2, and SLITRK1 loci was also tested. RESULTS: We included three healthy and 11 affected family members with M-D (n = 3), dystonia alone (n = 2), GTS (n = 1), tics (n = 1) or a combination of these with obsessive compulsive disorder (OCD) (M-D + OCD: n = 2; dystonia+OCD: n = 1; M-D + GTS + OCD: n = 1). There was no linkage to the SGCE, DYT15, DYT1 or DRD2 loci. No changes were found in the SLITRK1 gene. The presence of both M-D and GTS in one family, in which all known M-D loci and a recently discovered GTS locus were excluded, suggests a novel susceptibility gene for both M-D and GTS. [less ▲]

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See detailSleep apnea syndrome in Parkinson's disease. A case-control study in 49 patients.
Diederich, Nico UL; Vaillant, Michel; Leischen, Mike et al

in Movement disorders : official journal of the Movement Disorder Society (2005), 20(11), 1413-8

In PD, the impact of nocturnal respiration on sleep continuity and architecture has not been systematically investigated by polysomnography (PSG). We performed a case-control study with retrospective ... [more ▼]

In PD, the impact of nocturnal respiration on sleep continuity and architecture has not been systematically investigated by polysomnography (PSG). We performed a case-control study with retrospective analysis of PSG data of 49 PD patients. After classifying the PD patients according to their apnea/hypopnea index (AHI), they were matched with 49 controls in terms of age, gender, and AHI. There were 21 PD patients (43%) who had sleep apnea syndrome (SAS), classified as mild (AHI, 5-15) in 10 patients, moderate (AHI, >15-30) in 4 patients, and severe (AHI, > 30) in 7 patients. PD patients had more deep sleep (P = 0.02) and more nocturnal awakenings (P < 0.001) than the controls. Their body mass index (BMI) was lower (P = 0.04), and they maintained a more favorable respiratory profile, with higher mean and minimal oxygen saturation values (P = 0.006 and 0.01, respectively). These differences were preserved when only considering PD patients with AHI > 15. PD patients had less obstructive sleep apneas (P = 0.035), independently from the factor AHI. Only the respiratory changes of 4 PD patients with BMI > 27 and AHI > 15 (8%) approximated those seen in the controls. At an early or middle stage of the disease, non-obese PD patients frequently have AHI values suggesting SAS, however, without the oxygen desaturation profile of SAS. Longitudinal studies of patients with such "abortive" SAS are warranted to establish if this finding reflects benign nocturnal respiratory muscle dyskinesia or constitutes a precursor sign of dysautonomia in PD. [less ▲]

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