The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Protocol of a cross-sectional, multicentre and multidisciplinary study describing phenotype and burden of a midfacial segment pain

Background: Midfacial segment pain is a term used in the past in the diagnosis of patients mainly from ear, nose and throat clinics. This type of pain cannot be attributed to other primary or secondary facial pain, but is to a large extent similar to tension-type headache with midfacial location. The purpose of this study is to describe midfacial segment pain phenotype, burden and comorbidities in a multicentre and multidisciplinary setting. The ultimate goal is a comprehensive description of this type of pain allowing for its implementation in future classifications. Methods: This cross-sectional study is designed to describe midfacial segment pain in a clinical setting. Patients from rhinologic, headache and facial pain or oral medicine/dentistry secondary care centres will be recruited during a 1 year period. Individuals with other facial pain according to current classification such as sinonasal disorders, neoplasms, local infections, history of significant trauma associated with pain onset will be excluded. Data will be collected through a structured questionnaire covering pain characteristics, coexisting diagnoses, pain-related burden and consequences, physical examination and paranasal sinuses imaging

Effects of plantar automated mechanical stimulation (AMPS) on motor symptoms of patients with advanced Parkinson's disease: Preliminary data of a double blind randomized clinical trial

Objective: The aim of this study is to develop and evaluate methods for quantifying motor symptoms in Parkinson’s disease (PD) using combined upper limb motor test data collected during tapping and spiral drawing tasks by a smart phone. Background: PD is a multidimensional and complex disorder affecting motor and non motor functionalities. Assessments of PD symptoms are usually done by clinical rating scales. One of them is the Unified PD Rating Scale (UPDRS) developed to provide comprehensive, efficient and flexible means to monitor PD-related disability and impairments. It has been the most commonly used rating scale. It is composed of four main parts where the third part is designed for rating of motor symptoms. However, UPDRS has relatively poor inter-rater reliability. Another scale that is used to grade motor function of patients is Treatment Response Scale (TRS). A limitation is that there is no general agreement on which parts of the symptomatology should be included in the TRS score. However, the scales have low intra- and inter-rater reliability and their use is limited, as they are only used during in-clinic observations. Methods: Participants: Nine-teen patients diagnosed with PD and 22 healthy controls were recruited in a single center, open label, single dose clinical observational study in Sweden. Simultaneous clinical- and smartphone-based measures were collected up to 15 times following a single levodopa/carbidopa morning dose (50% over normal to induce dyskinesias). Clinical assessment: Subjects were asked to perform standardized motor tests in accordance with UPDRS and were videotaped. The videos were blindly rated by three movement disorder specialists. The ratings were given based on TRS ranging from -3, 'Very Off' to 0, 'On' to +3, 'Very dyskinetic', three UPDRS motor items (item 23, finger taps; item 25, rapid alternating movements of hands, item 31, body bradykinesia and hypokinesia) and dyskinesia score. Means of the three specialists' assessments per time point on these scales were used in subsequent analysis. Smartphone-based data collection: On each test occasion, the subjects performed upper limb motor tests (tapping and spiral drawings) using a smartphone. The subjects were instructed to perform the tests using an ergonomic pen stylus with the device placed on a table and to be seated in a chair. During tapping tests, the subjects were asked to alternately tap two fields (as shown in the screen of the device) as fast and accurate as possible, using first right hand and then left hand. Each tapping test lasted for 20 seconds. During spiral tests, the subjects were instructed to trace a pre-drawn Archimedes spiral as fast and accurate as possible, using the dominant hand. The spiral test was repeated three times per test occasion. The smartphone recorded both position and time-stamps (in milliseconds) of the pen tip. Data processing and analysis: The raw tapping and spiral data were processed with time series analysis methods, including both time- and frequency-domains methods. Nineteen and 22 spatiotemporal features were extracted from spiral and tapping data, respectively. Features were calculated to represent various kinematic quantities during the motor tests such as acceleration, speed, time delay, and distance. The features from both tapping and spiral data were used in a Principal Component Analysis and 7 principal components (PCs) were retained, which in turn were used as inputs to a Support Vector Machines (SVM) to be mapped to mean clinical ratings. The analyses were performed with a stratified 10-fold cross-validation. Test-retest reliability of the spiral tests were assessed after calculating correlations between the first PCs for the three spiral tests and then calculating the mean of all possible correlations. Results: The correlation coefficients between SVM predictions and mean clinical ratings were as follows: 0.59 for TRS, 0.6 for dyskinesia score, 0.52 for item 23 of UPDRS (finger taps), 0.47 for item 25 of UPDRS (rapid alternating movements of hands), and 0.57 for item 31 of UPDRS (body Bradykinesia and Hypokinesia). The spiral test had a good test-retest reliability with a coefficient of 0.84, indicating that spiral scores are stable and consistent over time. When assessing the ability of the PCs to distinguish between patients and healthy controls the means of 3 out of 7 PCs (PC1, PC2 and PC4) were different between the two groups (p<0.005). Conclusions: The upper limb motor tests of the smartphone were able to capture important and relevant symptom information of the clinical rating scales. The methods for quantifying the upper limb motor symptoms of PD patients: had adequate correlations to clinical ratings were able to differentiate between movements of patients and healthy controls, and(Spiral tests) had good test-retest reliability

Frequency of mutations in PRKN, PINK1, and DJ1 in Patients With Early-Onset Parkinson Disease from neighboring countries in Central Europe

INTRODUCTION: Approximately 10% of patients with Parkinson disease (PD) present with early-onset disease (EOPD), defined as diagnosis before 50 years of age. Genetic factors are known to contribute to EOPD, with most commonly observed mutations in PRKN, PINK1, and DJ1 genes. The aim of our study was to analyze the frequency of PRKN, PINK1, and DJ1 mutations in an EOPD series from 4 neighboring European countries: Czech Republic, Germany, Poland, and Ukraine. METHODS: Diagnosis of PD was made based on UK Brain Bank diagnostic criteria in departments experienced in movement disorders (1 from Czech Republic, 1 from Germany, 9 from Poland, and 3 from Ukraine). EOPD was defined as onset at or before 50 years of age. Of the 541 patients recruited to the study, 11 were Czech, 38 German, 476 Polish, and 16 Ukrainian. All cohorts were fully screened with Sanger sequencing for PRKN, PINK1, and DJ1 and multiplex ligation-dependent probe amplification for exon dosage. RESULTS: PRKN homozygous or double heterozygous mutations were identified in 17 patients: 1 Czech (9.1%), 1 German (2.6%), 14 Polish (2.9%), and 1 Ukrainian (6.3%). PINK1 homozygous mutations were only identified in 3 Polish patients (0.6%). There were no homozygous or compound heterozygous DJ1 mutations in analyzed subpopulations. One novel variant in PRKN was identified in the Ukrainian series. CONCLUSION: In the analyzed cohorts, mutations in the genes PRKN, PINK1, and DJ1 are not frequently observed

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

10.1212/WNL.0000000000001012Neurology83211906-191

Cathepsin B p.Gly284Val variant in Parkinsons disease pathogenesis

Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk