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Andrea H. Németh

Bio: Andrea H. Németh is an academic researcher from University of Oxford. The author has contributed to research in topics: Ataxia & Medicine. The author has an hindex of 32, co-authored 96 publications receiving 4090 citations. Previous affiliations of Andrea H. Németh include John Radcliffe Hospital & Nuffield Orthopaedic Centre.


Papers
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Journal ArticleDOI
TL;DR: The causative mutations in AOA2 are identified in 15 families, which allows this entity to be clinically defined by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein.
Abstract: Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.

452 citations

Journal ArticleDOI
TL;DR: The results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries and should be seen as conservative and an under-estimate of the true prevalence of dystonian disorders.
Abstract: There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorders (and botulinum toxin) clinics. The crude annual period prevalence rate (1996–1997) for primary dystonia was 152 per million (95% confidence interval 142–162), with focal dystonia having the highest rate of 117 per million (108–126). Prevalence rates for cervical dystonia, blepharospasm and writer's cramp were as follows: 57 (95% confidence interval 51–63), 36 (31–41), and 14 (11–17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focus dystonias with the exception of writer's cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writer's cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.

321 citations

Journal ArticleDOI
Jenny C. Taylor1, Jenny C. Taylor2, Hilary C. Martin2, Stefano Lise2, John Broxholme2, Jean-Baptiste Cazier2, Andrew J. Rimmer2, Alexander Kanapin2, Gerton Lunter2, Simon Fiddy2, Chris Allan2, A. Radu Aricescu2, Moustafa Attar2, Christian Babbs3, Jennifer Becq4, David Beeson3, Celeste Bento5, P Bignell3, Edward Blair3, Veronica J. Buckle3, Katherine R. Bull3, Katherine R. Bull2, Ondrej Cais6, Holger Cario7, Helen Chapel3, Richard R. Copley2, Richard R. Copley1, Richard J. Cornall3, Jude Craft1, Jude Craft2, Karin Dahan8, Emma E. Davenport2, Calliope A. Dendrou3, Olivier Devuyst9, Aimee L. Fenwick3, Jonathan Flint2, Lars Fugger3, Rodney D. Gilbert10, Anne Goriely3, Angie Green2, Ingo H. Greger6, Russell J. Grocock4, Anja V. Gruszczyk3, Robert W. Hastings3, Edouard Hatton2, Doug Higgs3, Adrian V. S. Hill3, Adrian V. S. Hill2, Christopher Holmes2, Christopher Holmes3, Malcolm F. Howard2, Malcolm F. Howard1, Linda Hughes2, Peter Humburg2, David W. Johnson3, Fredrik Karpe3, Zoya Kingsbury4, Usha Kini3, Julian C. Knight2, Jon P. Krohn2, Sarah Lamble2, Craig B. Langman11, Lorne Lonie2, Joshua Luck3, Davis J. McCarthy2, Simon J. McGowan3, Mary Frances McMullin12, Kerry A. Miller3, Lisa Murray4, Andrea H. Németh3, M. Andrew Nesbit3, David J. Nutt13, Elizabeth Ormondroyd3, Annette Bang Oturai14, Alistair T. Pagnamenta1, Alistair T. Pagnamenta2, Smita Y. Patel3, Melanie J. Percy15, Nayia Petousi3, Paolo Piazza2, Sian E. Piret3, Guadalupe Polanco-Echeverry2, Niko Popitsch1, Niko Popitsch2, Fiona Powrie3, Christopher W. Pugh3, Lynn Quek3, Peter A. Robbins3, Kathryn J. H. Robson3, Alexandra Russo, Natasha Sahgal2, Pauline A. van Schouwenburg3, Anna Schuh1, Anna Schuh3, Earl D. Silverman, Alison Simmons3, Per Soelberg Sørensen14, Elizabeth Sweeney, John Taylor3, John Taylor1, Rajesh V. Thakker3, Ian Tomlinson2, Ian Tomlinson1, Amy Trebes2, Stephen R.F. Twigg3, Holm H. Uhlig3, Paresh Vyas3, Timothy J. Vyse16, Steven A. Wall3, Hugh Watkins3, Michael P. Whyte17, Lorna Witty2, Ben Wright2, Christopher Yau2, David Buck2, Sean Humphray4, Peter J. Ratcliffe3, John I. Bell3, Andrew O.M. Wilkie3, David Bentley4, Peter Donnelly2, Peter Donnelly3, Gilean McVean2 
TL;DR: It is found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy.
Abstract: To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

318 citations

Journal ArticleDOI
TL;DR: This work has identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis, which encodes an evolutionarily conserved protein that is probably involved in protein sorting.
Abstract: Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.

302 citations

Journal ArticleDOI
TL;DR: A novel measure of disease progression and a genome-wide significant signal on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2 is generated, suggesting this mechanism as an area for future therapeutic investigation.
Abstract: Summary 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. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

225 citations


Cited by
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Journal ArticleDOI
01 Jan 2014-Nature
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

4,104 citations

01 Jul 2014
TL;DR: High rates of somatic mutation were seen, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification, and MAPK and PI(3)K pathway activity was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen(mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

2,847 citations

01 Aug 2001
TL;DR: The study of distributed systems which bring to life the vision of ubiquitous computing systems, also known as ambient intelligence, is concentrated on in this work.
Abstract: With digital equipment becoming increasingly networked, either on wired or wireless networks, for personal and professional use alike, distributed software systems have become a crucial element in information and communications technologies. The study of these systems forms the core of the ARLES' work, which is specifically concerned with defining new system software architectures, based on the use of emerging networking technologies. In this context, we concentrate on the study of distributed systems which bring to life the vision of ubiquitous computing systems, also known as ambient intelligence.

2,774 citations

Journal Article
TL;DR: Definition: To what extent does the study allow us to draw conclusions about a causal effect between two or more constructs?
Abstract: Definition: To what extent does the study allow us to draw conclusions about a causal effect between two or more constructs? Issues: Selection, maturation, history, mortality, testing, regression towrd the mean, selection by maturation, treatment by mortality, treatment by testing, measured treatment variables Increase: Eliminate the threats, above all do experimental manipulations, random assignment, and counterbalancing.

2,006 citations

01 Jan 1979
TL;DR: This special issue aims at gathering the recent advances in learning with shared information methods and their applications in computer vision and multimedia analysis and addressing interesting real-world computer Vision and multimedia applications.
Abstract: In the real world, a realistic setting for computer vision or multimedia recognition problems is that we have some classes containing lots of training data and many classes contain a small amount of training data. Therefore, how to use frequent classes to help learning rare classes for which it is harder to collect the training data is an open question. Learning with Shared Information is an emerging topic in machine learning, computer vision and multimedia analysis. There are different level of components that can be shared during concept modeling and machine learning stages, such as sharing generic object parts, sharing attributes, sharing transformations, sharing regularization parameters and sharing training examples, etc. Regarding the specific methods, multi-task learning, transfer learning and deep learning can be seen as using different strategies to share information. These learning with shared information methods are very effective in solving real-world large-scale problems. This special issue aims at gathering the recent advances in learning with shared information methods and their applications in computer vision and multimedia analysis. Both state-of-the-art works, as well as literature reviews, are welcome for submission. Papers addressing interesting real-world computer vision and multimedia applications are especially encouraged. Topics of interest include, but are not limited to: • Multi-task learning or transfer learning for large-scale computer vision and multimedia analysis • Deep learning for large-scale computer vision and multimedia analysis • Multi-modal approach for large-scale computer vision and multimedia analysis • Different sharing strategies, e.g., sharing generic object parts, sharing attributes, sharing transformations, sharing regularization parameters and sharing training examples, • Real-world computer vision and multimedia applications based on learning with shared information, e.g., event detection, object recognition, object detection, action recognition, human head pose estimation, object tracking, location-based services, semantic indexing. • New datasets and metrics to evaluate the benefit of the proposed sharing ability for the specific computer vision or multimedia problem. • Survey papers regarding the topic of learning with shared information. Authors who are unsure whether their planned submission is in scope may contact the guest editors prior to the submission deadline with an abstract, in order to receive feedback.

1,758 citations