Nicholas W Wood

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (413)3547.97 Total impact

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    Brain 11/2014; · 10.23 Impact Factor
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    ABSTRACT: Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 11/2014; 95(5):611-21. · 10.99 Impact Factor
  • Neurology 10/2014; · 8.30 Impact Factor
  • Neurology 10/2014; · 8.30 Impact Factor
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    ABSTRACT: The catechol-O-methyltransferase (COMT) enzyme is a major determinant of prefrontal dopamine levels. The Val(158)Met polymorphism affects COMT enzymatic activity and has been associated with variation in executive function and affective processing. This study investigated the effect of (COMT) genotype on the flexible modulation of the balance between processing self-generated and processing stimulus-oriented information, in the presence or absence of affective distractors. Analyses included 124 healthy adult participants, who were also assessed on standard working memory (WM) tasks. Relative to Val carriers, Met homozygotes made fewer errors when selecting and manipulating self-generated thoughts. This effect was partly accounted for by an association between COMT genotype and visuospatial WM performance. We also observed a complex interaction between the influence of affective distractors, genotype and sex on task accuracy: male, but not female, participants showed sensitivity to the affective distractors that was dependent on COMT genotype. This was not accounted for by WM performance. This study provides novel evidence of the role of dopaminergic genetic variation on the ability to select and manipulate self-generated thoughts. The results also suggest sexually dimorphic effects of COMT genotype on the influence of affective distractors on executive function.
    Social Cognitive and Affective Neuroscience 09/2014; · 5.88 Impact Factor
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    Journal of neurology. 08/2014;
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    ABSTRACT: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
    Nature genetics. 07/2014;
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    Practical Neurology 06/2014;
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    ABSTRACT: Working memory (WM) refers to mental processes that enable temporary retention and manipulation of information, including information about other people ("social working memory"). Previous studies have demonstrated that nonsocial WM is supported by dopamine neurotransmission. Here, we investigated in 131 healthy adults whether dopamine is similarly involved in social WM by testing whether social and nonsocial WM are influenced by genetic variants in three genes coding for molecules regulating the availability of dopamine in the brain: catechol-O-methyltransferase (COMT), dopamine active transporter (DAT), and monoamine-oxidase A (MAOA). An advantage for the Met allele of COMT was observed in the two standard WM tasks and in the social WM task. However, the influence of COMT on social WM performance was not accounted for by its influence on either standard WM paradigms. There was no main effect of DAT1 or MAOA, but a significant COMT x DAT1 interaction on social WM performance. This study provides novel preliminary evidence of effects of genetic variants of the dopamine neurotransmitter system on social cognition. The results further suggest that the effects observed on standard WM do not explain the genetic effects on effortful social cognition.
    Social Neuroscience 06/2014; · 2.87 Impact Factor
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    ABSTRACT: The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function.
    Open Biology 05/2014; 4(5):140051. · 4.56 Impact Factor
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    ABSTRACT: Oligomers of the amyloid-β (Aβ) peptide have been implicated in the neurotoxicity associated with Alzheimer's disease. We have used single-molecule techniques to examine quantitatively the cellular effects of adding well characterized Aβ oligomers to primary hippocampal cells and hence determine the initial pathway of damage. We found that even picomolar concentrations of Aβ (1-40) and Aβ (1-42) oligomers can, within minutes of addition, increase the levels of intracellular calcium in astrocytes but not in neurons, and this effect is saturated at a concentration of about 10 nM of oligomers. Both Aβ (1-40) and Aβ (1-42) oligomers have comparable effects. The rise in intracellular calcium is followed by an increase in the rate of ROS production by NADPH oxidase in both neurons and astrocytes. The increase in ROS production then triggers caspase-3 activation resulting in the inhibition of long-term potentiation. Our quantitative approach also reveals that only a small fraction of the oligomers are damaging and that an individual rare oligomer binding to an astrocyte can initiate the aforementioned cascade of responses, making it unlikely to be due to any specific interaction. Preincubating the Aβ oligomers with an extracellular chaperone, clusterin, sequesters the oligomers in long-lived complexes and inhibits all of the physiological damage, even at a ratio of 100:1, total Aβ to clusterin. To explain how Aβ oligomers are so damaging but that it takes decades to develop Alzheimer's disease, we suggest a model for disease progression where small amounts of neuronal damage from individual unsequestered oligomers can accumulate over time leading to widespread tissue-level dysfunction.
    Biochemistry 04/2014; · 3.38 Impact Factor
  • Una‐Marie Sheerin, Henry Houlden, Nicholas W. Wood
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    ABSTRACT: Over the last 16 years, insights in clinical and genetic characteristics of Parkinson's disease (PD) have increased substantially. We summarize the clinical, genetic, and pathological findings of autosomal dominant PD linked to mutations in SNCA, leucine-rich repeat kinase 2, vacuolar protein sorting-35, and eukaryotic translation initiation factor 4 gamma 1 and autosomal recessive PD linked to parkin, PINK1, and DJ-1, as well as autosomal recessive complicated parkinsonian syndromes caused by mutations in ATP13A2, FBXO7, PLA2G6, SYNJ1, and DNAJC6. We also review the advances in high- and low-risk genetic susceptibility factors and present multisystem disorders that may present with parkinsonism as the major clinical feature and provide recommendations for prioritization of genetic testing. Finally, we consider the challenges of future genetic research in PD.
    Movement Disorders Clinical Practice. 04/2014; 1(1).
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    ABSTRACT: Background Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.Methods Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.ResultsWe did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.Conclusion Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations. © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 04/2014; · 5.63 Impact Factor
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    ABSTRACT: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia. A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used. Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene. We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype.
    Neurology 02/2014; · 8.30 Impact Factor
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    ABSTRACT: Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 International Parkinson and Movement Disorder Society.
    Movement Disorders 01/2014; · 5.63 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.Genes and Immunity advance online publication, 16 January 2014; doi:10.1038/gene.2013.70.
    Genes and immunity 01/2014; · 4.22 Impact Factor
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    ABSTRACT: GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
    Brain 01/2014; 137(9):2480-2492. · 10.23 Impact Factor
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    ABSTRACT: Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.
    Nature Communications 01/2014; 5:4204. · 10.74 Impact Factor
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    ABSTRACT: Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease. We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members. We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative. Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).
    New England Journal of Medicine 11/2013; 369(20):1904-14. · 54.42 Impact Factor
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    Movement Disorders 11/2013; · 5.63 Impact Factor

Publication Stats

18k Citations
3,547.97 Total Impact Points

Institutions

  • 2014
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2008–2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2002–2014
    • Philipps University of Marburg
      Marburg, Hesse, Germany
    • Institute of Neurology
      Moskva, Moscow, Russia
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 1998–2014
    • University College London
      • • Sobell Department of Motor Neuroscience and Movement Disorders
      • • Department of Molecular Neuroscience
      • • Institute of Neurology
      Londinium, England, United Kingdom
  • 2011
    • Wellcome Trust
      Londinium, England, United Kingdom
  • 2007–2010
    • Duke University Medical Center
      • • Center for Human Genome Variation
      • • Institute for Genome Sciences and Policy
      Durham, NC, United States
    • Royal College of Surgeons in Ireland
      • Department of Clinical Neurological Sciences
      Dublin, Leinster, Ireland
    • Beaumont Hospital
      Dublin, Leinster, Ireland
  • 2002–2010
    • Imperial College London
      • Faculty of Medicine
      London, ENG, United Kingdom
  • 1999–2009
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • University of São Paulo
      • Departamento de Neurologia (FM) (São Paulo)
      Ribeirão Preto, Estado de Sao Paulo, Brazil
  • 2005–2006
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1998–2004
    • London Research Institute
      Londinium, England, United Kingdom
  • 2003
    • Universidade de Ribeirão Preto
      Entre Rios, São Paulo, Brazil
    • University College London Hospitals NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1997–2002
    • University of London
      • The School of Pharmacy
      Londinium, England, United Kingdom
    • University of Alberta
      Edmonton, Alberta, Canada
  • 2001
    • Sapienza University of Rome
      • Department of Anatomical, Histological, Forensic Medicine and Orthopedic Science
      Roma, Latium, Italy
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 2000
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • University of Oxford
      • Department of Biochemistry
      Oxford, ENG, United Kingdom
  • 1994–1995
    • University of Cambridge
      • MRC Biostatistics Unit
      Cambridge, ENG, United Kingdom