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  • Asymmetrical late onset motor neuropathy associated with a novel mutation in the small heat shock protein HSPB1 (HSP27).

    24 October 2018

    Distal hereditary motor neuropathy, also known as distal spinal muscular atrophy, is characterised by slowly progressive weakness and wasting of the hands and feet and has a heterogeneous genetic basis. One form of distal hereditary motor neuropathy is associated with mutations in the gene for the small heat shock protein HSPB1 (hsp27). Families have been described in which slowly progressive, symmetrical, lower limb predominant motor weakness is usually evident by middle age. Here we report a novel mutation, G84R, in an elderly patient presenting with strikingly asymmetrical weakness. Expression of this and other known mutations in cell culture demonstrated enhanced aggregation of mutant HSPB1 protein compared with wild-type.

  • Characterisation of novel point mutations in the survival motor neuron gene SMN, in three patients with SMA.

    24 October 2018

    We report two novel mutations in three cases of spinal muscular atrophy (SMA), including two distant cousins who followed an unexpectedly severe course. Diagnosis was confirmed by reduced SMN protein and full-length SMN mRNA levels. Sequencing of the non-deleted SMN1 gene revealed a single G insertion at the end of exon 1 in the two cousins and a novel G275S exon 6 missense mutation in the milder case.

  • Murray Valley encephalitis in an adult traveller complicated by long-term flaccid paralysis: case report and review of the literature.

    24 October 2018

    Murray Valley encephalitis (MVE) virus, a mosquito-borne flavivirus, is the most common cause of viral encephalitis in the tropical 'Top End' of northern Australia. Clinical encephalitis due to MVE virus has a mortality rate of approximately 30%, with a similar proportion of patients being left with significant neurological deficits. We report the case of a 25-year-old man from the UK who acquired MVE while travelling through northern Australia. He required prolonged admission to the Intensive Care Unit and several years later remains partly ventilator-dependent, with flaccid quadriparesis. To our knowledge, this is the first reported case of MVE virus-induced flaccid paralysis in an adult in northern Australia, although it is well described in children. Paralysis was thought to be due to anterior horn cell involvement in the spinal cord and extensive bilateral thalamic destruction, both of which are well recognised complications of infection with MVE virus. Cases of flaccid paralysis with similar pathology have been described following infection with the related flavivirus Japanese encephalitis virus as well as more recently with West Nile virus. Our case highlights the potential severity of flavivirus-induced encephalitis and the importance of avoiding mosquito bites while travelling through endemic areas.

  • GARS axonopathy: not every neuron's cup of tRNA.

    24 October 2018

    Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.

  • A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).

    24 October 2018

    Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation.

  • Treatment of vasculitic peripheral neuropathy: a retrospective analysis of outcome.

    24 October 2018

    BACKGROUND: Vasculitis of the peripheral nervous system (PNS) is rare. There are no controlled treatment trials, and clinical practice is guided by experience from case series and indirectly by analogy with systemic vasculitis. METHODS: We identified patients (n=212) with possible vasculitic peripheral neuropathy (VPN) from the neuropathology and neurophysiology records of two centres over 28 years. Case-notes were available for 181, from which, 106 cases of clinicopathological VPN were identified. Adequate treatment data were available in 100; follow-up data, in 93. RESULTS: Of 106 cases, 95 had systemic vasculitis and 11 had vasculitis confined to the PNS. Pharmacological treatment (94/100 cases) was corticosteroid-based, and included cyclophosphamide in 54; 17 received additional agents. Initial stabilization was achieved in all but six. One-year survival was 90.3%. Of the nine who died in the first years (mean age 73 years), seven had received cyclophosphamide, and all but two had severe, multisystem vasculitis. The neurological relapse rate was 10%. Only one relapse occurred after cyclophosphamide treatment. Outcome was reported as good in 72% (78% in those who relapsed). DISCUSSION: Death and relapse were infrequent in treated patients. Relapse occurred almost exclusively in patients treated with prednisolone alone. Aggressive early treatment with cyclophosphamide may prevent relapse. The current management approach to VPN appears largely effective, especially if cyclophosphamide is used.

  • A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.

    24 October 2018

    Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.

  • NIHR LCRN Studies

    30 June 2016

    The Critical Care Research Group undertakes a number of studies that are adopted by the NIHR local research network portfolio.

  • HAVEN

    10 May 2016

    The HAVEN project is funded by the Health Innovation Challenge Fund, a joint venture supported by the Wellcome Trust and the Department of Health.

  • HAVEN

    10 May 2016

    The HAVEN project is funded by the Health Innovation Challenge Fund, a joint venture supported by the Wellcome Trust and the Department of Health.

  • OXVASC Study

    15 January 2013

  • Preventing a Stroke

    15 January 2013

  • Research results

    15 January 2013

  • Useful Links

    15 January 2013

  • Directions

    15 January 2013

  • Frequently Asked Questions

    15 January 2013

  • ABCD Tool

    15 January 2013

  • Oxford Vascular Study

    26 August 2016

    CPSD

    The Oxford Vascular Study (OxVasc) investigates vascular diseases (e.g. strokes, heart attacks) in patients registered with eight general practices in Oxfordshire. We run a rapid-access clinic for patients with suspected Transient Ischaemic Attacks (TIAs) or minor strokes.

  • OPTIMA

    26 August 2016

    CPSD

    The Oxford Project to Investigate Memory and Ageing (OPTIMA) started in 1988 and the last LEAD participants were seen in March 2015. We are no longer recruiting to any of the cohorts. However, we are currently creating the OPTIMA Legacy Resource from which data collected from the OPTIMA cohorts is available and samples are biobanked and available. Brain tissue is available as part of the Brains For Dementia Research (BDR) collection.

  • Models of Brain Decision Networks

    21 July 2014

    DCN

    Our group uses computer simulations and mathematical analyses to understand the information processing and activity dynamics of brain networks underlying decision making. We use these models to investigate how neural circuits work in the healthy state, how their dynamics deteriorate in neurological disorders, and how their dynamics and information processing may be best restored by treatments.

  • Translational Molecular Neuroscience Group

    14 February 2018

    NDCN

    Drug discovery in neuroscience is very challenging but the need is greater than ever. Perhaps the most important factor for successfully developing an effective therapy, is the identification of human disease relevant drug targets. Our group aims to elucidate the pathophysiological basis of human neurological disorders from genetic molecular networks to complex neural systems using human genetics, human models and human tissue wherever possible.

  • Congenital Myasthenia Service

    15 January 2013

    DCN

    We provide a nationally commissioned specialised service for the diagnosis and management of children and adults in whom a congenital myasthenic syndrome is suspected.

  • Breathe Oxford

    13 May 2014

    NDA

  • Cognitive and Motivational Disorders

    6 July 2018

    DCN NDCN

    Our group studies changes in motivation, memory and decision-making that occur in neurological disease. We combine behavioural, neuroimaging, and pharmacological experiments to apply cognitive neuroscience to clinical problems.

  • Oxford University Global Surgery Group

    1 August 2018

    The Oxford University Global Surgery Group brings together Medical Sciences Division clinicians in surgery, anaesthesia, obstetrics and gynaecology with an interest in global surgical issues.

  • Oxford Epilepsy Research Group

    2 April 2014

    DCN

    We are a forward-looking dynamic group interested in all aspects of clinical and experimental epileptology with an emphasis on clinically relevant research. The Group draws together all relevant disciplines across Oxford University Hospitals and the University of Oxford.