Patrick F Chinnery

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-on-Tyne, England, United Kingdom

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Publications (450)3268.45 Total impact

  • Developmental Medicine and Child Neurology, Newcastle; 01/2015
  • Helen Griffin, Angela Pyle, Patrick F Chinnery
    Annals of Neurology 01/2015; · 11.91 Impact Factor
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    ABSTRACT: Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.
    PLoS ONE 12/2014; 9(12):e115433. · 3.53 Impact Factor
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    ABSTRACT: Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Brain : a journal of neurology. 12/2014;
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    ABSTRACT: Mitochondria form a highly interconnected tubular network throughout the cell via a dynamic process, with mitochondrial segments fusing and breaking apart continuously. Strong evidence has emerged to implicate disturbed mitochondrial fusion and fission as central pathological components underpinning a number of childhood and adult-onset neurodegenerative disorders. Several proteins that regulate the morphology of the mitochondrial network have been identified, the most widely studied of which are optic atrophy 1 and mitofusin 2. Pathogenic mutations that disrupt these two pro-fusion proteins cause autosomal dominant optic atrophy and axonal Charcot-Marie-Tooth disease type 2A, respectively. These disorders predominantly affect specialized neurons that require precise shuttling of mitochondria over long axonal distances. Considerable insight has also been gained by carefully dissecting the deleterious consequences of imbalances in mitochondrial fusion and fission on respiratory chain function, mitochondrial quality control (mitophagy), and programmed cell death. Interestingly, these cellular processes are also implicated in more-common complex neurodegenerative disorders, such as Alzheimer disease and Parkinson disease, indicating a common pathological thread and a close relationship with mitochondrial structure, function and localization. Understanding how these fundamental processes become disrupted will prove crucial to the development of therapies for the growing number of neurodegenerative disorders linked to disturbed mitochondrial dynamics.
    Nature Reviews Neurology 12/2014; · 15.52 Impact Factor
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    ABSTRACT: Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 11/2014; · 10.99 Impact Factor
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    ABSTRACT: Mutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens. A de novo mutation in STXBP1 (c.416C>T, p.(Pro139Leu)) was detected with exome sequencing together with profound impairment of complex I of the mitochondrial respiratory chain on muscle biopsy. These findings implicate a secondary impairment of mitochondrial function in the progressive nature of the disease phenotype.
    Neurogenetics 11/2014; · 2.66 Impact Factor
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    ABSTRACT: Progressive external ophthalmoplegia (PEO) is a common feature in adults with mitochondrial (mt) DNA maintenance disorders associated with somatic mtDNA deletions in muscle, yet the causal genetic defect in many patients remains undetermined. Whole-exome sequencing identified a novel, heterozygous p.(Gly671Trp) mutation in the AFG3L2 gene encoding an mt protease-previously associated with dominant spinocerebellar ataxia type 28 disease-in a patient with indolent ataxia and PEO. Targeted analysis of a larger, genetically undetermined cohort of patients with PEO with suspected mtDNA maintenance abnormalities identified a second unrelated patient with a similar phenotype and a novel, heterozygous p.(Tyr689His) AFG3L2 mutation. Analysis of patient fibroblasts revealed mt fragmentation and decreased AFG3L2 transcript expression. Western blotting of patient fibroblast and muscle showed decreased AFG3L2 protein levels. Our observations suggest that AFG3L2 mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance.
    JAMA Neurology 11/2014; · 7.01 Impact Factor
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    ABSTRACT: Here we describe a clinical approach and differential diagnosis for chronic muscle diseases which include early respiratory failure as a prominent feature in their presentation (i.e. respiratory failure whilst still ambulant). These patients typically present to neurology or respiratory medicine out-patient clinics and a distinct differential diagnosis of neuromuscular aetiologies should be considered. Amyotrophic lateral sclerosis and myasthenia gravis are the important non-muscle diseases to consider, but once these have been excluded there remains a challenging differential diagnosis of muscle conditions, which will be the focus of this review. The key points in the diagnosis of these disorders are being aware of relevant symptoms, which are initially caused by nocturnal hypoventilation or diaphragmatic weakness; and identifying other features which direct further investigation. Important muscle diseases to identify, because their diagnosis has disease-specific management implications, include adult-onset Pompe disease, inflammatory myopathy, and sporadic adult-onset nemaline myopathy. Cases which are due to metabolic myopathy or muscular dystrophy are important to diagnose because of their implications for genetic counselling. Myopathy from sarcoidosis and colchicine each has a single reported case with this presentation, but should be considered because they are treatable. Disorders which have recently had their genetic aetiologies identified include hereditary myopathy with early respiratory failure (due to TTN mutations), the FHL1-related syndromes, and myofibrillar myopathy due to BAG3 mutation. Recently described syndromes include oculopharyngodistal muscular dystrophy that awaits genetic characterisation.
    Journal of Neurology 11/2014; · 3.84 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).
    Neurology 11/2014; · 8.30 Impact Factor
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    ABSTRACT: Background Leber¿s hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON).Methods From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann¿Whitney-U-Test for two independent groups of sampled data.ResultsThe proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m.11778G¿>¿A and m.3460G¿>¿A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m.11778G¿>¿A, m.3460G¿>¿A and m.14484 T¿>¿C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset- and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset.Conclusion As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients.
    Orphanet Journal of Rare Diseases 10/2014; 9(1):158. · 3.96 Impact Factor
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    ABSTRACT: Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-epsilon2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.
    Brain 09/2014; · 10.23 Impact Factor
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    ABSTRACT: Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as "definite", "probable" or "possible" MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
    Journal of Neurology 09/2014; · 3.84 Impact Factor
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    ABSTRACT: Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously asso-ciated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Syn-aptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with heredi-tary motor axonopathies. Synaptotagmin 2 (SYT2), a synaptic vesicle protein, is the major isoform of the synaptotagmin family at mammalian neuromuscular junctions (NMJs) and functions as a cal-cium sensor for neurotransmission. 1,2 The C2B domain
    The American Journal of Human Genetics 09/2014; · 10.99 Impact Factor
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    ABSTRACT: Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.
    Journal of Neurology 09/2014; · 3.84 Impact Factor
  • Patrick Yu-Wai-Man, Patrick F Chinnery
    Brain 08/2014; · 10.23 Impact Factor
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    ABSTRACT: Background Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.Methods We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.ResultsSequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G¿>¿A (splice site), c.409C¿>¿T (p.Arg137*) and c.877¿+¿3G¿>¿T (splice site), and compound heterozygous c.871C¿>¿T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.Conclusion We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.
    Orphanet Journal of Rare Diseases 08/2014; 9(1):119. · 3.96 Impact Factor
  • Patrick Yu-Wai-Man, Valerio Carelli, Patrick F. Chinnery
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    ABSTRACT: •Disturbed mitochondrial dynamics is an important cause of neuromuscular disorders.•OPA1 and MFN2 are two important mediators of mitochondrial fusion.•Pathogenic OPA1 mutations cause autosomal dominant optic atrophy (DOA).•Pathogenic MFN2 mutations cause axonal Charcot-Marie-Tooth disease (CMT-2A).•Treatment options are currently limited and remain mostly supportive.
    Neuromuscular Disorders 08/2014; · 3.13 Impact Factor
  • Brendan Ai Payne, Kristian Gardner, Patrick F Chinnery
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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations cause neurological and multi-system disease. Somatic (acquired) mtDNA mutations are also associated with degenerative diseases and with normal human ageing. It is well established that certain nucleoside analogue reverse transcriptase inhibitor (NRTI) anti-retroviral drugs cause inhibition of the mtDNA polymerase, pol γ, leading to a reduction in mtDNA content (depletion). Given this effect of NRTI therapy on mtDNA replication, it is plausible that NRTI treatment may also lead to increased mtDNA mutations. Here we review recent evidence for an effect of HIV infection or NRTI therapy on mtDNA mutations, as well as discussing the methodological challenges in addressing this question. Finally, we discuss the possible implications for HIV-infected persons, with particular reference to ageing.
    Antiviral therapy 07/2014; · 3.14 Impact Factor
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    Patrick Yu-Wai-Man, Patrick F Chinnery
    Brain 07/2014; · 10.23 Impact Factor

Publication Stats

12k Citations
3,268.45 Total Impact Points


  • 1997–2014
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • • Institute of Genetic Medicine
      • • Department of Neurology
      Newcastle-on-Tyne, England, United Kingdom
  • 1996–2014
    • Newcastle University
      • • Institute of Genetic Medicine
      • • Institute for Ageing and Health
      • • Faculty of Medical Sciences
      • • School of Mathematics and Statistics
      Newcastle-on-Tyne, England, United Kingdom
  • 2009–2013
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany
    • Vanderbilt University
      • • Department of Molecular Physiology and Biophysics
      • • Center for Human Genetics Research (CHGR)
      Nashville, MI, United States
  • 2008–2013
    • University of Cambridge
      • Department of Psychology
      Cambridge, England, United Kingdom
    • Boston University
      • Department of Neurology
      Boston, MA, United States
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2012
    • University of Duisburg-Essen
      Essen, North Rhine-Westphalia, Germany
    • Cardiff University
      • Centre for Neuropsychiatric Genetics and Genomics
      Cardiff, WLS, United Kingdom
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
    • Hacettepe University
      • Department of Pediatrics
      Ankara, Ankara, Turkey
    • University College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
    • Karolinska Institutet
      • Department of Laboratory Medicine
      Solna, Stockholm, Sweden
  • 2011
    • Norfolk and Norwich University Hospitals NHS Foundation Trust
      • Department of Neurology
      Norwich, England, United Kingdom
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2003–2008
    • Virginia Polytechnic Institute and State University
      Blacksburg, Virginia, United States
  • 2007
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1999–2007
    • Newcastle University Medicine Malaysia
      Bharu, Johor, Malaysia
  • 2006
    • National Institute of Environmental Health Sciences
      • Laboratory of Molecular Genetics (LMG)
      Durham, North Carolina, United States
    • National Institutes of Health
      • Molecular Targets Laboratory
      Bethesda, MD, United States
  • 2004
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2001
    • Royal Surrey County NHS Foundation Trust
      Guilford, England, United Kingdom
  • 2000
    • University of Texas Medical Branch at Galveston
      • Department of Radiation Oncology
      Galveston, TX, United States