MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION

Summary

Principal Investigator: Salvatore DiMauro
Abstract: DESCRIPTION (Provided by Applicant): Mitochondrial encephalomyopathies are important causes of mental retardation. The investigators are focusing on disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). In Project I, Dr. Petra Kaufmann will continue to characterize the natural history of MELAS, correlating clinical course in probands and oligosymptomatic relatives with cerebral and muscle biomarkers assessed by MRSI and 31P-NMR. She will also initiate a clinical trial with idebenone, an effective ROS scavenger already tested in other mitochondrial disorders. This is a placebo controlled, randomized, blinded three-year study of a large cohort of MELAS patients. In Project II, Dr Eric Schon will concentrate on pharmacological approaches to mtDNA-related disorders by evaluating the effectiveness of compounds designed to facilitate electron transport through the respiratory chain in cybrid cultures grown under the pressure of ketogenic medium replacing glucose. He will also assess whether heteroplasmic shifting in ketogenic media is due to selective autophagy of mitochondria harboring mtDNA mutations. In Project III, Dr Mercy Davidson will employ an in vitro model of the blood-brain barrier (BBB) that she has constructed to confirm neuropathological data suggesting a breakdown of BBB function in MELAS. She will also test candidate therapeutic agents on the BBB model in which the co-cultures of human astrocytes and endothelial celis will be either normal or homoplasmic for the m.3243A>G MELAS mutation. In the Administrative Core, Dr Salvatore DiMauro and Dr. Michio Hirano will provide direction, administration, and external consultation. In the Technical Core, Dr. Ali Naini will provide technical service (tissue culture, cybrid generation), diagnostic tools (histochemistry, biochemistry, molecular genetics), and manage shared equipment for the project as a whole. RELEVANCE: Mitochondrial encephalomyopathies due to mutations in mtDNA are generally devastating diseases for which there is no effective therapy. The relevance of this program project is two-fold: (i) it will explore rational therapeutic approaches both in a clinical trial and in experimental settings;and (ii) it will directly or indirectly explore pathogenic mechanisms, which, in turn, may lead to novel therapeutic strategies.
Funding Period: 1996-12-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, 630 W 168th St, P and S 4 423, New York, NY 10032, USA
    FASEB J 24:3733-43. 2010
  2. ncbi Metabolic disorders of fetal life: glycogenoses and mitochondrial defects of the mitochondrial respiratory chain
    S DiMauro
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    Semin Fetal Neonatal Med 16:181-9. 2011
  3. pmc Mitochondria: the next (neurode)generation
    Eric A Schon
    Department of Neurology, Columbia University, New York, NY 10032, USA
    Neuron 70:1033-53. 2011
  4. pmc In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis
    Carlo Viscomi
    Unit of Molecular Neurogenetics, The Foundation Carlo Besta Institute of Neurology IRCCS, Milan, Italy
    Cell Metab 14:80-90. 2011
  5. pmc Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy
    Caterina Garone
    Department of Neurology, Columbia University Medical Centre, New York, NY 10032, USA
    Brain 134:3326-32. 2011
  6. pmc Primary and secondary CoQ(10) deficiencies in humans
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, New York, USA
    Biofactors 37:361-5. 2011
  7. pmc MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, 630 West 168th Street, P and S 4 423, New York, New York 10032, USA
    Muscle Nerve 44:448-51. 2011
  8. pmc Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition
    Robert W Gilkerson
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Hum Mol Genet 21:978-90. 2012
  9. pmc Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype
    P Kaufmann
    The Neurological Institute, Columbia University, 710 W 168th Street, New York, NY 10032, USA
    Neurology 77:1965-71. 2011
  10. pmc Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Neurol Sci 303:39-42. 2011

Research Grants

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  3. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  4. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  5. Cerebral Artery Alpha1 Adrenergic and PKC Regulatory Mechanisms
    Lawrence D Longo; Fiscal Year: 2013
  6. SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM
    Arthur W English; Fiscal Year: 2013

Detail Information

Publications87

  1. pmc Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, 630 W 168th St, P and S 4 423, New York, NY 10032, USA
    FASEB J 24:3733-43. 2010
    ..Our results confirm that varying degrees of CoQ(10) deficiency cause variable defects of ATP synthesis and oxidative stress. These findings may lead to more rational therapeutic strategies for CoQ(10) deficiency...
  2. ncbi Metabolic disorders of fetal life: glycogenoses and mitochondrial defects of the mitochondrial respiratory chain
    S DiMauro
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    Semin Fetal Neonatal Med 16:181-9. 2011
    ....
  3. pmc Mitochondria: the next (neurode)generation
    Eric A Schon
    Department of Neurology, Columbia University, New York, NY 10032, USA
    Neuron 70:1033-53. 2011
    ..These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders...
  4. pmc In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis
    Carlo Viscomi
    Unit of Molecular Neurogenetics, The Foundation Carlo Besta Institute of Neurology IRCCS, Milan, Italy
    Cell Metab 14:80-90. 2011
    ..These results open new perspectives for therapy of mitochondrial disease...
  5. pmc Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy
    Caterina Garone
    Department of Neurology, Columbia University Medical Centre, New York, NY 10032, USA
    Brain 134:3326-32. 2011
    ....
  6. pmc Primary and secondary CoQ(10) deficiencies in humans
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, New York, USA
    Biofactors 37:361-5. 2011
    ..Respiratory chain defects, ROS production, and apoptosis variably contribute to the pathogenesis of primary CoQ(10) deficiencies...
  7. pmc MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, 630 West 168th Street, P and S 4 423, New York, New York 10032, USA
    Muscle Nerve 44:448-51. 2011
    ..This mutation has been reported with MELAS, myopathy, and deafness with cognitive impairment. This is the first description with a MERRF/KSS syndrome...
  8. pmc Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition
    Robert W Gilkerson
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Hum Mol Genet 21:978-90. 2012
    ..It appears that mitophagy can be accomplished by the endogenous autophagic machinery, but requires the full engagement of both of these pathways...
  9. pmc Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype
    P Kaufmann
    The Neurological Institute, Columbia University, 710 W 168th Street, New York, NY 10032, USA
    Neurology 77:1965-71. 2011
    ..To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning...
  10. pmc Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Neurol Sci 303:39-42. 2011
    ..Single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient (65%) than in normal fibers (45%). This novel mutation has to be added to the molecular causes of recurrent myoglobinuria...
  11. pmc Pathogenesis and treatment of mitochondrial myopathies: recent advances
    S DiMauro
    Department of Neurology, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA
    Acta Myol 29:333-8. 2010
    ....
  12. pmc Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation
    Beatriz Dorado
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Hum Mol Genet 20:155-64. 2011
    ..Understanding the molecular mechanisms that allow Tk2 mutant organs to be spared may help design therapies for Tk2 deficiency...
  13. pmc Therapeutic prospects for mitochondrial disease
    Eric A Schon
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    Trends Mol Med 16:268-76. 2010
    ..Among these are techniques to upregulate mitochondrial biogenesis, enhance organellar fusion and fission, "shift heteroplasmy" and eliminate the burden of mutant mtDNAs via cytoplasmic transfer...
  14. ncbi Metabolic myopathies
    Salvatore DiMauro
    Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, Room 4 424B, 630 West 168th Street, New York, NY 10032, USA
    Curr Rheumatol Rep 12:386-93. 2010
    ..For the mitochondrial myopathies, we discuss the importance of homoplasmic mitochondrial DNA mutations and review the rapid progress made in our understanding of the coenzyme Q(10) deficiencies, which are often treatable...
  15. pmc Glut1 deficiency: inheritance pattern determined by haploinsufficiency
    Michael Rotstein
    Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University, New York, NY, USA
    Ann Neurol 68:955-8. 2010
    ..These cases demonstrate that Glut1 DS may present as an autosomal recessive trait. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency...
  16. pmc Treatment of CoQ(10) deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time- and compound-dependent effects
    Luis C Lopez
    Department of Neurology, Columbia University Medical Center, New York, New York, United States of America
    PLoS ONE 5:e11897. 2010
    ..However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress...
  17. ncbi Autonomic symptoms in carriers of the m.3243A>G mitochondrial DNA mutation
    Timothy Parsons
    Department of Neurology, Columbia University, 710 W 168th St, New York, NY 10032, USA
    Arch Neurol 67:976-9. 2010
    ..The m.3243A>G mutation can cause multisystem medical problems and can affect the autonomic nervous system...
  18. pmc Historical perspective on mitochondrial medicine
    Salvatore DiMauro
    Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
    Dev Disabil Res Rev 16:106-13. 2010
    ..We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water...
  19. pmc Coenzyme Q and mitochondrial disease
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA
    Dev Disabil Res Rev 16:183-8. 2010
    ..In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies...
  20. ncbi Morphological assessment of mitochondrial respiratory chain function on tissue sections
    Kurenai Tanji
    Neuromuscular Pathology Laboratory, Division of Neuropathology, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
    Methods Mol Biol 837:181-94. 2012
    ..In this chapter, we provide updated protocols of essential histochemical and immunohistochemical methods that, in our opinion, are the most reliable morphological tool to visualize respiratory chain abnormality on tissue sections...
  21. pmc CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders
    Michio Hirano
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Biochim Biophys Acta 1820:625-31. 2012
    ..Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)...
  22. pmc Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing
    Sarah E Calvo
    Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Sixth Floor, Boston, MA 02114, USA
    Sci Transl Med 4:118ra10. 2012
    ..The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings...
  23. pmc Mitochondrial encephalomyopathies--Fifty years on: The Robert Wartenberg Lecture
    Salvatore DiMauro
    From the Department of Neurology, Columbia University Medical Center, New York, NY
    Neurology 81:281-91. 2013
    ..1.) ..
  24. pmc Longitudinal clinical follow-up of a large family with the R357P Twinkle mutation
    Carmen Paradas
    Unidad de Enfermedades Neuromusculares, Servicio de Neurologia, Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla Consejo Superior de Investigaciones Científicas Universidad de Sevilla, Seville, Spain2Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain3Department of Neurology, Columbia University Medical Center, New York, New York
    JAMA Neurol 70:1425-8. 2013
    ..The aim of this study was to provide a 16-year clinical follow-up of autosomal dominant progressive external ophthalmoplegia due to the p.R357P gene mutation in PEO1...
  25. pmc Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4
    Gordon J Hildick-Smith
    Division of Hematology, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Am J Hum Genet 93:906-14. 2013
    ..Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia. ..
  26. ncbi Long survival in patients with leigh syndrome and the m.10191T>C mutation in MT-ND3 : a case report and review of the literature
    Rebecca J Levy
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Child Neurol 29:NP105-10. 2014
    ..This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation. ..
  27. pmc Mixing and matching mitochondrial aminoacyl synthetases and their tRNAs: a new way to treat respiratory chain disorders?
    Henna Tyynismaa
    Research Programs Unit Molecular Neurology, Biomedicum Helsinki, Helsinki, Finland
    EMBO Mol Med 6:155-7. 2014
    ....
  28. pmc Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers
    Nora Weiduschat
    From the Department of Radiology N W, X M, D S, Weill Cornell Medical College, New York and Department of Neurology P K, K M E, V H, S D, D D V, Columbia University College of Physicians and Surgeons, New York, NY
    Neurology 82:798-805. 2014
    ..To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H MRSI) and to assess their potential as prognostic biomarkers...
  29. pmc Mitochondrial myopathy with dystrophic features due to a novel mutation in the MTTM gene
    Lorenzo Peverelli
    Department of Neurology, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, New York, USA
    Muscle Nerve 50:292-5. 2014
    ....
  30. pmc Mitochondrial encephalomyopathy due to a novel mutation in ACAD9
    Caterina Garone
    Department of Neurology, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York2Human Genetics, Joint PhD Program, Universities of Turin and Bologna, Italy
    JAMA Neurol 70:1177-9. 2013
    ..The patient had an infantile-onset but slowly progressive encephalomyopathy and responded favorably to riboflavin therapy...
  31. pmc The clinical maze of mitochondrial neurology
    Salvatore DiMauro
    College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
    Nat Rev Neurol 9:429-44. 2013
    ..An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. ..
  32. pmc TK2 mutation presenting as indolent myopathy
    Carmen Paradas
    Unidad de Enfermedades Neuromusculares, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla, Seville, Spain
    Neurology 80:504-6. 2013
    ..Herein, we describe a man who had several unusual features. Clinically, he was weak as a child but sought medical attention as an adult. At the molecular level, multiple mtDNA deletions in muscle were more prominent than mtDNA depletion...
  33. pmc Decreased hippocampal expression of calbindin D28K and cognitive impairment in MELAS
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    J Neurol Sci 317:29-34. 2012
    ..We postulate that the reduced CB expression may play a role in the cognitive abnormalities associated with MELAS...
  34. pmc Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations
    Alberto Casarin
    Clinical Genetics Unit, Dept of Pediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy
    Orphanet J Rare Dis 7:21. 2012
    ..Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene...
  35. pmc Mutation in an mtDNA protein-coding gene: prenatal diagnosis aided by fetal muscle biopsy
    Sara Shanske
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    J Child Neurol 28:264-8. 2013
    ..This second girl is now 18 months old and healthy. Our observations support the concept that the pathogenic mutation in this patient appeared de novo and that fetal muscle biopsy is a useful aide in prenatal diagnosis...
  36. pmc A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome
    Valentina Emmanuele
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Child Neurol 28:236-42. 2013
    ..This case demonstrates that MTCYB must be included in the already long list of mitochondrial DNA genes that have been associated with the MELAS phenotype...
  37. ncbi Congenital megaconial myopathy due to a novel defect in the choline kinase Beta gene
    Purificación Gutiérrez Ríos
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Arch Neurol 69:657-61. 2012
    ....
  38. ncbi A novel mutation in PNPLA2 leading to neutral lipid storage disease with myopathy
    Daniel B Ash
    Department ofNeurology, H Houston Merritt Clinical Research Center, Columbia University Medical Center, 630W168th St, P and S 4 423, New York, NY 10032, USA
    Arch Neurol 69:1190-2. 2012
    ..Mutations in PNPLA2, a gene encoding adipose triglyceride lipase, lead to neutral lipid storage disease with myopathy...
  39. pmc Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions
    Dario Ronchi
    Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
    Brain 135:3404-15. 2012
    ....
  40. pmc Human mitochondrial DNA: roles of inherited and somatic mutations
    Eric A Schon
    Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA
    Nat Rev Genet 13:878-90. 2012
    ..Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis...
  41. pmc Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy
    Beatriz García-Diaz
    1 Department of Neurology, Columbia University Medical Centre, New York, NY, 10032, USA
    Brain 137:1337-49. 2014
    ..Our mouse studies provide insights into the pathogenic role of thymidine and deoxyuridine imbalance in mitochondrial neurogastrointestinal encephalopathy and an excellent model to study new therapeutic approaches. ..
  42. ncbi A history of mitochondrial diseases
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    J Inherit Metab Dis 34:261-76. 2011
    ..In each section, I follow a chronological order of the salient discoveries and I show only the portraits of distinguished deceased mitochondriacs and those whose names became eponyms of mitochondrial diseases...
  43. ncbi Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
    Stacey H K Tay
    Department of Pediatrics, National University of Singapore, Singapore
    Arch Neurol 63:281-3. 2006
    ..Microangiopathy has been well described in the brain and muscle of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)...
  44. ncbi Wolff-Parkinson-White syndrome in Patients With MELAS
    Douglas M Sproule
    Division of Pediatric Neurology, Department of Neurology, Columbia University, New York, NY, USA
    Arch Neurol 64:1625-7. 2007
    ..Tissues with high energy demands, such as the heart, are susceptible to the effects of mitochondrial DNA point mutations...
  45. ncbi Mitochondrial mutations: genotype to phenotype
    Eric A Schon
    Department of Neurology, Columbia University Medical School, 630 West 168th Street, New York, NY 10032, USA
    Novartis Found Symp 287:214-25; discussion 226-33. 2007
    ..All four categories will be discussed...
  46. ncbi Juvenile Alpers disease
    Esko Wiltshire
    Department of Pediatrics and Child Health, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
    Arch Neurol 65:121-4. 2008
    ..Alpers disease is commonly associated with polymerase gamma deficiency and usually affects infants or young children...
  47. pmc Progressive external ophthalmoplegia and vision and hearing loss in a patient with mutations in POLG2 and OPA1
    Silvio Ferraris
    Department of Pediatrics, University of Turin, Turin, Italy
    Arch Neurol 65:125-31. 2008
    ..To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase gamma (POLG2) and a mutation in the OPA1 gene...
  48. pmc Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency
    Catarina M Quinzii
    Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA
    FASEB J 22:1874-85. 2008
    ....
  49. pmc ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency
    Clotilde Lagier-Tourenne
    Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS INSERM Universite Louis Pasteur, et Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France
    Am J Hum Genet 82:661-72. 2008
    ....
  50. ncbi The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases
    Sara Shanske
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Arch Neurol 65:368-72. 2008
    ..Among these, mutations in the ND5 gene (OMIM 516005) of mitochondrial DNA are important, and the A13513A change has emerged as a hotspot...
  51. ncbi Amyotrophic lateral sclerosis with ragged-red fibers
    Michio Hirano
    Department of Neurology, Columbia University Medical Center, 3 317 Russ Berrie Medical Science Pavilion, 1150 St Nicholas Ave, New York, NY 10032, USA
    Arch Neurol 65:403-6. 2008
    ..Motor neuron diseases (amyotrophic lateral sclerosis [ALS] and spinal muscular atrophy [SMA]) have been rarely associated with mitochondrial respiratory chain defects...
  52. pmc Mitochondrial myopathy associated with a novel mutation in mtDNA
    Jacklyn Pancrudo
    Dept of Neurology, H Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia University Medical Center, 630 W 168th Street, New York, NY 10032, USA
    Neuromuscul Disord 17:651-4. 2007
    ..The mutation was not detected in any accessible tissues from his mother or siblings. It appears that this mutation arose de novo in the proband, probably early in embryogenesis...
  53. ncbi Optical imaging techniques (histochemical, immunohistochemical, and in situ hybridization staining methods) to visualize mitochondria
    Kurenai Tanji
    Department of Pathology, Columbia University, New York, NY 10032, USA
    Methods Cell Biol 80:135-54. 2007
  54. ncbi Severe encephalomyopathy in a patient with homoplasmic A5814G point mutation in mitochondrial tRNACys gene
    Carmela Scuderi
    Dipartimento di Neurologia, IRCCS Oasi Maria SS, Troina, Italy
    Neuromuscul Disord 17:258-61. 2007
    ..This report also extends the clinical spectrum associated with the A5814G mutation...
  55. ncbi Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial
    P Kaufmann
    Department of Neurology, Columbia University, New York 10032, USA
    Neurology 66:324-30. 2006
    ..To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)...
  56. ncbi Measurement of ATP production in mitochondrial disorders
    R K Shepherd
    Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonard s, NSW, Australia
    J Inherit Metab Dis 29:86-91. 2006
    ..The clinical comparisons observed in patients with nDNA- and mtDNA-related disorders may be explained by differences in the disturbance of ATP synthesis measured in the two conditions...
  57. ncbi Early-onset familial parkinsonism due to POLG mutations
    Guido Davidzon
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Ann Neurol 59:859-62. 2006
    ..To define the molecular etiology of early-onset parkinsonism and peripheral neuropathy...
  58. ncbi Nerve conduction abnormalities in patients with MELAS and the A3243G mutation
    Petra Kaufmann
    Department of Neurology, Columbia University, 710 W 168th Street, New York, NY 10032, USA
    Arch Neurol 63:746-8. 2006
    ..Neuropathy has been associated with several mitochondrial diseases, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes)...
  59. ncbi Approaches to the treatment of mitochondrial diseases
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, 4 420 College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA
    Muscle Nerve 34:265-83. 2006
    ..Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders...
  60. pmc Navajo neurohepatopathy is caused by a mutation in the MPV17 gene
    Charalampos L Karadimas
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Am J Hum Genet 79:544-8. 2006
    ..Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations...
  61. ncbi Mitochondrial myopathies
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Curr Opin Rheumatol 18:636-41. 2006
    ..In this review, I will give the latest information on disorders affecting predominantly or exclusively skeletal muscle...
  62. pmc Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations
    Luis Carlos López
    Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Am J Hum Genet 79:1125-9. 2006
    ..This is the first description of pathogenic mutations in PDSS2 and confirms the molecular and clinical heterogeneity of primary CoQ(10) deficiency...
  63. ncbi Mitochondrial disorders in the nervous system
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Annu Rev Neurosci 31:91-123. 2008
    ....
  64. pmc A functionally dominant mitochondrial DNA mutation
    Sabrina Sacconi
    Féderation des maladies neuromusculaires, CHU de Nice and INSERM U638, Nice, France
    Hum Mol Genet 17:1814-20. 2008
    ..Moreover, similar mutations arising stochastically and accumulating in a minority of mtDNA molecules during the aging process may severely impair RC function in cells...
  65. pmc Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene
    Belen Bornstein
    Departamento de Bioquimica, Hospital Universitario Puerta de Hierro, Instituto de Investigaciones Biomedicas, CSIC UAM, CIBERER, ISCIII, Madrid, Spain
    Neuromuscul Disord 18:453-9. 2008
    ....
  66. pmc Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy
    Rita Horvath
    Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
    Brain 132:3165-74. 2009
    ..This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis...
  67. pmc Slowly progressive encephalopathy with hearing loss due to a mutation in the mtDNA tRNA(Leu(CUN)) gene
    Jorida Coku
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Neurol Sci 290:166-8. 2010
    ..Sequencing of the 22 tRNA mitochondrial genes is indicated in all unusual neurological syndromes, even in the absence of maternal inheritance...
  68. pmc A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes
    Bulent Kurt
    Columbia University College of Physicians and Surgeons, 630 W 168th Street, New York, NY 10032, USA
    Arch Neurol 67:239-44. 2010
    ..To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children...
  69. pmc A novel mutation in the tRNAIle gene (MTTI) affecting the variable loop in a patient with chronic progressive external ophthalmoplegia (CPEO)
    Andres Berardo
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Neuromuscul Disord 20:204-6. 2010
    ..Like tRNA(Leu(UUR)), tRNA(Ile) appears to be a "hot spot" for mtDNA mutations causing CPEO...
  70. pmc Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy
    J Montes
    SMA Clinical Research Center, Department of Neurology, Columbia University, 180 Ft Washington Ave, 5th Floor, New York, NY 10032, USA
    Neurology 74:833-8. 2010
    ..The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children...
  71. ncbi Pathogenesis and treatment of mitochondrial disorders
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, 3 313 Russ Berrie Medical Science Pavilion, New York, NY 10032, USA
    Adv Exp Med Biol 652:139-70. 2009
    ..g. boosting ATP production or scavenging ROS), which are inconsistently and incompletely effective, but can be safe and helpful...
  72. ncbi Is Alzheimer's disease a disorder of mitochondria-associated membranes?
    Eric A Schon
    Department of Neurology, Columbia University Medical Center, New York, NY, USA
    J Alzheimers Dis 20:S281-92. 2010
    ....
  73. pmc The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier
    Mercy M Davidson
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, United States
    Mitochondrion 9:463-70. 2009
    ..These data support our hypothesis that respiratory chain defects in the components of the BBB cause changes in permeability...
  74. pmc VMA21 deficiency: a case of myocyte indigestion
    Michio Hirano
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Cell 137:213-5. 2009
    ..In this issue, Ramachandran et al. (2009) report that mutations in the gene encoding the human homolog VMA21 cause the disease X-linked myopathy with excessive autophagy through an unexpected mechanism...
  75. pmc The m.3244G>A mutation in mtDNA is another cause of progressive external ophthalmoplegia
    Evangelia Sotiriou
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Neuromuscul Disord 19:297-9. 2009
    ..The m.3244G>A mutation affects a highly conserved nucleotide in the dihydrouridine loop and has been associated with a wobble modification deficiency of the mutant tRNA...
  76. pmc Neonatal mitochondrial encephaloneuromyopathy due to a defect of mitochondrial protein synthesis
    Claudia C Ferreiro-Barros
    Department of Neurology, Columbia University, New York, NY, USA
    J Neurol Sci 275:128-32. 2008
    ..Our studies indicate that the patient has a novel autosomal recessive defect of mitochondrial protein synthesis...
  77. ncbi Light microscopic methods to visualize mitochondria on tissue sections
    Kurenai Tanji
    Department of Pathology, Columbia University, New York, NY 10032, USA
    Methods 46:274-80. 2008
    ....
  78. ncbi A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases
    Salvatore DiMauro
    Department of Neurology, Columbia University Medical Center, 313 Russ Berrie Medical Science Pavilion, 1150 St Nicholas Avenue, New York, NY 10032, USA
    Biochim Biophys Acta 1792:1159-67. 2009
    ..We finally discussed the emerging genetic-based strategies that show some promise, even if much work remains to be done...
  79. pmc Mitochondrial dysfunction in mut methylmalonic acidemia
    Randy J Chandler
    Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
    FASEB J 23:1252-61. 2009
    ....
  80. pmc Human CoQ10 deficiencies
    C M Quinzii
    Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
    Biofactors 32:113-8. 2008
    ..In many patients with CoQ10 deficiencies, the causative molecular genetic defects remain unknown; therefore, it is likely that mutations in additional genes will be identified as causes of CoQ10 deficiencies...
  81. ncbi Protean phenotypic features of the A3243G mitochondrial DNA mutation
    Petra Kaufmann
    Department of Neurology, The Neurological Institute, Columbia University Medical Center, New York, NY 10032, USA
    Arch Neurol 66:85-91. 2009
    ....
  82. pmc Evidence for nuclear modifier gene in mitochondrial cardiomyopathy
    Mercy M Davidson
    Department of Neurology, Columbia University, Russ Berrie Medical Pavilion, NY 10032, USA
    J Mol Cell Cardiol 46:936-42. 2009
    ..From these results it is evident that a tissue specific nuclear modifier gene may interact synergistically with the mtDNA mutation to cause COX deficiency...
  83. pmc Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS
    Mahsa Mehrazin
    Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
    Am J Med Genet A 149:584-7. 2009
    ..This study suggests that A3243G mutant load in DNA isolated from blood is neither useful for prognosis nor for functional assessment...
  84. ncbi Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach
    J Halter
    Department of Hematology, University Hospital Basel, Basel, Switzerland
    Bone Marrow Transplant 46:330-7. 2011
    ..Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE...

Research Grants30

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  4. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  5. Cerebral Artery Alpha1 Adrenergic and PKC Regulatory Mechanisms
    Lawrence D Longo; Fiscal Year: 2013
    ....
  6. SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM
    Arthur W English; Fiscal Year: 2013
    ..This PPG brings together a team of established scientists from diverse backgrounds, with a common goal to continue to strengthen the science base underlying clinical rehabilitation. ..