Michio Hirano

Columbia University, New York, New York, United States

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Publications (291)1786.89 Total impact

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    ABSTRACT: Purpose:The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. Methods:The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Results:Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.Conclusion:The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.Genet Med advance online publication 11 December 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.177.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2014; DOI:10.1038/gim.2014.177 · 6.44 Impact Factor
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    ABSTRACT: Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 12/2014; DOI:10.1016/j.ymgme.2014.11.016 · 2.83 Impact Factor
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    ABSTRACT: A member of the four-and-a half-LIM (FHL) domain protein family, FHL1 is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at 3 time points (3-5 months, 7-10 months, and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7-10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to humans patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice.
    Human Molecular Genetics 09/2014; 24(3). DOI:10.1093/hmg/ddu490 · 6.68 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; 261(11). DOI:10.1007/s00415-014-7476-7 · 3.84 Impact Factor
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    ABSTRACT: Introduction. A 61-year-old woman with a five-year history of progressive muscle weakness and atrophy had a muscle biopsy characterized by a combination of dystrophic features (necrotic fibers and endomysial fibrosis) and mitochondrial alterations [ragged-red cytochrome c oxidase (COX)-negative fibers].Methods.Sequencing of the whole mtDNA, assessment of the mutation load in muscle and in accessible non-muscle tissues, and single fiber polymerase chain reaction (PCR).Results. Muscle mitochondrial DNA (mtDNA) sequencing revealed a novel heteroplasmic mutation (m.4403G>A) in the gene (MTTM) that encodes tRNAMet. The mutation was not present in accessible non-muscle tissues from the patient or 2 asymptomatic sisters.Discussion. The clinical features and muscle morphology in this patient are very similar to those described in a previous patient with a different mutation, also in MTTM, which suggests that mutations in this gene confer a distinctive “dystrophic” quality. This may be a diagnostic clue in patients with isolated mitochondrial myopathy. © 2014 Wiley Periodicals, Inc.
    Muscle & Nerve 08/2014; 50(2). DOI:10.1002/mus.24262 · 2.31 Impact Factor
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  • New England Journal of Medicine 07/2014; 371(1):81-2. DOI:10.1056/NEJMc1311763#SA4 · 54.42 Impact Factor
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    ABSTRACT: Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous syndrome which has been associated with 5 major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) nephropathy, (4) cerebellar ataxia, and (5) isolated myopathy. Of these phenotypes, cerebellar ataxia and syndromic or isolated nephrotic syndrome are the most common. CoQ10 deficiency predominantly presents in childhood. To date, causative mutations have been identified in a small proportion of patients, making it difficult to identify a phenotype-genotype correlation. Identification of CoQ10 deficiency is important because the disease, in particular muscle symptoms and nephropathy, frequently responds to CoQ10 supplementation.
    Molecular syndromology 07/2014; 5(3-4):141-6. DOI:10.1159/000360490
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    ABSTRACT: Primary coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder associated with 5 major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) steroid-resistant nephrotic syndrome. Growth retardation, deafness and hearing loss have also been described in CoQ10-deficient patients. This heterogeneity in the clinical presentations suggests that multiple pathomechanisms may exist. To investigate the biochemical and molecular consequences of CoQ10 deficiency, different laboratories have studied cultures of skin fibroblasts from patients with CoQ10 deficiency. In this review, we summarize the results obtained in these studies over the last decade.
    Molecular syndromology 07/2014; 5(3-4):163-9. DOI:10.1159/000360494
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    ABSTRACT: Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2−/−) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2−/− mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2−/−200dCMP/dTMP) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency. Subject Categories Genetics, Gene Therapy & Genetic Disease; Metabolism
    EMBO Molecular Medicine 06/2014; 6(8). DOI:10.15252/emmm.201404092 · 8.25 Impact Factor
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    ABSTRACT: Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no established biological marker. Recent observation of a reduced number of gems (survival motor neuron protein (SMN)-positive nuclear bodies) in cells from patients with familial ALS and the mouse models suggests an involvement of SMN in ALS pathology. At a molecular level, fused in sarcoma (FUS), one of the familial ALS-linked proteins, has been demonstrated to directly interact with SMN, while impaired nuclear localization of mutated FUS causes defective gem formation. Our objective was to determine whether gems and/or nuclear FUS levels in skin derived fibroblasts from sporadic ALS patients are consistently reduced and thus could constitute a novel and readily available biomarker of the disease. Fibroblasts from 20 patients and 17 age-matched healthy controls were cultured and co-immunostained for SMN and FUS. Results showed that no difference was detected between the two groups in the number of gems and in expression pattern of FUS. The number of gems negatively correlated with the age at biopsy in both ALS and control subjects. In conclusion, the expression pattern of SMN and FUS in fibroblasts cannot serve as a biomarker for sporadic ALS. Donor age-dependent gem reduction is a novel observation that links SMN with cellular senescence.
    05/2014; DOI:10.3109/21678421.2014.907319
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    ABSTRACT: Suicide gene therapy (SGT) is a promising strategy for treating cancer. In this work, we show that thymidine phosphorylase (TP) deficiency, the underlying genetic defect in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presents an opportunity to apply SGT using capecitabine, a commonly used prodrug that is converted into 5-fluorouracil by TP. Using an immortalised B-lymphoblastoid cell line from a patient with MNGIE, the tumourigenic EL-4 cell line, lentiviral vectors encoding TP and a double knockout (Tymp(-/-)Upp1(-/-)) murine model, we found that EL-4 cell-derived TP(+) tumours were exquisitely sensitive to capecitabine and generated a significant local bystander effect. In addition, we detected a spontaneous cytolytic immune response in a significant fraction of the animals surviving more than 20 days after termination of the therapy. These data indicate that, in individuals lacking TP expression, TP is a highly specific suicide gene, which can be used to treat tumours that could hypothetically arise in MNGIE patients undergoing gene therapy, as these tumours will likely originate from the gene-modified cells and will be selectively targeted by capecitabine. These observations have important implications for gene therapy for MNGIE.Gene Therapy advance online publication, 8 May 2014; doi:10.1038/gt.2014.41.
    Gene therapy 05/2014; DOI:10.1038/gt.2014.41 · 4.20 Impact Factor
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    ABSTRACT: Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis. Levels of mitochondrial DNA were depleted not only in the brain but also in the small intestine, and deoxyribonucleoside triphosphate imbalance was observed in the brain. The relative proportion, rather than the absolute amount of deoxyribonucleoside triphosphate, was critical for mitochondrial DNA maintenance. Thus, our results demonstrate that stress of exogenous pyrimidine nucleosides enhances the mitochondrial phenotype of our knockout mice. 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.
    Brain 04/2014; 137(5). DOI:10.1093/brain/awu068 · 10.23 Impact Factor
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    ABSTRACT: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, enconding thymidine phosphorylase (TP). TP deficiency results in systemic accumulation of thymidine and deoxyuridine, which interferes with mitochondrial DNA (mtDNA) replication and leads to mitochondrial dysfunction. To date, the only treatment available for MNGIE patients is allogeneic hematopoietic stem cell transplantation, which is associated with high morbidity and mortality. Here, we report that AAV2/8-mediated transfer of the human TYMP coding sequence (hcTYMP) under the control of a liver-specific promoter prevents the biochemical imbalances in a murine model of MNGIE. hcTYMP expression was restricted to liver, and a dose as low as 2x10(11) genome copies/kg led to a permanent reduction in systemic nucleoside levels to normal values in about 50% of treated mice. Higher doses resulted in reductions to normal or slightly below normal levels in virtually all mice treated. The nucleoside reduction achieved by this treatment prevented dCTP depletion, which is the limiting factor affecting mtDNA replication in this disease. These results demonstrate that the use of AAV to direct TYMP expression in liver is feasible as a potentially safe gene therapy strategy for MNGIE.Molecular Therapy (2014); doi:10.1038/mt.2014.6.
    Molecular Therapy 01/2014; DOI:10.1038/mt.2014.6 · 6.43 Impact Factor
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    ABSTRACT: Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is characterized by a reduction in mtDNA copy number and consequent mitochondrial dysfunction in affected tissues. A subgroup of MDS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism, which ultimately leads to limited availability of one or several dNTPs, and subsequent mtDNA depletion. Here, using in vitro experimental approaches (primary cell culture of dGK-deficient cells and thymidine-induced mtDNA depletion in culture as a model of mitochondrial neurogastrointestinal encephalomyopathy, MNGIE), we show that supplements of those deoxyribonucleosides involved in each biochemical defect (deoxyguanosine or deoxycytidine) prevents mtDNA copy number reduction. Similar effects can be obtained by specific inhibition of deoxyribonucleoside catabolism using tetrahydrouridine (inhibitor of cytidine deaminase) or immucillin H (inhibitor of purine nucleoside phosphorylase). In addition, using a MNGIE animal model, we provide evidence that mitochondrial dNTP content can be modulated in vivo by systemic administration of deoxycytidine or tetrahydrouridine. In spite of the severity associated with diseases due to defects in mtDNA replication, there are currently no effective therapeutic options available. Only in the case of MNGIE, allogeneic hematopoietic stem cell transplantation has proven efficient as a long-term therapeutic strategy. We propose increasing cellular availability of the deficient dNTP precursor by direct administration of the deoxyribonucleoside or inhibition of its catabolism, as a potential treatment for mtDNA depletion syndrome caused by defects in dNTP metabolism.
    Human Molecular Genetics 12/2013; DOI:10.1093/hmg/ddt641 · 6.68 Impact Factor

Publication Stats

11k Citations
1,786.89 Total Impact Points


  • 1993–2014
    • Columbia University
      • • Department of Neurology
      • • Department of Genetics and Development
      New York, New York, United States
  • 2013
    • Instituto de Biomedicina de Sevilla (IBIS)
      Hispalis, Andalusia, Spain
    • Instituto de Investigación Sanitaria Gregorio Marañón
      Madrid, Madrid, Spain
    • Universidad Pablo de Olavide
      Hispalis, Andalusia, Spain
  • 2012–2013
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2009–2012
    • Newcastle University
      • • Institute of Genetic Medicine
      • • Institute for Ageing and Health
      Newcastle upon Tyne, ENG, United Kingdom
  • 2011
    • The University of Western Ontario
      • Department of Clinical Neurological Sciences
      London, Ontario, Canada
  • 1992–2010
    • CUNY Graduate Center
      New York, New York, United States
  • 1993–2009
    • New York Presbyterian Hospital
      • Department of Ophthalmology
      New York City, New York, United States
  • 2008
    • Foundation of the Carlo Besta Neurological Institute
      Milano, Lombardy, Italy
    • University of Padova
      • Department of Pediatrics
      Padua, Veneto, Italy
  • 2005
    • Northwestern University
      Evanston, Illinois, United States
    • New York State Department of Health
      New York, New York, United States
  • 2001–2005
    • National Center of Neurology and Psychiatry
      • • Department of Neuromuscular Research
      • • Department of Ultrastructural Research
      Кодаиры, Tōkyō, Japan
  • 2002–2003
    • University Hospital Vall d'Hebron
      • • Centre d'Investigacions en Bioquimica i Biologia Molecular
      • • Department of Neurology
      Barcino, Catalonia, Spain
    • University of Florence
      Florens, Tuscany, Italy
  • 2000
    • Instituto de Neurología y Neurocirugía
      La Habana, Ciudad de La Habana, Cuba
  • 1999
    • Mid-Columbia Medical Center
      DLS, Oregon, United States
  • 1998
    • University at Buffalo, The State University of New York
      • School of Medicine and Biomedical Sciences
      Buffalo, NY, United States
  • 1997
    • Barrow Neurological Institute
      • Department of Neurology
      Phoenix, AZ, United States
  • 1996
    • King Faisal Specialist Hospital and Research Centre
      • Department of Medicine
      Jeddah, Mintaqat Makkah, Saudi Arabia
  • 1994
    • Weill Cornell Medical College
      New York, New York, United States