title: Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content.
abstract: Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Claudio
authors.initials: C
authors.lastname: Asencio
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Rodríguez-Hernandez
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Sección de Errores Congénitos del Metabolismo (IBC U737), Servicio de Bioquímica y Genética Molecular, Hospital Clinic de Barcelona, IDIBAPS and CSIC, Barcelona, Spain.
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Emperador
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Gavilán
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Sección de Errores Congénitos del Metabolismo (IBC U737), Servicio de Bioquímica y Genética Molecular, Hospital Clinic de Barcelona, IDIBAPS and CSIC, Barcelona, Spain.
authors.forename: Dèlia
authors.initials: D
authors.lastname: Yubero
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Clinical Chemistry, Departments of Pathology and Neurology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Montero
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Clinical Chemistry, Departments of Pathology and Neurology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Clinical Chemistry, Departments of Pathology and Neurology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: O'Callaghan
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Alcázar-Fabra
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, and IRP Città della Speranza, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Clinical Chemistry, Departments of Pathology and Neurology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Plácido
authors.initials: P
authors.lastname: Navas
mesh_terms: D001483:Base Sequence; D001927:Brain Diseases / Q000201:enzymology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017809:Fatal Outcome; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics*; D012867:Skin / Q000473:pathology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D014451:Ubiquinone; C024989:coenzyme Q10