Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q 10 content

Asencio, C. ; Rodríguez-Hernandez, M. A. ; Briones, P. ; Montoya, J. (Universidad de Zaragoza) ; Cortés, A. ; Emperador, S. ; Gavil''n, A. ; Ruiz-Pesini, E. (Universidad de Zaragoza) ; Yubero, D. ; Montero, R. ; Pineda, M. ; O''Callaghan, M. M. ; Alcázar-Fabra, M. ; Salviati, L. ; Artuch, R. ; Navas, P.

Resumen: Coenzyme Q 10 (CoQ 10) 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 CoQ 10 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 CoQ 10 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 CoQ 10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ 10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.

Idioma: Inglés

DOI: 10.1038/ejhg.2015.112

Año: 2016

Publicado en: European Journal of Human Genetics 24, 3 (2016), 367-372
ISSN: 1018-4813

Factor impacto JCR: 4.287 (2016)

Categ. JCR: GENETICS & HEREDITY rank: 35 / 165 = 0.212 (2016) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 71 / 286 = 0.248 (2016) - Q1 - T1

Factor impacto SCIMAGO: 2.092 - Genetics (clinical) (Q1) - Genetics (Q1)

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)