title: Secondary metabolic effects in complex I deficiency.
abstract: The objective of this study was to investigate clinical, biochemical, and genetic features in 7 probands (a total of 11 patients) with nicotine-amide adenine dinucleotide (NADH) dehydrogenase (complex I) deficiency. We screened the mitochondrial DNA for mutations and found pathogenic mutations in complex I genes (mitochondrial NADH dehydrogenase subunit (MTND) genes) in three probands. The 10191T>C mutation in MTND3 and the 14487T>C mutation in MTND6 were present in two probands with Leigh's-like and Leigh's syndrome, respectively. Four siblings with a syndrome consisting of encephalomyopathy with hearing impairment, optic nerve atrophy, and cardiac involvement had the 11778G>A mutation in MTND4, previously associated with Leber hereditary optic neuropathy. These findings demonstrate that mutations in MTND genes are relatively frequent in patients with complex I deficiency. Biochemical measurements of respiratory chain function in muscle mitochondria showed that all patients had a moderate decrease of the mitochondrial adenosine triphosphate production rate. Interestingly, the complex I deficiency caused secondary metabolic alterations with decreased oxaloacetate-induced inhibition of succinate dehydrogenase (complex II) and excretion of Krebs cycle intermediates in the urine. Our results thus suggest that altered regulation of metabolism may play an important role in the pathogenesis of complex I deficiency.
authors.affiliation: Department of Women and Childrens Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nayla
authors.initials: N
authors.lastname: Esteitie
authors.forename: Reetta
authors.initials: R
authors.lastname: Hinttala
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Helene
authors.initials: H
authors.lastname: Nilsson
authors.forename: Nicole
authors.initials: N
authors.lastname: Hance
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.forename: Kristina
authors.initials: K
authors.lastname: Teär-Fahnehjelm
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western / Q000379:methods; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D013912:Threonine / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D013912:Threonine; D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I