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Secondary metabolic effects in complex I deficiency
Author(s) -
Esteitie Nayla,
Hinttala Reetta,
Wibom Rolf,
Nilsson Helene,
Hance Nicole,
Naess Karin,
TeärFahnehjelm Kristina,
Von Döbeln Ulrika,
Majamaa Kari,
Larsson NilsGöran
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20570
Subject(s) - mitochondrial dna , proband , biology , mitochondrion , mitochondrial respiratory chain , succinate dehydrogenase , respiratory chain , mitochondrial encephalomyopathy , mutation , endocrinology , citric acid cycle , medicine , genetics , gene , metabolism
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. Ann Neurol 2005