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At a glance

This is the most common type of respiratory chain disease. Complex I is the largest respiratory chain complex and involved in numerous clinical conditions (see Table C-1). Forty-six polypeptide subunits form Complex I, of which seven are encoded by mitochondrial DNA (mtDNA) and the residual 39 by nuclear DNA (nDNA). The major subunits are flavoprotein, iron-sulfur protein, and hydrophobic fraction. Complex I is involved in the electron transport from NADH to ubiquinone, from where the electrons are transported to the next respiratory chain complex. This is the most commonly identified respiratory chain disease phenotype, which is most likely related to the large number of subunits encoded by both, nuclear and mitochondrial DNA and the size of the complex subunit. Complex I deficiency is often part of a combined deficiency because deficiencies in other complexes may result in a loss of Complex I function. It is the result of a number of situations where mtDNA point mutations are associated with deletions. In the absence of known mtDNA abnormalities, it may be associated with fatal infantile encephalomyopathy. As an isolated deficit, the clinical presentation occurs at the age of 4 to 5 months and in about 70% of patients death occurs within 2 years. Severe lactic acidosis occurs in 85% of patients. Most infants also present with severe cardiomyopathy, childhood encephalopathy, macrocephaly with progressive leukodystrophy, hepatomegaly, and real tubulopathy. The most frequent myopathy is known as ☞MELAS Syndrome.

Synonyms

NADH-Coenzyme Q Reductase Deficiency; NADH-Ubiquinone Oxido-reductase Deficiency.

Incidence

Estimated to be about 1 per 4-5,000 live births. The male-to-female ratio is approximately 3.5:1.

Genetic inheritance

Mutations in more than 20 different nuclear- (about 70% of cases) or mitochondrial-encoded genes can lead to mitochondrial complex I deficiency and inheritance can be autosomal recessive, X-linked dominant, or mitochondrial. Consanguinity is an important risk factor. No obvious genotype-phenotype correlations exist and the clinical picture is highly variable, even among family members with the same genetic mutation. Complex I deficiency is the most common single mitochondrial enzyme deficiency in patients with a mitochondrial disorder, which in part is explained by its complex structure (46 units, with 14 being core subunits and at least 18 accessory subunits) that involves the input of over 100 different genes. Complex I (NADH:ubiquinone oxidoreductase) is also the first and the largest enzyme in the respiratory chain and the rate-limiting step in overall respiration. It plays a central role in the energy metabolism and oxidizes NADH from the Krebs cycle (tricarboxylic acid cycle) and from β-oxidation of fatty acids, and contributes to the proton-motive force by transporting protons across the inner membrane. The two electrons from NADH oxidation are used to reduce ubiquinone to ubiquinol and supply the other components of the electron transport chain with electrons for the reduction of O2 to water. The released energy from this ...

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