Complex I Deficiency

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-2). Forty-six polypeptide subunits form Complex I, of which 7 are encoded by mitochondrial DNA (mtDNA) and the residual 39 by nuclear DNA (nDNA). The major subunits are flavoprotein, iron-sulphur 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.

NADH-Coenzyme Q Reductase Deficiency; NADH-Ubiquinone Oxidoϲeductase Deficiency.

The estimated incidence for all forms of respiratory chain diseases combined is approximately 1 in 10,000 live births. The male-to-female ratio is approximately 3.5:1.

Inheritance is usually autosomal recessive. It can also be caused, as with all mitochondrial encephalopathies, by mutations in multiple different genes. Complex I deficiency presents both nuclear-encoded and mitochondrial-encoded mutations. Human complex I (NADH-ubiquinone reductase) consists of at least 36 nuclear-encoded and 7 mitochondrial-encoded subunits. Mutations in any of these subunits can cause the disorder, which explains the complexity of this disorder.