Mitochondrial oxidative phosphorylation disorders

[Becky]

Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the central nervous system, retina, and muscle.
See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism.
Cellular respiration (oxidative phosphorylation) occurs in the mitochondria, where a series of enzymes catalyze the transfer of electrons to molecular oxygen and the generation of energy-storing adenosine triphosphate (ATP). Defects involving enzymes used in this process impair cellular respiration, decreasing the ATP:ADP (adenosine diphosphate) ratio. Mitochondria have their own DNA (mitochondrial DNA [mtDNA]), which is maternally derived. However, mtDNA shares responsibility with nuclear DNA for mitochondrial function. Thus, both mitochondrial and nuclear mutations can cause mitochondrial disorders.
Tissues with a high energy demand (eg, brain, nerves, retina, skeletal and cardiac muscle) are particularly vulnerable to defects in oxidative phosphorylation.
The most common clinical manifestations are

Seizures
Hypotonia
Ophthalmoplegia
Strokelike episodes
Muscle weakness
Severe constipation
Cardiomyopathy

Biochemically, there is profound lactic acidosis because the NADH:NAD ratio increases, shifting the equilibrium of the lactate dehydrogenase reaction toward lactate. The increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation defects from other genetic causes of lactic acidosis, such as pyruvate carboxylase or pyruvate dehydrogenase deficiency, in which the lactate:pyruvate ratio remains normal. A large number of oxidative phosphorylation defects have been described; only the most common ones are outlined here, along with their distinguishing features.
Mitochondrial mutations and variants have also been implicated in a number of diseases of aging (eg, Parkinson disease, Alzheimer disease, diabetes, deafness, cancer).
The following disorders are conditions with a known phenotype/genotype correlation. Other less well-defined defects in mitochondrial function exist. Additionally, there are a number of conditions in which a genetic defect causes secondary mitochondrial dysfunction.