- Leber hereditary optic neuropathy (LHON)
- Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
- Myoclonic epilepsy with ragged-red fibers (MERRF)
- Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO)
- Neurogenic muscle atrophy and retinitis pigmentosa (NARP) and Leigh disease
Mitochondrial Oxidative Phosphorylation Disorders
Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the CNS, retina, and muscle.
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 ATP. Mitochondrial or nuclear genetic defects involving enzymes used in this process impair cellular respiration, decreasing the ATP:ADP ratio. Tissues with a high energy demand (eg, brain, nerves, retina, skeletal and cardiac muscle) are particularly vulnerable. The most common clinical manifestations are seizures, hypotonia, ophthalmoplegia, strokelike episodes, muscle weakness, severe constipation, and 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.
This disease is characterized by acute or subacute bilateral central vision loss caused by retinal degeneration. Onset usually occurs in the patient’s 20s or 30s but can occur from childhood to adulthood. Male:female ratio is 4:1. Many mutations have been defined, but 3 common ones account for 90% of those in European patients. LHON pedigrees usually show a pattern of maternal inheritance typical of mitochondrial disorders.
This progressive disorder is characterized by uncontrolled muscle contractions (myoclonic seizures), dementia, ataxia, and myopathy, which shows ragged-red fibers (indicating mitochondrial proliferation) with specialized stains when biopsied. Mutations are in the mitochondrial tRNAlys gene. Heteroplasmy is common; thus, expression is variable.
These disorders are characterized by ophthalmoplegia, ptosis, atypical retinitis pigmentosa, ragged-red fiber myopathy, ataxia, deafness, and cardiomyopathy typically occurring before age 20 yr. Most mutations involve contiguous deletion/duplication of part of the mitochondrial transfer RNA and other protein-coding genes.