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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, stroke-like episodes, muscle weakness, 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's disease, Alzheimer's disease, diabetes, deafness, cancer).
Leber's
hereditary optic neuropathy (LHON):
This is a disease with 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.
Mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes (MELAS):
Mutations in the mitochondrial tRNA
leu
gene cause this progressive neurodegenerative disease characterized by repeated episodes of “chemical strokes,” myopathy, and lactic acidosis. In many cases, cells contain both wild-type and mutant mitochondrial DNA (heteroplasmy); thus, expression is variable.
Myoclonic
epilepsy with ragged-red fibers (MERRF):
This is a progressive disease 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.
Kearns-Sayre
syndrome and chronic progressive external ophthalmoplegia (CPEO):
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 tRNA and other protein-coding genes.
Neurogenic
muscle atrophy and retinitis pigmentosa (NARP) and Leigh disease:
Pigmentary retinopathy in the presence of neuromuscular degeneration and Leigh disease (subacute necrotizing encephalopathy characterized by ataxias and basal ganglia degeneration) is a genetically heterogeneous syndrome. Mutations can be seen in the ATP6 gene of the mitochondrial genomes.
Last full review/revision November 2005
Content last modified November 2005
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