The mitochondrion is the only extranuclear organelle containing
DNA (
mtDNA). As such, genetically determined
mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of
mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear
DNA. Large-scale rearrangements (deletions and insertions) and point mutations of
mtDNA are commonly associated with RRF and
lactic acidosis, e.g.
Kearns-Sayre syndrome (KSS) (major large-scale rearrangements),
Pearson syndrome (large-scale rearrangements),
myoclonus epilepsy with RRF (
MERRF) (point mutation affecting
tRNA(lys) gene), mitochondrial
myopathy,
lactic acidosis, and
stroke-like episodes (
MELAS) (two point mutations affecting
tRNA(leu)(UUR) gene) and a maternally-inherited
myopathy with cardiac involvement (MIMyCa) (point mutation affecting
tRNA(leu)(UUR) gene). However, RRF and
lactic acidosis are absent in
Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the
apocytochrome b subunit of
complex III), and the condition associated with maternally inherited sensory neuropathy (N),
ataxia (A),
retinitis pigmentosa (RP), developmental delay,
dementia,
seizures, and limb weakness (NARP) (point mutation affecting
ATPase subunit 6 gene). The point mutations in
MELAS, MIMyCa, and
MERRF, and the large-scale
mtDNA rearrangements in KSS and
Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of
mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of
mitochondrial diseases principally catalogues these nuclear defects. This classification divides
mitochondrial diseases into five categories. Primary and secondary deficiencies of
carnitine are examples of a substrate transport defect. A
lipid storage myopathy is often present. Disturbances of
pyruvate or
fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known:
fumarase deficiency,
dihydrolipoyl dehydrogenase deficiency,
alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle
succinate dehydrogenase and
aconitase.
Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function.
Leigh syndrome may result from different
enzyme defects, most notably
pyruvate dehydrogenase complex deficiency,
cytochrome c oxidase deficiency, complex I deficiency, and
complex V deficiency associated with the recently described NARP point mutation. A new group of
mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)