Leber's hereditary optic neuropathy and Kearns-Sayre syndrome: mitochondrial DNA mutations

Mitochondrial DNA (mt DNA) supplies extranuclear (cytoplasmic) genes which program the manufacture of 13 of the 67 peptides of the mitochondrial respiratory enzymes. The remaining 54 are coded by nuclear DNA. All human children and adults, male and female, are entirely dependent on the cytoplasm of the ovum for their complement of mt DNA; the sperm contributes none. Accordingly, mutations in the mt DNA in a mother's ova will be passed on to all her children, although not all are clinically affected. Leber's hereditary optic neuropathy is in most cases due to a mutation that leads to the replacement of guanine by adenine at position 11778 in mt DNA. This causes histidine to be inserted instead of the normal arginine at the site of the 340th amino acid in the respiratory enzyme NADH subunit 4, hence its defective function. Other point mutations in the mt DNA coding for polypeptides of the respiratory chain complex or controlling sequences coded by mt DNA have been found in other families with Leber's hereditary optic neuropathy. Mitochondrial DNA is the site of other mutations as well. For ophthalmologists, the most important of these is the rare Kearns-Sayre syndrome (pigmentary retinopathy plus muscular dystrophies, especially of the extraocular muscles). Kearns-Sayre syndrome is due to deletions in the mt DNA, which vary in size and so affect a number of different respiratory enzymes, hence the variable manifestations. Cases are usually sporadic because the disease is often so severe that affected individuals do not reproduce if they survive, but in some cases inheritance from the mother has been reported.