Improved Molecular-Genetic Diagnosis of Leber's Hereditary Optic Neuropathy

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Abstract
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by optic neuropathy and cardiac dysrhythmia. A single mitochondrial DNA mutation, a G-to-A substitution at position 11778 that converts a highly conserved arginine to histidine in the fourth subunit of NADH dehydrogenase, has been demonstrated in several families.1 2 3 4 5 This mutation causes the loss of an SfaNI restriction site, and the absence of this site has been exploited as a means of diagnosis with the use of mitochondrial DNA amplified with the polymerase chain reaction (PCR) and Southern blot analysis of genomic DNA. However, the SfaNI recognition site consists of five nucleotides (GCATC) ( Fig. 1 ), two of which are in the third position of a codon. Thus, any change in these five nucleotides will result in the loss of this SfaNI site and will be interpreted as a positive test for LHON. Mitochondrial DNA fixes mutations at a rate 5 to 10 times as high as nuclear DNA6; thus, the possibility of a false positive result is proportionately increased.