Lightning strikes twice: Leber hereditary optic neuropathy families with two pathogenic mtDNA mutations.

Abstract

To report the clinical and mitochondrial genetic analyses of two families, each of which carries both the 11778 and 14484 Leber hereditary optic neuropathy (LHON) mutations in mitochondrial DNA. In addition to detailed clinical histories, the complete sequence of the mitochondrial DNA (mtDNA) from each family was determined. A small Australian LHON family (Vic20) and a family from the United States carry the 11778 and 14484 LHON mutations. In addition to the optic neuropathy, one branch of the Baltimore LHON pedigree had a high incidence of a fatal infantile encephalopathy. In both families, the 14484 LHON mutation was homoplasmic, whereas the 11778 LHON mutation was heteroplasmic. There are no additional mtDNA sequence changes that explain the encephalopathy in the Baltimore LHON family, and a nuclear gene involvement is an alternative explanation that is supported by the available data. The ophthalmological characteristics and penetrance in the 11778 and 14484 "two-mutation" LHON families are not markedly more severe than those of classic LHON families who carry a single mtDNA mutation.