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Lightning strikes twice: Leber hereditary optic neuropathy families with two pathogenic mtDNA mutations
Neil Howell1, Neil R Miller, David A Mackey
1MitoKor, San Diego, California 92121, USA. howelln@mitokor.com
Objective:
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.
Methods:
In addition to detailed clinical histories, the complete sequence of the mitochondrial DNA (mtDNA) from each family was determined.
Results:
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.
Conclusions:
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.