Intrafamilial variation in Leber hereditary optic neuropathy revealed by direct mutation analysis.

Leber hereditary optic neuropathy (LHON) has been associated with a mitochondrial mutation at position 11,778 in the ND4 gene in about 50% of families. Individuals from six Swedish families with LHON were investigated for the presence of this mutation using allele-specific oligonucleotides and a sensitive chemoluminescent detection system. The point mutation was seen in mitochondrial DNA extracted from leukocytes in five families, four of which showed a homoplasmic pattern. One family showed a heteroplasmic pattern and one family was negative for the mutation. Six adults without impaired vision from three LHON families were detected as carriers with a degree of mutated mitochondrial DNA similar to that in affected relatives. The results show that the penetrance of LHON varies remarkably among carriers of the 11,778 mutation within families. We conclude that the prognosis for carriers should be stated cautiously when interpreting results from mutation analysis of mitochondrial DNA in leukocytes.