Clinical, genetic, and biochemical characterization of a leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations

Four mitochondrial DNA (mtDNA) mutations at nps 3460, 11778, 14484, and 144 59 account for roughly 90% of cases of Leber hereditary optic neuropathy (L HON) and are designated as "primary" LHON mutations since they act as major predisposition factors for LHON. Although each primary mutation can arise independently on different mtDNA backgrounds during human evolution, they c haracteristically do not co-occur in LHON patients. We report here a family with the simultaneous occurrence of the 11778A and 14484C mutations. Neuro ophthalmological examination of the proband, a nine-year-old Caucasian fema le, revealed the bilateral optic atrophy, central scotomas, and reduced vis ual acuity typical of LHON. Her mother had normal appearing optic discs and is today visually asymptomatic. Analysis of the proband blood mtDNA reveal ed that she harbored both the 11778A (heteroplasmic, 94% mutant) and the 14 484C (homoplasmic mutant) mutation. This genotype was maintained in proband lymphoblasts and transmitochondrial cybrids. The mother also had both muta tions, with the 14484C mutation homoplasmic in all cell types examined. How ever, only 31% of her blood mtDNAs carried the 11778 mutation, which segreg ated to essentially 100% wild-type in lymphoblast and cybrid mtDNA. Complex I-linked respiration and specific enzyme activity were consistently lowest in proband lymphoblast and cybrid mitochondria compared to those from the mother, 11778A patients, 14484C patients, or controls, thus demonstrating b oth a deleterious synergistic interaction between the 11778A and 14484C mut ations and the magnitude of 11778A-associated complex I dysfunction. Remark ably, spontaneous vision recovery occurred in the proband, highlighting the complexities encountered when associating mtDNA genotype and complex I fun ction with LHON expression. (C) 2001 Wiley-Liss, Inc.