Mitochondrial DNA mutation in Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) causes acute or subacute central visual loss in healthy young males. Recently, it has been thought to be caused by a single nucleotide change in the ND4 gene in the mitochondrial genome. Mitochondrial DNA (mtDNA) of leukocytes and hair follicle cells from five patients in four families with LHON and nine relatives were analyzed by Sfa NI and Mae III enzyme digestion and DNA sequencing. Loss of Sfa NI site was found in all patients and maternal lineages but not in nonmaternal lineages and normal controls. Mae HI digested all the mtDNAs that lost the Sfa NI site. The restriction fragment pattern of polymerase chain reaction (PCR) products exhibited mtDNA heteroplasmy in the hair follicle cells but not in blood cells of the proband in one family. Direct sequencing of PCR-amplified mtDNA fragments encompassing the ND4 gene of the patients disclosed a transition from guanine to adenine at nucleotide position 11778. These results confirm previous reports that a G to A point mutation is associated with LHON and that tissue variability and heteroplasmy of mtDNA exist in some, but not all, LHON patients. Invest Ophthalmol Vis Sci 33:2561-2566,1992 Leber's hereditary optic neuropathy (LHON) is characterized by sudden loss of central vision in the second and third decades of a patient's life. Males are most affected. Initially, the optic discs are hyperemic and the nerve fiber layer is swollen and opacified. There is peripapillary telangiectasis without leakage of fluorescein dye. Loss of visual acuity generally is severe (6/60 or less). Optic atrophy is apparent within 2 mo. The disease is familial, but the transmission does not follow the classic mendelian law. It is transmitted exclusively by women to offsprings of both sexes. 1 Parental transmission has never been described. Because mitochondrial DNA (mtDNA) is the only maternally inherited component of human genetic materials, mitochondrial inheritance has been implicated in the eti