Molecular diagnosis of Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a blinding disease that causes acute or subacute loss of vision in healthy young males. A guanine(G) to adenine(A) transition was recently identified at the 11778th nucleotide position in the NADH dehydrogenase subunit 4 gene (ND4) in the mitochondrial genome of LHON patients from various ethnic groups. In this study, we analyzed the mitochondrial DNA (mtDNA) of leukocytes from six patients in five families with LHON and 14 relatives by Sfa NI and Mae III enzyme digestion. From the pedigree study, four patients were found to be clinically sporadic cases. However, a molecular study revealed that the Sfa NI site was lost in the 515-bp PCR product of mtDNAs from all patients and their maternal relatives but not in nonmaternal lineages and normal controls. Mae III digested the 515-bp PCR product of mtDNAs from LHON patients who had lost the Sfa NI site. These results confirm previous reports that a G to A point mutation at the 11778th nucleotide position is associated with LHON and that the disease is transmitted through maternal inheritance. Molecular analysis of mtDNA thus provides a simple and useful method for diagnosis of this disease.