LEBERS HEREDITARY OPTIC NEUROPATHY PLUS DYSTONIA IS CAUSED BY A MITOCHONDRIAL-DNA POINT MUTATION

A novel point mutation in the ND6 subunit of complex I at position 14, 459 of the mitochondrial DNA (MTND6LDY T14459A) was identified as a c andidate mutation for the highly tissue-specific disease. Leber's here ditary optic neuropathy plus dystonia. Since the MTND6LDYT14459A muta tion was identified in a single family, other pedigrees with the mutat ion are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additiona l pedigrees. Leber's hereditary optic neuropathy developed in two fami ly members in one pedigree. The daughter had clinically silent basal g anglia lesions. In a second pedigree, a single individual presented wi th childhood-onset generalized dystonia and bilateral basal ganglia le sions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6LDYT14459A mutation, suggesting th at this mutation displays a high degree of tissue specificity, thus pr oducing a narrow phenotypic range. These results confirm the associati on of the MTND6LDYT14459A mutation with Leber's hereditary optic neur opathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylati on genes are important considerations in the pathogenesis of dystonia.