LEBERS HEREDITARY OPTIC NEUROPATHY - CLINICAL MANIFESTATIONS OF THE 15257 MUTATION

Background: Leber's hereditary optic neuropathy is associated with fou r known pathogenetic mutations of mitochondrial DNA (mtDNA) at nucleot ide positions (np) 11778, 3460, 15257, and 14484. Methods: The authors collected clinical data from 12 visually symptomatic patients from se ven different pedigrees with the 15257 mutation and compared these dat a with previously published clinical features of the 11 778 and 3460 m utations. Results: The authors' results indicate that these three grou ps of patients are similar in most clinical characteristics evaluated. However, patients with the 15257 mutation are more likely to experien ce significant recovery of visual acuity than patients with the 11778 mutation (25% versus 4% of eyes; P < 0.001). Patients with the 1 5257 mutation who also have an associated mutation at np 15812 are less lik ely to recover vision than those without this association (P = 0.001). Patients with the 15257 mutation also have a higher incidence of spin al cord and peripheral neurologic symptoms (42%) than patients with th e other pathogenetic mutations. Conclusions: The phenotypic expression of the 15257 mutation differs from the 11778 and 3460 mutations and i s affected by the presence of an associated mutation at np 15812. This is the first clinical evidence to support the concept of multiple sim ultaneous mtDNA mutations producing additive deleterious effects in pa tients with Leber's hereditary optic neuropathy. The clinical differen ces between the various genotypes associated with Leber's hereditary o ptic neuropathy have implications for risk factor management and visua l prognosis and, thus, underscore the importance of molecular genetic testing in patients with suspected Leber's hereditary optic neuropathy .