Dominant optic atrophy - Refining the clinical diagnostic criteria in light of genetic linkage studies

Objective: To describe the clinical findings and refine the clinical diagno stic criteria for dominant optic atrophy based on eight British families in which the diagnosis was confirmed by linkage analysis. Design and Participants: Case series; 92 subjects in 8 pedigrees had both e yes examined. Intervention: Family members received a domiciliary examination based on be st-corrected visual acuity, color vision using Ishihara and Hardy Richter R and (HRR) plates, confrontation field testing using a red target, and optic disc evaluation using a direct ophthalmoscope. Genomic DNA was extracted f rom leukocytes or buccal mucosal cells and genotyped using 12 fluorescently labeled microsatellite markers from the region 3q27-q29. Main Outcome Measures: Subjects were classified clinically as definitely or possibly affected on the basis of the domiciliary examination before genet ic analysis, and these results were compared with the haplotype analysis. Results: Clinically, 43 subjects were identified as definitely affected, 4 as possibly affected; and 45 as unaffected. Visual acuity in affected subje cts ranged from 6/6 to count fingers and declined with age. On genetic anal ysis, a haplotype was identified in each family, which was found in all def initely affected members but not in those regarded as unaffected. The four possibly affected individuals also bore the haplotype that segregated with the disease. Conclusions: Simple clinical tests are highly efficacious in diagnosing dom inant optic atrophy. Contrary to accepted criteria, symptoms begin before t he age of 10 years in only 58% of affected individuals. Visual acuity in af fected subjects is highly variable. A mild degree of temporal or diffuse pa lter of the optic disc and minimal color vision defects, in the context of a family with dominant optic atrophy, are highly suggestive of an individua l being affected, even if the visual acuity is normal. This widens the gene rally accepted diagnostic criteria for this disease.