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Juvenile onset dominant optic atrophy (DOA) is the most common inherited optic atrophy with a variable prevalence of between 1 in 10 000 (Denmark) and 1 in 50 000.1,2 The majority of cases have been shown to have mutations in the OPA1 gene on chromosome 3.3–5 Reduced visual acuity of insidious onset, temporal pallor of the optic disc, centrocaecal scotoma, and generalised dyschromatopsia are the key clinical features.6 Recent studies, however, have shown that penetrance within families is much lower than first realised and the assignment of status using clinical criteria alone can result in misdiagnosis.5 This is well illustrated by the following family.
Fifteen family members were asked about perceived visual difficulties before measurement of visual acuity, colour vision (City University Test), and visual field analysis (Humphry 24-2). Fundal examination and photography were performed. Blood was taken for screening of the OPA1 coding region using single stranded polymorphism analysis (SSCP) and automated DNA sequencing as previously described.5
Seven family members were diagnosed as having optic atrophy from clinical tests alone (Fig 1). Where visual disability was recognised the age of onset ranged from 5.5 to 20 years (Table 1). Eight family members were classed as affected from molecular testing. All individuals exhibited an abnormal banding pattern on SSCP analysis of exon 27 (Fig 2). Sequencing revealed a four base pair deletion of TTAG at the start of exon 27 (nt2708 delTTAG). This deletion has been described previously and causes a frameshift resulting in two amino acid substitutions (Val903Gly, Arg904Asp) and a premature stop codon.
Dominant optic atrophy may be the result of mutations in genes other than OPA1.7 However, where DNA linkage analysis or mutation screening implicates the OPA1 gene we feel that all family members should be offered molecular testing. In DOA it is well recognised that the clinical manifestation of the same mutation within a family can be very variable.6 This is well illustrated in Table 1. Genetic screening is the only reliable way of identifying individuals at risk of passing on defective genes to their offspring. In this family the combination of SSCP and DNA sequencing resulted in an alteration of the status of individual II:7 from unaffected to affected. If clinical tests alone had been relied upon, this individual would have most likely received incorrect genetic advice.