Leber's hereditary optic neuropathy: Diagnostic pitfalls in genetic testing

To investigate the possibility and consequences of false positive testing for Leber's hereditary optic neuropathy (LHON) using repeated testing.

In three cases of suspected LHON, initial mutation analysis using restriction fragment length polymorphism (RFLP) and direct sequencing showed rare mtDNA mutations at nt 14482 in two cases and a mutation in nt 14484 in the third case which has been associated with a mild variant of LHON. All three patients consulted a specialized neuro-ophthalmology center for a second opinion. During the examinations the clinical diagnosis of LHON was questioned. Therefore the initial DNA samples were reevaluated again using the same probes.

The reevaluation by the testing laboratory of the DNA samples of the three patients revealed misinterpreted initial results and could show that there were no LHON typical mutations in none of the three patients.

A high level of suspicion is important when an accumulation of rare mutations occurs. It is only because of the attentiveness of a specialized neuro-ophthalmologist and the testing laboratory that the diagnosis of LHON was averted. Every laboratory testing can produce false positive results. Therefore, we emphasize that a positive test should be confirmed by a second independent laboratory, at least if the clinical findings seem not to be typical for LHON.