Frequency of rare mitochondrial DNA mutations in patients with suspected Leber’s hereditary optic neuropathy

eber's hereditary optic neuropathy (LHON (MIM 535000))characteristically presents with subacute painless bilateral visual failure in young adults, with a predilection for males. 1 2 In the largest multicentre study of white people with LHON, 3 97% of those affected were found to harbour one of three "primary" mitochondrial DNA (mtDNA) point mutations affecting genes that code for different subunits of complex I (NADH-ubiquinone oxidoreductase, or ND) of the respiratory chain, G11778A, G3460A, and T14484C, which affect the ND4, 4 ND1, 5 6 and ND6, 7 subunits respectively.This work had profound implications for the clinical investigation of patients with suspected LHON, indicating that a simple molecular genetic blood test would confirm the diagnosis in 19 out of 20 cases, and that a negative result reduces the likelihood of LHON to less than 1 in 20.In the original multicentre study of Mackey et al, 3 cases were carefully selected to avoid the inclusion of pedigrees with autosomal dominant or autosomal recessive optic atrophy.The authors only analysed pedigrees where there were at least two affected people related through an unaffected woman, and most of the pedigrees spanned several generations displaying strict maternal inheritance. 3Although this approach enriched their cohort for definite cases of LHON, it reduced the likelihood of including small pedigrees, which account for up to a third of genetically confirmed cases of LHON. 8Several additional mtDNA sequence variants have been described in patients with LHON over the past 10 years.Some of these sequence changes are also found in healthy controls at a lower frequency than in cases of LHON, 9-11 and the role of these "secondary mutations" has yet to be established. 124][15][16][17][18][19][20][21][22] These new mutations often occur in small pedigrees that would not have been included in the original study. 3This raises the possibility that rare primary LHON mtDNA mutations are more common than was previously thought.To consider this issue it is necessary to carry out a population based genetic epidemiological study of LHON, looking for novel rare LHON mutations in patients not harbouring the G11778A, G3460A, or T14484C mutations.We recently carried out a rigorous population based genetic epidemiology study of LHON in a population of 2 173 800 people in the north east of England. 23This established LHON as one of the most common inherited eye diseases.In this region, at least 1 in 14 067 males develop visual failure owing to the G11778A, G3460A, and T14484C mtDNA mutations, which were found in about 1 in 8500 of the general population.While carrying out this study we identified a cohort of patients with suspected LHON who did not harbour the G11778A, G3460A, or T14484C mutations.Here we report the results of further investigations carried out on these patients.This was done with three aims: (1) to determine the incidence of rare LHON mutations in the general population; (2) to determine the relative frequency of rare LHON mutations when compared with G11778A, G3460A, or T14484C; and (3) to determine the role of extensive mtDNA sequencing when investigating suspected LHON.