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We reported that a group of 19 patients with non‐arteritic ischaemic optic neuropathy (NAION) had an increased number of mitochondrial (mt) DNA nucleotide changes1 and significantly increased relative mtDNA content compared to age and sex matched controls.2 We were pleased that Carelli and Sadun thought that our most recent manuscript in BJO warranted an editorial response.3 In this letter, we clarify data about mtDNA nucleotide changes and relative mtDNA content in NAION.
Referring to our first report, they stated that “… most of the polymorphisms found in NAION patients are ancient, well known mtDNA variants defining specific haplogroups (mtDNA maternal lineages) of European populations.” In fact, we made two observations in that report.1 The first was that both synonymous and non‐synonymous nucleotide changes from the Cambridge Reference Sequence4 were more common in NAION patients than in ethnic controls. Second, the NAION group also had 11 novel mtDNA changes and one other nucleotide change that was reported previously in a single mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) patient. These unusual changes in 10 patients of the NAION group were clearly not ancient polymorphisms.
Referring to our recent report of increased relative mtDNA content in NAION patients,2 Carelli and Sadun noted that metabolic stresses known to be associated with NAION, such as diabetes and hypertension, could increase relative mtDNA content. We agreed that a control group matched for major atherosclerotic risk factors would address the question of whether these metabolic stresses are responsible for increased relative mtDNA content in NAION patients. Therefore, we have simultaneously assessed relative mtDNA content as described previously2 in the same 19 NAION patients and in 85 controls selected from a previous cardiovascular study5 who were matched for ethnic background, age, sex, diabetes, hypertension, smoking history and coronary artery disease.
Table 11 shows that age, sex and prevalence of diabetes, hypertension, smoking and coronary artery disease were well matched between NAION patients and controls. Nevertheless, relative mtDNA content in NAION patients was again more than twice that in controls, indicating that these metabolic stresses were not responsible for the dramatic increase in relative mtDNA content. This data is pertinent to the points raised by Carelli and Sadun for at least two other reasons. First, new mtDNA content values in NAION patients were strongly correlated with values reported previously2 (Pearson correlation 0.977, p<0.001), proving the reproducibility of relative mtDNA content measurement. Second, increased relative mtDNA content was again predictive of worse vision in both eyes (Pearson's correlation −0.383, p=0.018).
These data answer the concern that known metabolic stresses might induce changes in relative mtDNA content in NAION patients. Compared to controls, this small group of NAION patients in Saudi Arabia has more total mtDNA sequence changes, more novel mtDNA changes and elevated relative mtDNA content. These observations taken together with the association between mtDNA content and visual acuity suggest that mitochondrial abnormalities may constitute a risk for NAION. Similar studies should be performed in NAION populations from other ethnic backgrounds.
This study was partially funded by the Prince Salman Center for Disability Research.
Competing interests: None.