We recently reported that a group of patients with non‐arteritic anterior ischaemic optic neuropathy (NAION) had an increased prevalence of potentially pathological mitochondrial DNA (mtDNA) mutations, implying a link between mitochondrial disease and this optic neuropathy.1 We decided to investigate the association of other risk factors for NAION in these same patients.
Case reports
NAION patients were genotyped for the presence of prothrombotic polymorphisms that have been reported in association with NAION,2,3 including factor II G20210A prothrombin variant, factor V Leiden G1691A variant, MTHFR C677T and A1298C variants, platelet glycoprotein receptor IIIa (PIA2) allele, and apolipoprotein E (∈4) allele, as described previously.4,5,6,7,8 These reports included large control groups that were ethnically matched to our NAION patients and that had been queried regarding the presence of atherosclerotic risk factors. Controls older than 50 years were selected for comparison with NAION patients.
Table 1 shows that the prevalence rates for prothrombotic variants among NAION patients did not differ from controls. Reported prevalence of diabetes, hypertension, and hyperlipidaemia was relatively high in NAION patients but was also not significantly different from controls.
Table 1 Comparison of risk factors in NAION patients and controls.
| Risk factor | NAION patients | Controls | Odds ratio | 95% CI | p Value | |
|---|---|---|---|---|---|---|
| Apo E4 | Homo | 0/19 | 0/593 | 31.2 | 0.60 to 1615.3 | 1 |
| Factor II G20210A | Homo | 0/19 | 0/593 | 31.2 | 0.60 to 1615.3 | 1 |
| Hetero | 0/19 | 10/593 | 0 | 0.00 to 17.52 | 1 | |
| Factor V G1691A | Homo | 0/19 | 0/200 | 10.5 | 0.20 to 545.6 | 1 |
| Hetero | 0/19 | 5/200 | 0 | 0.00 to 13.10 | 1 | |
| MTHFR C677T | Homo | 0/19 | 12/625 | 0 | 0.00 to 15.06 | 1 |
| Hetero | 4/19 | 161/625 | 0.77 | 0.21 to 2.52 | 0.79 | |
| MTHFR A1298C | Homo | 0/19 | 57/625 | 0 | 0.00 to 2.71 | 0.39 |
| Hetero | 7/19 | 322/625 | 0.55 | 0.19 to 1.52 | 0.30 | |
| PIA2 allele | Homo | 0/19 | 12/509 | 0 | 0.00 to 12.22 | 1 |
| Hetero | 3/19 | 137/509 | 0.51 | 0.12–1.89 | 0.41 | |
| Age, mean (SD) | – | 58.8 (8.5) | 57.1 (4.2) | – | – | 0.40 |
| Sex (M:F) | – | 14:5 | 351:160 | 1.28 | 0.42 to 4.13 | 0.64 |
| Diabetes | – | 13/19 | 256/511 | 2.16 | 0.75 to 6.47 | 0.18 |
| Hypertension | – | 10/19 | 209/511 | 1.61 | 0.59 to 4.38 | 0.43 |
| Hyperlipidaemia | – | 2/19 | 59/511 | 0.68 | 0.11 to 3.17 | 1 |
| CAD | – | 1/19 | 27/511 | 0.55 | 0.03 to 4.03 | 1 |
| NS mtDNA changes | – | 14/19 | 11/100 | 22.6 | 6.03 to 91.07 | < 0.001 |
NAION, non‐arteritic ischaemic optic neuropathy; CAD, coronary artery disease; NS mtDNA changes, non‐synonymous (changing an amino acid in the resultant protein) mitochondrial DNA nucleotide change; Homo, homozygous; Hetero, heterozygous. Diabetes, hypertension, hyperlipidaemia, and CAD were assessed by patient report both from NAION patients and from controls. Controls previously reported for mtDNA changes and for atherosclerotic and prothrombotic risk factors (see text). Odds ratio and p values compare prevalence of different risk factors in NAION patients to controls.
Comment
The lack of a significant association between NAION patients and controls in relation to thrombophilic genetics markers has been reported before,9 and the role of these factors remains uncertain. More surprising is the lack of a statistical association with atherosclerotic risk factors. For example, in our group of NAION patients, 68% were diabetic, but this figure did not differ significantly from the prevalence of more than 50% in well matched controls. This observation reflects the high, and rising, frequency of diabetes and other atherosclerotic risk factors in the developing world.
A few qualifications are appropriate. NAION patients were a relatively small group of Middle Eastern Arabs, and it is possible that a larger group would have yielded statistically significant results or that the observations reported here are specific to this genetically homogeneous population. Atherosclerotic risk factors were assessed by individual report from patients and controls, and the actual prevalence of these disorders may be different from that recognised. Finally, other risk factors, such as homocysteine levels, nocturnal hypotension, or environmental factors10 were not consistently investigated.
Nevertheless, the fact that the occurrence of NAION cannot be easily explained by the presence of prothrombotic or atherosclerotic risk factors shifts focus to the possibility that mitochondrial abnormalities may be important in the development of NAION. Based on these observations, testing for mitochondrial abnormalities may be warranted in NAION patients, especially the ones without a medical or family history of a thrombotic or vascular event.
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