We evaluated 27 patients who met age, funduscopic, visual field, and anterior segment criteria that define POAG in contrast to other causes of optic nerve disease and other types of glaucoma. All these patients had documentation of elevated IOP during follow-up. Their nerve fiber bundle visual field loss would be atypical for hereditary optic neuropathies, and these patients were unusually old for LHON and other hereditary optic neuropathies. They were in an appropriate age range for nonarteritic anterior ischemic optic neuropathy (NAION),
13 but a swollen optic disc was never observed, and characteristic glaucomatous optic nerve cupping was diagnosed by a glaucoma specialist (JM). No patient reported a maternal family history of visual loss.
No patient with POAG had a nucleotide change in
MYOC or
OPTN that was likely to be pathologic. All three nucleotide changes in these nuclear genes were present in control subjects and were likely to be polymorphisms in this population. The prevalence of
MYOC and
OPTN mutations in Arabic patients with POAG has not been evaluated before, but these results are not surprising, given the reported low prevalence of
MYOC and
OPTN mutations in open-angle glaucoma in other populations.
21
No patient with POAG had a primary LHON mutation. The presence of primary LHON mutations has been investigated previously in normal-tension glaucoma
12 but not in POAG. In addition, no patient had a secondary, intermediate, or provisional LHON mutation. Of course, LHON, which involves the subacute injury of the majority of optic nerve fibers,
9 often in a young adult male with a maternal family history of visual loss, is a very different optic neuropathy from POAG, which causes the gradual loss of optic nerve fiber bundles over a period of years in an older individual.
However, several other mitochondrial abnormalities were detected in patients with POAG. More than 60% (17/27) of patients with POAG had nonsynonymous mtDNA changes not considered LHON mutations and not found in control subjects, most of which were predicted to cause pathologic changes. Most (17/27) had relatively increased mtDNA content, which may suggest a compensatory response to oxidative stress.
22 In addition, almost 90% (24/27) of patients with POAG had reduced MRA, a measure of mitochondrial respiration.
11 The coincidence of changes in the mitochondrial genome and in mitochondrial respiration raises the argument that the optic neuropathy of POAG is broadly associated with mitochondrial abnormalities. In fact, mitochondrial disturbances were much more frequent than
MYOC or
OPTN mutations in this Arabic population.
The list of optic neuropathies currently associated with mitochondrial abnormalities includes LHON, certain patients with optic neuritis and multiple sclerosis, Wolfram’s syndrome, dominant optic atrophy (DOA),
9 and NAION.
13 The maternal inheritance pattern of LHON led to initial mtDNA investigations, but even primary LHON mutations are incompletely penetrant with erratic reporting of family history.
23 The penetrance of mtDNA changes reported herein may be somewhat less than primary LHON mutations with later presentation of symptoms and more interaction with other risk factors such as nuclear mitochondrial changes, anatomy of the anterior globe, IOP, race, and age, which is itself related in part to mitochondrial changes.
24 These factors may obscure maternal inheritance in our patients and other POAG populations.
25
The mechanisms by which mitochondrial abnormalities may place the optic nerve at risk remain uncertain.
9 The high concentration of mitochondria at the optic nerve head implies dependency on some aspect of mitochondrial function,
26 and mitochondrial disease in LHON, for example, has been linked to abnormalities in complex I activity.
23 In contrast, some patients with LHON do not have primary LHON mutations
20 27 or, at times, any mtDNA change at all.
28 Patients with Wolfram’s syndrome
29 or NAION
13 have widely distributed mtDNA changes, and patients with dominant optic atrophy have mutations of
OPA1 affecting a dynamin-related mitochondrial wall protein rather than a component of the electron chain.
30 One hypothesis suggests that progressive optic nerve damage in POAG is the result of optic nerve fiber apoptosis.
6 Mitochondria-induced apoptosis, which may be a mechanism of injury in experimental glaucoma
31 and other optic neuropathies,
32 may also be a pathologic factor in POAG.
mtDNA transition changes comprise almost 70% (23/33) of the primary, secondary, intermediate, and provisional LHON mutations reported currently in MitoMap.
14 Similarly, 75% (12/16) of nonsynonymous mtDNA changes found in a group of 19 NAION patients were transitions.
13 Unlike patients with LHON and NAION, patients with POAG had a high frequency of mtDNA transversion changes (25/34; 73.5%). The guanine base has the lowest oxidation potential of the four DNA nucleobases, making G:C→T:A or G:C→C:G transversion mutations frequent in the setting of oxidative stress.
33 The presence of mtDNA transversions in POAG may be evidence that alternative mitochondrial damage and repair mechanisms are involved in the generation of mtDNA mutations in patients with POAG as part of a response to oxidative stress early in development. Transversions, in turn, may contribute to the unique optic nerve injury in POAG.
Mitochondrial pathology was variable in this POAG group, but mitochondrial abnormalities of one type or another were present in every individual. It is intriguing that potentially pathogenic mtDNA sequence changes (particularly transversions), increased relative mtDNA content, and reduced MRA levels all imply oxidative stress. Oxidative stress has also been reported to induce human trabecular meshwork degenerative changes that favor increased intraocular pressure.
34 Therefore, oxidative stress early in development and/or throughout life could precipitate both metabolic and anatomic sequelae that increase the risk of optic nerve damage in POAG.
This report describes a relatively small number of patients with POAG from a restricted ethnic population. However, if these results are confirmed in other populations, knowledge that mtDNA mutations and/or mitochondrial dysfunction are present in POAG may lead to a better understanding of glaucoma pathophysiology.
35 Clever approaches are now available for studying mitochondrial disease in the eye, and a novel in vitro treatment has already been devised for the metabolic defect of at least one mtDNA mutation.
36 These tools might be applicable to investigating and treating POAG.
The authors thank George Spaeth for reviewing the manuscript and the staff of the Research Department at King Khaled Eye Specialist Hospital for their assistance.