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Review Article Mechanisms of Disease

Primary Open-Angle Glaucoma
Young H. Kwon, M.D., Ph.D., John H. Fingert, M.D., Ph.D., Markus H. Kuehn, Ph.D., and Wallace L.M. Alward, M.D. N Engl J Med 2009; 360:1113-1124March 12, 2009 Article Glaucoma is a chronic, degenerative optic neuropathy that can be distinguished from most other forms of acquired optic neuropathy by the characteristic appearance of the optic nerve. In glaucoma, the neuroretinal rim of the optic nerve becomes progressively thinner, thereby enlarging the optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause is the loss of retinal ganglion cell axons, along with supporting glia and vasculature. The remaining neuroretinal rim retains its normal pink color. In other optic neuropathies, the optic-nerve tissue loses its pink color and cupping does not develop. A rare exception is arteritic anterior ischemic optic neuropathy, in which cupping can occur.1 Patients with glaucoma typically lose peripheral vision and may lose all vision if not treated. Although glaucoma frequently occurs without an elevation of intraocular pressure, the disease is nonetheless classified according to anterior-segment variations that can elevate intraocular pressure. The anterior segment of the eye has its own circulatory system, which nourishes the crystalline lens and cornea, both of which lack a blood supply. Aqueous humor, produced by the ciliary body, circulates throughout the anterior chamber and drains through the trabecular meshwork in the iridocorneal angle, which is the angle formed by the iris and cornea (Figure 1Figure 1

Circulation of the Aqueous Humor.).2 Elevated intraocular pressure does not result from increased aqueous humor production but rather from reduced aqueous outflow. The glaucomas are classified by the appearance of the iridocorneal angle. There are open-angle, closed-angle, and developmental categories, which are further divided into primary and secondary types. Primary open-angle glaucoma can occur with or without elevated intraocular pressure; the latter is sometimes called normal-tension

glaucoma. Primary open-angle glaucoma includes both adult-onset disease (occurring after 40 years of age) and juvenile-onset disease (occurring between the ages of 3 and 40 years of age). Examples of secondary open-angle glaucomas include those associated with exfoliation or pigment-dispersion syndrome. Closed-angle glaucoma can be primary (e.g., pupillary block) or secondary (e.g., inflammatory or neovascular causes). Developmental forms of glaucoma include primary congenital glaucoma and glaucoma associated with syndromes (e.g., aniridia or the Axenfeld–Rieger syndrome). Primary open-angle glaucoma, the predominant form of glaucoma in Western countries, probably comprises several clinically indistinguishable diseases. In this review, we discuss primary open-angle glaucoma, in which the iridocorneal angle is open (unobstructed) and normal in appearance but aqueous outflow is diminished. We discuss the clinical features of primary open-angle glaucoma and mechanisms of elevated intraocular pressure and optic-nerve damage. To illustrate the mechanisms of elevated intraocular pressure, we focus on mutations in the myocilin (MYOC) gene. Approximately 4% of cases of adult-onset primary open-angle glaucoma and more than 10% of juvenile-onset cases are associated with MYOC mutations.3,4 These adult-onset cases feature an elevated intraocular pressure with resultant optic-nerve damage and visual loss, and they are clinically indistinguishable from cases of primary open-angle glaucoma in patients without MYOC mutations.5 To address the mechanisms of optic-nerve damage, we broaden the discussion to include primary open-angle glaucoma with elevated intraocular pressure, with or without MYOC mutations. Primary open-angle glaucoma is the second leading cause of blindness in the United States and the leading cause of blindness among black Americans.6 There is good evidence that black race, older age, elevated intraocular pressure, family history of primary open-angle glaucoma, myopia, and low diastolic perfusion pressure are risk

factors for primary open-angle glaucoma.6,7, (Table 1Table 1 Major Risk Factors Associated with Primary Open-Angle Glaucoma.). Among patients with an elevated intraocular pressure, a relatively thin central cornea is another major risk factor for the disease.14 Evidence for other risk factors (diabetes mellitus, elevated systolic blood pressure, and migraine, among others) is less consistent. 15 The main clinical features of primary open-angle glaucoma are an open iridocorneal angle and cupping of the optic-nerve head (or optic disk), with corresponding loss of visual field. Elevated intraocular pressure is not part of the clinical definition because primary open-angle glaucoma can occur when intraocular pressure is normal (typically 10 to 21 mm Hg). Nevertheless, elevated intraocular pressure is an important risk factor and is also considered to be a causative factor in glaucoma16; currently, it is the only modifiable causative factor. Many randomized clinical trials have shown that reducing intraocular pressure slows the onset and progression of glaucoma.17,18 Therefore, all current treatments of primary open-angle glaucoma are aimed at reducing intraocular pressure by medical or surgical means.19,20 The Case

which is in the GLC1E locus.32 but less is known about the role of WDR36.22 Subsequent linkage studies of other glaucoma pedigrees have mapped the chromosomal locations of 13 additional glaucoma-related genes (GLC1B through GLC1N).Presentation Case Presentation: Primary Open-Angle Glaucoma recounts a typical presentation of primary open-angle glaucoma (see Figure 2Figure 2 Optic Disks and Corresponding Visual Fields in a Patient with Primary Open-Angle Glaucoma and a MYOC Mutation.36 A central clinical feature of myocilin-associated glaucoma is elevated intraocular pressure. and some mutations cause higher intraocular pressure than others. including OPTN (encoding optineurin) and WDR36 (encoding a T-cell activation WD repeat-containing protein).34 Some MYOC mutations have been detected in a sufficient number of patients to allow identification of mutation-specific glaucoma phenotypes. which encodes the protein myocilin. and analyses of genetic markers in such pedigrees have mapped a glaucoma-related gene to a region of chromosome 1q designated GLC1A.27-31 Mutations in MYOC are among the most common causes of inherited eye disease with a known molecular basis. A variety of MYOC mutations have been detected in 3 to 5% of patients with adult-onset primary open-angle glaucoma in cohorts around the world. except that in the juvenile-onset form the intraocular pressure is often extremely high (frequently >40 mm Hg).35 In patients . Myocilin is produced in many tissues.3. Mutations in other genes. Mutations associated with juvenile-onset primary open-angle glaucoma lead to the greatest elevations in intraocular pressure — often more than 40 mm Hg. including age at onset and maximum intraocular pressure.23 The relevant gene at the GLC1A locus is MYOC (Online Mendelian Inheritance in Man number.25 the two ocular tissues that regulate intraocular pressure. adult-onset form of primary open-angle glaucoma has been explored by testing large cohorts of patients for mutations. It has the same clinical features as the adult-onset condition. Mutations associated with adult-onset primary open-angle glaucoma typically cause maximum pressures of 25 to 40 mm Hg.31. which is in the GLC1G locus.21 Large pedigrees with autosomal-dominant inheritance of juvenile-onset primary open-angle glaucoma have been reported. and see video showing an optic nerve examination). Juvenile-onset primary open-angle glaucoma is rare.26 In several studies of pedigrees. including the ciliary body24 and trabecular meshwork. OPTN. have also been studied as potential causes of primary open-angle glaucoma.27 The role of MYOC in the pathogenesis of the common. has been associated with a small fraction of cases of low-pressure glaucoma. 601652).35. mutations in MYOC were always coinherited with juvenile-onset primary open-angle glaucoma.33 These genes have recently been reviewed elsewhere. for examination results. a strong indication that MYOC is the glaucoma gene in the GLC1A locus.

e. 48 Glaucoma-associated mutations also reduce the secretion of myocilin in vitro and in vivo. MYOC mutations greatly reduce the quantity of myocilin that is secreted into the aqueous humor. MYOC mutations may prevent the secretion of myocilin by exposing a cryptic domain that directs proteins to peroxisomes. whereas benign sequence polymorphisms have no such effect.25. These effects suggest that MYOC mutations encode a protein that causes microscopic abnormalities in the structures of an otherwise normal-appearing iridocorneal angle..31 Myocilin has been detected in the trabecular meshwork.40-42 Recombinant myocilin protein. The N-terminal of myocilin has a signal sequence that targets proteins for secretion. MYOC mutations associated with glaucoma do alter the properties of the protein — disease-associated mutations reduce the solubility of myocilin in a detergent.43 MYOC mutations do not appear to cause glaucoma as a result of haploinsufficiency or overexpression.37 Wild-type myocilin protein is secreted. Secretion of myocilin is dramatically reduced in trabecular-meshwork cells cultured from patients with glaucoma-associated MYOC mutations. Indeed. glaucoma does not develop in mice with overexpression of myocilin or with deficient myocilin production. Analysis of its amino acid sequence has revealed functional domains. high intraocular pressure appears to be important not only for the onset of glaucoma but also for progression of the disease.25.with MYOC mutations. indicating that myocilin is secreted from trabecular-meshwork cells in vitro and that in vivo it is secreted from ocular tissues that may include the trabecular meshwork or ciliary body. including a leucine zipper domain for protein–protein interactions and two domains that can influence protein localization. which suggests that the peroxisomal targeting sequence is not functional under normal circumstances. It has also been found secreted in the growth medium of primary cultures of human trabecular-meshwork cells and in human and mouse aqueous humor. Arg46Stop)45 do not cause glaucoma.38. Similarly.46. which is the principal structure of the eye that regulates intraocular pressure.). and myocilin in medium from cultured cells can self-associate and form multimers. a family of secreted proteins with unknown function. myocilin in aqueous humor. especially the trabecular meshwork. whereas the last three amino acids at the C-terminal of myocilin encode a sequence that directs intracellular proteins to peroxisomes. The function of myocilin is unknown.40 Similarly. The vast majority of glaucoma-associated MYOC mutations lie within a large segment of myocilin protein that is homologous to olfactomedin proteins. These results suggest that disease-causing mutations alter the myocilin protein in such a way that it disrupts the regulation of intraocular pressure. Deficiencies in myocilin production resulting from a hemizygous deletion44 or a presumed homozygous null mutation (i. and there is evidence that mutant myocilin may be retained within the intracellular space by means of an abnormal association with .40 supporting the idea that failure to secrete myocilin is a central feature in the pathogenesis of myocilin-associated glaucoma (Figure 3Figure 3 Proposed Pathways for Normal Secretion of Myocilin into the Aqueous Humor and for Secretion Reduced by a MYOC Mutation.

these animal models will facilitate studies of the effects of MYOC mutations on the health and numbers of trabecular-meshwork cells and the organization of the extracellular structure of the trabecular meshwork. We limit the discussion to recent literature.53 Mutant myocilin that accumulates in the intracellular space may be toxic to trabecular-meshwork cells.57. The optic-nerve head consists of axons projected from retinal ganglion cells. The finding that aqueous humor outflow is reduced in patients with MYOC mutations supports this hypothesis. A reduction in cellularity and alterations in the architecture of the trabecular meshwork have been observed in glaucoma.55.54 The development of animal models of myocilin-associated glaucoma50. and oligodendrocytes (the oligodendrocytes are present only in the postlaminar region and are important in postlaminar axon myelination). and subcellular levels.59-61 Elevated intraocular pressure has direct effects on retinal ganglion cells. initiating a cascade of events that begins with loss of function in these cells.proteins of the peroxisome-targeting system.56 provides new tools for exploring the effects of mutations in the myocilin gene on the structure and function of the outflow pathway at the tissue. which damages the outflow pathway and results in elevated intraocular pressure. astrocytes.51 Endothelial cells of the trabecular meshwork maintain its structure and facilitate the outflow of aqueous humor from the eye by remodeling this porous tissue and preventing debris from occluding the outflow pathway.). a collagenous structure with sievelike openings (Figure 4AFigure 4 The OpticNerve Head and Proposed Events Leading to Retinal Ganglion-Cell Death in Glaucoma.58 We outline several key mechanisms of optic-nerve damage that are caused by elevated intraocular pressure. Injury or death of trabecular-meshwork cells has been implicated in the pathogenesis of open-angle glaucoma. In particular. cellular.50 Regardless of the mechanism of retention. The optic-nerve head also contains retinal vasculature (the central retinal artery and vein) and such glial elements as microglia.49 Other studies in mice have shown that mutations in the murine myocilin gene (Myoc) can inhibit secretion of myocilin and cause some signs of glaucoma without a cryptic targeting domain. The lamina cribrosa separates unmyelinated prelaminar retinal ganglioncell axons from myelinated postlaminar retinal ganglion-cell axons. It is generally believed that elevated intraocular pressure — regardless of its cause — triggers a common set of cellular events. thereby elevating intraocular pressure and eventually damaging the optic nerve. more comprehensive reviews of the subject can be found elsewhere. decreased secretion and increased accumulation of intracellular myocilin appear to be initial steps in the pathogenesis of myocilinassociated glaucoma. Axonal transport decreases in the presence of elevated intraocular pressure.62 The reduced retrograde axoplasmic flow can stress retinal ganglion cells and cause their death from .51. which exit the eye through the lamina cribrosa.52 and these changes may increase resistance to aqueous outflow. although damage that is independent of elevated intraocular pressure may also occur in primary open-angle glaucoma.

87 In a mouse model of glaucoma. and these changes can have biomechanical effects on the opticnerve head that in turn increase stress on retinal ganglion-cell axons. including increased synthesis of collagen IV.87 These morphologic findings are accompanied by changes in the composition of the extracellular matrix of the opticnerve head. even in the absence of elevated intraocular pressure. The biomechanical consequences of these changes are believed to strain retinal ganglion-cell axons.74.94.95 Clinical observations have indicated that the optic-nerve head. the lamina cribrosa bows posteriorly (Figure 4C). which further compromises their function. make the cup larger and deeper.81 Glial cells in the optic-nerve head (microglia and astrocytes) become activated in response to the elevated intraocular pressure in glaucoma82-85 (Figure 4B).83.91 Cupping of the optic-nerve head results from the loss of prelaminar tissue and posterior deformation of the lamina cribrosa. These changes in the lamina cribrosa.88. activated glial cells released tumor necrosis factor α (TNF-α).99 In these mice. and this accumulation causes cellular stress and malfunction. proteoglycans. and presumably also in human glaucoma.76-79 and increased expression of markers of hypoxia and glial activation. Activated astrocytes synthesize molecules that lead to degradation and remodeling of the extracellular matrix. is the initial site of glaucomatous damage.65. The presence of TNF-α in human glaucomatous retina90 and optic-nerve head91 has been detected by immunohistochemical analysis. These results suggest that TNF-α can be a mediator of damage of retinal ganglion-cell axons when intraocular pressure is elevated. and soon thereafter.92 This change is accompanied by microglial proliferation.69-73 The use of microarray technology in animal models has shown that changes in the geneexpression profile of the retina occur rapidly in response to elevated intraocular pressure.86.96 In animal models. this evidence suggests that glial activation and TNF-α are important mediators of damage to retinal ganglion-cell axons.75 These changes include decreased expression of many genes specific to retinal ganglion cells74.86. In the DBA2/J mouse strain.93 Subsequently. the . adhesion molecules.87. and antioxidant treatments have some benefit in animal models.88 Deletion of the genes encoding TNF-α or its receptor increased the survival of retinal ganglion cells in this model.89 Intravitreal injection of TNF-α causes loss of retinal ganglion-cell axons and subsequently loss of entire cells.68 In glaucoma. a proinflammatory cytokine. combined with the eventual loss of prelaminar tissue.62-64 If blood perfusion at the optic-nerve head is persistently reduced. even though the soma of the retinal ganglion cells appears normal. and matrix metalloproteinases and a loss of gap-junction communication that accompanies astrocyte activation.deprivation of neurotrophic factors such as brain-derived neurotrophic factor. Three-dimensional histomorphometric studies of primates with experimentally induced glaucoma raised the possibility that one of the early changes in the structure of the optic-nerve head in glaucoma is the thickening — rather than thinning — of prelaminar tissue. axonal shrinkage and decreased retrograde transport occur. proteins and lipids with oxidative modifications accumulate in the retina and optic-nerve head. and more specifically the lamina cribrosa. damage to retinal ganglion-cell axons precedes the death of the cells97. elevated intraocular pressure develops spontaneously at 7 to 9 months of age. Collectively.88.90.98 (Figure 4B and 4C).80.65-67 tissue hypoxia can induce the formation and accumulation of reactive oxygen species in the retina.

97 Thus. Most. and these processes may further contribute to the degeneration of retinal ganglion cells. glial expression of major-histocompatibility-complex (MHC) class II molecules108 and synthesis of components of the complement cascade109. if not all. a process distinct from the adaptive immune response and more akin to a reaction of the innate immune system. perhaps involving excessive synthesis of extracellular matrix material83. Altermatt Professorship. The most important risk factor for glaucoma is elevated intraocular pressure. Hadley Glaucoma Research Fund and Research to Prevent Blindness. the degradation of the retinal ganglion-cell axon and soma may involve separate mechanisms. of the loss of retinal ganglion cells in the glaucomatous retina occurs through apoptosis. glial cells phagocytose cellular debris and initiate a scar response after retinal ganglion-cell death.110 occur as retinal ganglion-cell death continues. we provide treatment for the only known risk factor that can be modified.102. the ganglion-cell axons that make up the optic nerve are damaged by a variety of factors. elevated intraocular pressure.103 Axonal damage and chronic stress result in the death of retinal ganglion cells.104. Because the optic-nerve damage in glaucoma is not yet amenable to direct treatment. . although there is indirect evidence of inflammatory processes. a major cause of blindness.86. and Dr.105 Inhibition of apoptosis by deletion of the Bax gene in a mouse model of glaucoma almost completely rescues the retinal ganglion-cell soma. As more is understood about the molecular biology of the trabecular meshwork and optic nerve in health and disease.81 Instead. damage to retinal ganglion-cell axons occurs despite the absence of the collagenous lamina cribrosa plates typically found in primates. Retinal ganglion-cell death is not accompanied by prominent infiltration of mononuclear cells. suggesting that damage to the axons occurs in an area that corresponds to the lamina cribrosa in primates. Inflammation-like glial activity is frequently observed in degenerative disorders of the central nervous system and is referred to as neuroinflammation.97 However.77. Blodi Chair.100 By means of noninvasive direct imaging of apoptotic cell death.retinal ganglion-cell axons proximal to the point of myelination survive. In glaucoma. Coupled with thinning and further posterior bowing of the lamina cribrosa. and Leonard A.77. our ability to treat glaucoma will likely improve.107 In glaucoma.106 it has been possible to observe progressive loss of retinal ganglion-cell axons and cell bodies in a rat model of glaucoma. Dr. but axons are not preserved.100 In DBA/2 mice. as seen clinically in advanced glaucoma (Figure 4D). deep cup.101 This finding suggests that a cellmediated mechanism underlies the damage. Supported in part by grants from the Marlene S. Alward received support from the Frederick C. as indicated by the presence of autoantibodies against retinal antigens in patients with glaucoma.95 or elevation of intra-axonal calcium levels resulting from overexpression of ephrin-B2 (a receptor tyrosine kinase in glioma cells). retinal ganglion cells survive for only about 1 to 2 months after axonal degeneration. Kwon received support from the Clifford M. and Ruth M. apoptotic loss of the retinal ganglion cells results in a large.94. only some of which are understood.

4 Aldred MA. Low prevalence of MYOC mutations in UK primary open-angle glaucoma patients limits the utility of genetic testing. 1 Hayreh SS. Liebmann JM. Address reprint requests to Dr.108:1586-1594 CrossRef | Web of Science | Medline 2. Zimmerman MB. Biomedicine: a new angle on ocular development. and Dr. Science 2003. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. A case-control comparison of the clinical characteristics of glaucoma and ocular hypertensive patients with and without the myocilin Gln368Stop mutation. Optic disc morphology after arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 2002. University of Iowa.. et al. for her assistance with the preparation of the manuscript.Ph. Hum Genet 2004. We thank Patricia Duffel. et al. Hill A. Kwon at University of Iowa Health Care. Fingert reports receiving grant support from Alcon Research and holding several unlicensed patents related to gene discovery in glaucoma. From the Department of Ophthalmology and Visual Sciences. Alward reports holding an unlicensed patent for the diagnosis of MYOC mutations. Iowa City.. Iowa City. 200 Hawkins Dr.299:1527-1528 CrossRef | Web of Science | Medline 3. 5 Graul TA.8:899-905 CrossRef | Web of Science | Medline 4.115:428-431 CrossRef | Web of Science | Medline 5.134:884-890 CrossRef | Web of Science | Medline . References 1. R.. 3 Fingert JH. M.Dr. et al. IA 52242. Hum Mol Genet 1999. 2 Alward WL. Jonas JB. Ophthalmology 2001. Baumber L. Heon E. No other potential conflict of interest relevant to this article was reported.A. Kwon YH.

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