Chapter 212 – Mechanisms of Glaucoma
JANEY L. WIGGS
About 60 types of glaucoma are known. Classically, the glaucomas have been characterized by:
• Abnormality of the anterior portion of the eye that results in increased intraocular pressure (IOP);
• Loss of retinal ganglion cells in a distribution that suggests the injury occurred at the optic nerve head, often accompanied by a posterior bowing of the lamina cribrosa of the nerve head; and
• Corresponding nerve fiber layer pattern of visual field loss.
More recently, the diagnostic criteria of the glaucomas have been in a state of flux. The current preferred practice pattern for primary open-angle glaucoma (POAG) defines POAG as an optic neuropathy for which the level of IOP is merely a risk factor. Conversely, clinicians frequently refer to most other conditions in which the IOP is elevated as “glaucoma” (e.g., primary congenital glaucoma, primary angle-closure glaucoma, pigmentary glaucoma) even when, early in the condition, no optic nerve injury has occurred. What has been preserved in this era of unclear nomenclature is that the term glaucoma is used to describe patients who can be differentiated from those who are healthy by the presence of characteristic optic nerve damage and/or condition-associated findings (e.g., buphthalmos in congenital glaucoma, appositional angle closure in primary angle-closure glaucoma, pigment dispersion in pigmentary glaucoma) rather than simply by the level of IOP.
Here we first give an overview of the fairly well-characterized mechanisms that result in elevation of IOP and then discuss the rather poorly understood mechanisms of optic nerve injury in the glaucomas.
MECHANISMS THAT UNDERLIE ELEVATED IOP IN THE GLAUCOMAS
IOP is generated from the production of aqueous humor by the nonpigmented epithelium of the ciliary body. This tissue actively transports ions and nutrients, obtained from the vascular circulation of the ciliary body, into the posterior chamber. An osmotic gradient, created by the active transport, drags in water. In addition, a portion of the aqueous humor is derived by ultrafiltration of interstitial fluid, which is driven in by the pressure gradient between the ciliary body arterioles and the posterior chamber. The resultant clear, colorless fluid flows centripetally over the equator and anterior surface of the lens, forward through the pupil, into the anterior chamber, and centrifugally to and through the trabecular meshwork into Schlemm’s canal, circumferentially in the canal to about 70 collector channels, and through the limbal sclera in those channels to enter the aqueous veins and general circulation.
The aqueous humor nourishes the tissues in the visual axis that have no blood supply, carries away their wastes, maintains a reducing atmosphere (low oxygen tension, high concentrations of glutathione and ascorbate) that prevents oxidative cross-linking of sulfhydryl groups of lens protein, carries growth factors, and inflates the eye.
Although an elevation in IOP could be produced logically by either an excess of aqueous production or mechanisms that impede
Figure 212-1 Potential sites of increased resistance to aqueous flow.
aqueous egress, no condition of excess aqueous production has been observed. However, every major category of pathology is represented in one form of glaucoma or another. Developmental defects, hamartomas, hereditary biochemical defects, infections, inflammations, metaplasias and neoplasms, physical and chemical trauma, ischemic vascular conditions, and endocrine abnormalities have all been implicated.
In reaching a diagnosis and treatment plan for any type of glaucoma, it is useful to identify the site and nature of the impediment to aqueous flow ( Fig. 212-1 ). The site may be in the posterior chamber. For example, when the lens moves forward in the not fully inflated eye after filtration surgery in an angle-closure glaucoma patient and the ciliary body forms an “O-ring” against the lens, aqueous is forced posteriorly into the vitreous cavity. This results in the creation of a pressure gradient behind the lens that pushes the lens-iris diaphragm forward, covers the trabecular meshwork, and markedly elevates the IOP. This condition is known variously as ciliary block, aqueous misdirection, or malignant glaucoma (see Chapter 229 ).
The site may be at the pupil. For example, in the shorter than average eye of a hyperopic person in middle to old age, the continually growing lens may be sufficiently anterior to impede the flow of aqueous through the pupil and produce a pupillary block. This results in the development of a pressure gradient across the iris that causes the iris to bow forward, mechanically cover the trabecular meshwork, and elevate IOP. This condition is known as primary angle-closure glaucoma (see Chapter 222 ).
Aqueous flow through the pupil may also be blocked by the formation of adhesions of the iris to lens (posterior synechiae) in uveitis (see Chapter 226 ) or by a blood clot formed after trauma [eight-ball hyphema (see Chapter 227 )]. The site may be “pretrabecular,” as occurs when the trabecular meshwork becomes covered by a fibrovascular meshwork [in neovascular
glaucoma (see Chapter 225 ) and in Fuchs’ heterochromic iridocyclitis] or by an ingrowth of cells [fibroblasts in fibrous ingrowth, conjunctival epithelium in epithelial downgrowth, transformed corneal endothelial cells in the iridocorneal endothelial syndrome (see Chapter 230 ), or normal corneal endothelial cells altered after trauma].
The obstruction may be at the level of the trabecular meshwork, because of:
• Abnormalities in the extracellular matrix [as may be the case in POAG   (see Chapter 220 ), juvenile open-angle glaucoma, and corticosteroid-induced glaucoma (see Chapter 226 )];
• Injury to the trabecular cells by toxic substances (siderosis or chalcosis);
• Meshwork obstruction by cellular debris (white cells or macrophages in inflammatory conditions, degenerated, hemolyzed red blood cells in ghost-cell glaucoma, tumor cells in iris melanoma), by pigment liberated from the iris pigment epithelium [pseudoexfoliation (see Chapter 223 ) and pigmentary (see Chapter 224 ) glaucomas], by melanomas, by lens protein aggregates (released by an intumescent cataract), by vitreous, or by surgically placed viscoelastic substances.
The impediment to aqueous flow may be post-trabecular, as occurs when alkali burns cause loss of function of the collector channels and aqueous veins, or in vascular conditions that elevate episcleral venous pressure (carotid-cavernous or arteriovenous fistula, cavernous sinus thrombosis, Sturge-Weber syndrome) or orbital pressure (thyroid exophthalmos).
In addition, numerous developmental abnormalities are associated with glaucoma, which include:
• Primary congenital glaucoma (see Chapter 219 ), in which movement of the iris and ciliary body posteriorly relative to the trabecular meshwork during development is arrested such that the meshwork is covered by those tissues ;
• Various other forms of chamber angle maldevelopment (Peters’ syndrome, Rieger’s syndrome, and aniridia); and
• Numerous forms of maldevelopment of the lens and/or zonule (homocystinuria, Marfan syndrome, microspherophakia) that result in secondary pupillary block later in life (see Chapter 230 ).
MECHANISMS OF OPTICNERVE DAMAGE IN GLAUCOMA
Intraocular Pressure as a Risk Factor for Glaucoma Damage
Good evidence exists from epidemiology (see Chapter 210 ) and from treatment studies that the pathophysiology of glaucoma is dependent upon either an elevated IOP [>21?mmHg (>2.8?kPa)] or, in some cases of glaucoma that present initially with pressures in the upper portion of the normal pressure range (normal-tension glaucoma), an abnormal sensitivity to the level of IOP. That the pressure matters in even the latter cases is indicated by the observation that patients who have normal-tension glaucoma and who happen to have a consistent asymmetry in IOP also suffer greater damage in the eye that has the higher pressure in 85% of cases.
In epidemiological investigations, such as have been performed in Bedford in the United Kingdom and in Baltimore, about one half to two thirds of the glaucoma patients discovered (and thus not already receiving glaucoma treatment) had an elevated IOP at screening and most of the rest had a pressure in the upper normal [16–20?mmHg (2.1–2.7?kPa)] range. In the Baltimore Eye Survey, 13% of those who had newly diagnosed glaucoma versus 50% of the rest of the population initially had an IOP in the lower normal range. From these observations it may be estimated that, at a maximum, no more than 26% (13% in the lower half of the IOP range and an equal percentage in the upper half) of glaucoma patients could have suffered their damage on a pressure-independent basis.
On the other hand, a moderate elevation of IOP alone is insufficient to cause optic nerve damage in the majority of those
TABLE 212-1 — RISK OF PROGRESSIVE VISUAL FIELD LOSS OVER 5–18 YEARS AS A FUNCTION OF INTRAOCULAR PRESSURE
Intraocular Pressure (mmHg)
Number of Eyes
Progression of Visual Field Loss (%)
10–20, mostly <16
10–20, mostly >15
TABLE 212-2 — RISK OF PROGRESSIVE VISUAL FIELD LOSS OVER 3.5–5 YEARS AS A FUNCTION OF MEAN INTRAOCULAR PRESSURE OF GROUP
Mean Intraocular Pressure (mmHg)
Number of Eyes
Lamping et al. 
Roth et al.,  corticosteroid
Kidd and O’Connor
Maul et al. 
Greve and Dake
Roth et al.,  no corticosteroid
affected. About four fifths of those who have elevated IOP do not have detectable damage to the optic nerve tissue or visual field. A receiver-operator function analysis in which the distribution of IOPs of those with optic nerve damage was compared with that of those without suggested that only about one third of the difference in distributions is accounted for by pressure alone. Yet within the group that suffered damage, IOP surely matters both initially and in the subsequent clinical course.
Treatment studies suggest that a dose-response relationship exists between IOP and the risk of progressive visual field loss in glaucoma patients. Odberg  reported on a 5- to 18-year follow-up of a group of his patients who had advanced glaucoma damage and who underwent medical and/or surgical therapy ( Table 212-1 ).
Others have reported long-term outcomes after filtration surgery, and a comparison of the results at 3.5–5 years also indicates that for groups of patients a dose-response relationship exists between the mean IOP and the risk of progressive field loss ( Table 212-2 ).   However, because within these studies and in the Baltimore Eye Survey the risk of damage rises in a steeper than linear fashion as a function of IOP, the values in Table 212-2 for the risk of progressive field loss as a function of mean IOP of groups probably exceed the risk for an individual at any level of IOP above the population mean. For example, Greve and Dake reported that 29% of 31 eyes that had IOP <22?mmHg (<2.9?kPa) showed progressive field loss versus 55% of 11 eyes that had higher IOP.
The report of Roth et al. is instructive, particularly as it compared patients randomized to receive or not to receive topical corticosteroid in the postoperative period and demonstrated better filtration blebs and pressure control, as well as a correspondingly better visual field prognosis, for patients who received corticosteroid.
TABLE 212-3 — PRIMARY FILTRATION SURGERY WITH MITOMYCIN
Postoperative Time (years)
Mean Intraocular Pressure (mmHg)
Corrected Pattern Standard Deviation
Number of Eyes
-15.0 ± 7.4
8.0 ± 3.3
10.8 ± 3.6(se)
-13.7 ± 9.1
8.1 ± 3.6
11.1 ± 4.0
-13.9 ± 6.3
8.1 ± 3.6
10.9 ± 4.0
-15.1 ± 7.2
6.9 ± 2.7
TABLE 212-4 — COMBINED PHACOEMULSIFICATION AND FILTRATION SURGERY
Postoperative Time (years)
Mean Intraocular Pressure (mmHg)
Corrected Pattern Standard Deviation
Number of Eyes
The low end of the dose-response relationship between IOP and risk of progressive field loss was explored in patients who received mitomycin in primary and combined filtration procedures.  The results showed that the patients as a group maintained a mean IOP of about 11?mmHg (1.5?kPa) and demonstrated no net deterioration of either the mean deviation or corrected pattern standard deviation out to 3 years ( Tables 212-3 and 212-4 ). With the limited number of visual fields so far performed for each patients (done annually), it is difficult to determine whether the stability of mean values indicates that virtually no one worsens at these IOPs or that some worsen and an equivalent number improve. However, comparison of these published results indicates that it is beneficial to bring the mean IOP to a low normal level provided that the benefit with regard to field stabilization is not offset by the side effects of more aggressive therapy. An analysis of individual cases is to be carried out at 5 years to determine visual field and visual acuity outcomes.
It thus appears that the majority of patients who have moderate to severe visual field loss suffer additional loss at IOPs in the range 17–22?mmHg (2.3–2.9?kPa), that at IOPs in the midnormal range 6–26% of patients suffer such loss, and that in the low normal range the risk is even less. Thus, although IOP alone may account for only 35% of the separation between glaucomatous and undamaged populations, most glaucoma patients appear to have an abnormal sensitivity to IOP that may be offset if the IOP is lowered to the midnormal or low normal range, and perhaps 90% or more may benefit from a sufficiently low IOP.
Location of Optic Nerve Damage in Glaucoma
How and where do the IOP and other factors that modify susceptibility to IOP (or independently damage the optic nerve) act? One major clue is given by the pattern of damage observed. The tissue loss and pattern of visual field defects observed correspond to damage that occurs at the optic nerve head and not to retinal or retrobulbar sites of damage. This suggests that any damage does not result from processes that directly injure the ganglion cell bodies and that the effect is on the ganglion cell axons at the point where they pass through the optic nerve head and lamina cribrosa. Elevated IOP may interfere with antegrade and/or retrograde axoplasmic transport in that location by either compromising the local blood supply or mechanically pinching the axons. Blockade of axoplasmic transport has been demonstrated by Radius and Anderson in an animal model of glaucoma. Such a blockade of axoplasmic transport in other nerves in animal models blocks the return of trophic factors to the cell body and leads to death by a mechanism similar to apoptosis.
VASCULAR AND MECHANICALTHEORIES OF DAMAGE
Quigley and Addicks speculated that pressure-induced backward bowing of the lamina cribrosa may result in misalignment of the holes in the laminar sheets through which the ganglion cell axons pass; the axons are pinched and axoplasmic flow is blocked. In favor of this idea, the authors suggested that their observation of larger diameter pores in the upper and lower poles of the disc may correspond to weaker support for the axons that pass through these areas; indeed, the upper and lower poles of the disc are the most common sites of nerve fiber loss. Counter to this proposal is the observation that elderly persons, in whom collagen cross-linking strengthens the laminar sheets, are far more susceptible than younger persons to optic nerve damage when the IOP is elevated.
Anderson proposed that elevated IOP interferes with the vascular supply in the optic nerve region but only when the IOP is quite high or when other factors interfere with local autoregulation. Buus and Anderson observed that patients who have normal-tension glaucoma are four times as likely as age-matched controls to have retinal pigment epithelial and/or choroidal atrophy in a crescentic shape at the disc margin; patients who have POAG are twice as likely as controls, and ocular hypertensives are only half as likely as controls, to have such defects. Such crescents represent enlarged versions of the usual gap in the blood-ocular barrier present at the optic nerve head, where the optic nerve passes by the edge of the choroid and could allow vasoactive substances from the blood stream to reach the receptors for norepinephrine and angiotensin that are present on the outside surface of capillaries of the optic nerve head. Anderson and coworkers have shown that the vasoactive substance angiotensin can augment axoplasmic transport blockade in the optic nerve head in an animal mode and that angiotensin administered into the vitreous may cause vasoconstriction of retinal blood vessels and in culture can interfere in carbon dioxide regulation of pericyte contractility.
THE POTENTIAL FOR NEUROPROTECTION
If vasoactive substances interfere with optic nerve head autoregulation in response to elevated IOP and this results in reduced blood flow, the potential exists for vasodilating substances, such as calcium channel blocking agents selective for the central nervous system, to reduce the susceptibility of the optic nerve to pressure. Initial reports claim that calcium channel blockers may be helpful, but further work is needed to define the risk-benefit ratio of such treatment in long-term clinical trials.
Some agents used to treat glaucoma reduce penumbral damage to the optic nerve in a mouse model of a crush injury. The relevance of these observations to any actual clinical benefit of glaucoma treatment is entirely speculative and needs to be supported by long-term clinical trials of agents that either have or lack such activity.
Finally, the level of glutamate in the vitreous may be elevated in glaucoma patients compared with cataract patients, and the placement of glutamate in the vitreous may create a model of optic nerve damage in an animal. Glutamate is released by injured neurons of the central nervous system in stroke, and glutamate blockers help limit penumbral nerve damage in an animal model of stroke. However, the proposed connection of
glutamate and glaucoma damage requires confirmation. Against the likelihood of such a mechanism is that the pattern of injury of the optic nerve is not based on focal damage in the retina, as would be expected if dying ganglion cell bodies released glutamate and damaged their neighbor cells.
GENETICS OF GLAUCOMA
The past decade has produced a wealth of information about the molecular pathogenesis of many human disorders. The success of the molecular genetic approach results from the central dogma of molecular biology—a DNA sequence found in genes is transcribed into an RNA sequence that directs the synthesis of specific protein molecules that perform unique functions for maintenance, growth, and replication of an individual cell. Proteins that do not function normally because of an error in the DNA sequence can result in sick cells and eventually human disease. Identification of errors in the DNA sequence and evaluation of their impact on the function of the protein product provide important information about the mechanism of a disease. With the advent of techniques that enable precise evaluation of the DNA sequence of genes, to establish the molecular causes of human disease has become a practical reality for many disorders.
An aspect of the molecular genetic approach that has been particularly important in glaucoma research is that only DNA (usually obtained from a simple peripheral blood sample) from an individual affected by the disease is required for the analysis just outlined. Because genetic analysis investigates the disease process at the DNA level, the actual diseased tissue, or even knowledge about how the disease affects a particular tissue, is not necessary. The collection of sufficient quantities of trabecular meshwork to perform biochemical and cellular studies is a difficult problem. Moreover, tissue specimens taken from affected patients who undergo glaucoma surgery are exposed to numerous medical and laser treatments that may obscure the initial abnormalities responsible for the disease. The study of genes responsible for glaucoma may identify the role of specific protein products in the development of the disease without the need for direct access to the diseased tissue.
For many years, a family history of glaucoma has been recognized as an important risk factor for this disease.    Only recently, however, has glaucoma been accepted as an inherited disorder. Many forms of glaucoma are now recognized to be inherited as mendelian dominant or recessive traits, including juvenile open-angle glaucoma,            congenital glaucoma,   developmental glaucomas (Rieger’s syndrome and aniridia),   and pigmentary glaucoma.      Other types of glaucoma, such as adult POAG, have been shown to have a heritable susceptibility. Twelve loci for mendelian forms of glaucoma and seven susceptibility loci for adult-onset POAG have been mapped in the human genome ( Table 212-5 ).  Five genes responsible for different forms of glaucoma have been identified. The study of these and additional genes responsible for glaucoma will lead to important new advances in our understanding of this blinding condition in the years to come.
A reduction in outflow of aqueous humor through the trabecular meshwork is a major cause of the increase in IOP in open-angle glaucoma. Enzymes, structural proteins, and proteins involved in the embryogenesis and development of the eye may be important to the normal physiology of the trabecular meshwork, and defects in the genes that code for these proteins may play a role in the genetic predisposition to the disease. Once genes responsible for glaucoma have been identified, the normal biological function of the protein products of these genes must be established. Investigations to address the effects of these proteins on the normal biochemical and cellular processes of the trabecular meshwork and other components of the aqueous outflow pathways will provide important new information about the pathophysiology of this disease.
TABLE 212-5 — GENES RESPONSIBLE FOR DIFFERENT FORMS OF GLAUCOMA
Primary congenital glaucoma
Primary congenital glaucoma
Juvenile open-angle glaucoma
Primary open angle adult
Pigment dispersion syndrome
Primary open angle adult
Primary open angle adult
Primary open angle adult
Primary open angle adult
Primary open angle adult
Primary open angle adult angle adult
Susceptibility loci: 2p, 4p, 14q, 15q, 17p, 17q, 19
Nail patella syndrome/glaucoma
Current treatment for glaucoma is directed toward the regulation of aqueous humor formation by the ciliary body and increased outflow of aqueous humor through the trabecular meshwork or alternative pathways created by surgical procedures. Current therapy does not actually treat the cause of the disease because the cause is unknown. To clone the genes responsible for glaucoma and determine the functions of the normal and abnormal protein products of these genes will identify the processes that can result in this disease. This information will lead to the development of novel treatments designed to eradicate the abnormal molecular and cellular processes that may cause the disease. In addition to the development of new medical treatments for glaucoma, isolation of genes responsible for the disease may result in the development of gene therapy, in which damaged genes are replaced and the underlying defects corrected.
Isolation of genes responsible for glaucoma will also lead to new methods for diagnosis of the condition based on the DNA sequence changes that result in defective genes and protein products. Such DNA-based diagnostic tests can identify individuals at risk for the disease before any visual deterioration has occurred.
Overview of Recent Advances
Genes and chromosomal loci responsible for glaucoma are given in Table 212-5 .
Juvenile POAG is a rare disorder that develops during the first two decades of life. Affected patients typically present with a high IOP, which ultimately requires surgical therapy. Characteristic features include a high incidence of myopia and angle structures of normal appearance. These patients do not have a Barkan membrane or findings associated with anterior segment dysgenesis syndromes.  One histopathological study of 10 patients suggested the presence of a thick, compact tissue on the anterior segment of Schlemm’s
canal. Other specific ocular or systemic abnormalities have not been identified in these patients.
Juvenile glaucoma can be inherited as an autosomal dominant trait. Large pedigrees have been identified and used for genetic linkage analysis. Myocilin is one gene that can cause juvenile glaucoma. Mutations in this gene have also been associated with some cases of adult-onset POAG. The normal function of this gene and the role that dysfunctional forms play in the pathogenesis of glaucoma remain unknown. The protein contain several important functional domains, including a region with strong homology to the olfactomedin family of proteins. Although the function of the olfactomedin domain in myocilin is unknown, nearly all the mutations associated with glaucoma occur in this region. Studies of patients who have genetic abnormalities resulting in a reduction of myocilin suggest that mutations in the gene cause a gain of function or dominant negative effect rather than a loss of function or haploinsufficiency.  
ADULT-ONSET PRIMARY OPEN-ANGLE GLAUCOMA.
Adult-onset POAG (see Chapter 220 ) is the most common form of glaucoma and affects 7–8 million Americans. Previous studies suggest that susceptibility to POAG is inherited. The prevalence of POAG in first-degree relatives of affected patients has been documented to be as high as 7–10 times that of the general population. It is likely that the incidence of POAG in family members of affected patients is even higher, given the older age of diagnosis and the lack of patients’ awareness of the disease. Patients affected by POAG are more likely to develop an increase in IOP in response to dexamethasone eye drops, a trait shown to be inherited.  Several twin studies suggest a high concordance of glaucoma between monozygotic twins, consistent with a significant genetic predisposition to the disease.  The higher prevalence of POAG among African Americans compared with Caucasian Americans may reflect an underlying genetic difference in susceptibility to this disorder. Also, POAG has been associated weakly with the inheritance of various genetics markers, which include the Duffy blood group on chromosome 1 and inability to taste phenylthiourea. 
It is likely that multiple genes (independently or in combination) are responsible for the heritability of POAG. The variability in the age of onset of the disease, the apparent incomplete penetrance of the condition in some pedigrees, and the prevalence of the disease all suggest that more than one gene may be responsible for the disorder. Patients affected by POAG also vary with respect to the relationship between increased IOP and deterioration of the optic nerve. These observations are consistent with the conclusion that POAG is inherited not as a simple single gene disorder but as a complicated “complex trait.”
The origins of the genetic complexity of POAG are likely to stem from the diversity of ocular tissues and cell types potentially involved in the disease process. Many studies suggest that defects in the trabecular outflow pathways are responsible for the elevation of IOP associated with the majority of cases of POAG. However, the cell type and biochemical processes that are altered in the disease have not yet been identified. It is possible that mutations in a number of genes that encode different proteins may alter the normal function of the ocular outflow pathways. Many patients who have elevated IOPs do not develop the characteristic degeneration of the optic nerve that is the ultimate cause of blindness in patients affected by POAG. Indeed, elevation of IOP is an important risk factor for the disease but does not by itself define the disease process. Individuals who do develop degeneration of the optic nerve may have sustained additional gene defects that render the retinal ganglion cell and optic nerve more susceptible to damage. The reduced penetrance and genetic heterogeneity typical of complex traits may make genetic mapping studies difficult. Six loci for POAG and seven susceptibility loci have been reported.        Optineurin has been identified as the responsible for GLC1E. The optineurin protein is expressed in the eye and in many nonocular tissues including brain, heart, liver, skeletal muscle, kidney, and pancreas. In the eye the protein has been detected by reverse transcription–polymerase chain reaction (RT-PCR) in human trabecular meshwork, nonpigmented ciliary epithelium, and retina. The protein does not have significant homology to any known protein but may participate in the tumor necrosis factor a (TNF-a) signaling pathway. TNF-a has been proposed to be one factor that could induce apoptosis in retinal ganglion cells in patients with low-tension glaucoma and in patients with POAG. It has been speculated that the optineurin protein may function to protect the optic nerve from TNF-a–mediated apoptosis and that the loss of function of this protein may decrease the threshold for ganglion cell apoptosis in patients with glaucoma.
Congenital glaucoma (see Chapter 219 ) is a heterogeneous condition that is typically apparent at birth but may not be diagnosed before 3 years of age. As a result of the flexibility of the sclera in babies, the elevation of IOP associated with this condition causes buphthalmos, the usual indication that the child is affected. Increased IOP in eyes affected by congenital glaucoma is probably the result of abnormal development of the anterior segment of the eye. Specifically, in many cases of congenital glaucoma, a membrane that obstructs the path of aqueous humor may be visualized.
Previous studies suggested that congenital glaucoma is largely an inherited condition that is also genetically heterogeneous. Numerous pedigrees affected by autosomal recessive forms of the disease have been reported and include pedigrees of Czechoslovakian and Slovakian gypsies and pedigrees from the Middle East (such as Saudi Arabian and Turkish pedigrees ). Cytogenetic abnormalities have been described in many patients affected by congenital glaucoma. Many of these are complex rearrangements that may involve a number of genes, a type of abnormality that has been observed on chromosomes 1, 2, 3, 4, 6, 11, and 13.       Collectively, these results suggest that many different genes may be responsible for this condition.
Two loci responsible for autosomal recessive forms of congenital glaucoma have been located in the human genome (GLC3A at 2p21 and GLC3B at 1p36 ). CYP1B1 has been shown to be the causative gene responsible for cases of congenital glaucoma mapping to chromosome 2p21. This gene codes for cytochrome P4501B1. Mutations in this gene disrupt functional domains, implying that loss of function of the protein results in the phenotype. Mutations in CYP1B1 have been found in congenital glaucoma patients from populations all over the world. Some of the mutations in this gene are recurrent, and genetic studies have shown that they reside on the same ancient founder chromosome that has been distributed throughout the world population.  The gene located at 1p36 remains to be identified. It is likely that, because of the genetic heterogeneity of this condition, other genes responsible for congenital glaucoma will be identified in the future.
Variability in the phenotypic expression of mutant forms of CYP1B1 has led to the suggestion that modifier genes may also influence the severity of the disease resulting from mutations in this gene. A recent study suggests that patients carrying mutations in myocilin and CYP1B1 may have more severe disease, suggesting that the two proteins may interact in the same biochemical pathways.
PIGMENT DISPERSION SYNDROME AND PIGMENTARY GLAUCOMA.
The pigment dispersion syndrome, a common disorder in young adults, is associated with the development of pigmentary glaucoma. Studies have shown that up to 2–4% of the Caucasian American population between 20 and 40 years of age may be affected by this disorder, of which characteristic features include loss of iris contour and loss of pigment granules from the iris. The released pigment is deposited on the structures of the anterior segment of the eye, which include the trabecular meshwork. Although generally it is accepted that the dispersed iris pigment contributes to the development of glaucoma in affected patients, the pathogenesis of pigmentary glaucoma remains unknown (see Chapter 224 ).
Pigment dispersion has been shown to be inherited as an autosomal dominant trait, which suggests that specific gene defects may be responsible. One locus for this syndrome was located on 7q35-q36 in families of Irish decent, but the gene responsible has yet to be isolated. The high prevalence of this condition indicates that more than one gene may be responsible for this disorder.
Pseudoexfoliation is a condition characterized by a distinctive fibrillary degeneration of the lens capsule, but the fibrillar material, although most easily visualized on the lens capsule, is actually present throughout the anterior segment of the eye and has been found to exist systemically in the skin and blood vessels (see Chapter 223 ). Pseudoexfoliation is associated with a severe high-IOP glaucoma that results in rapid deterioration of the optic nerve. Although the biochemical defect responsible for this disease is unknown, basement membrane alterations observed in pathology specimens taken from affected individuals suggest that alterations of the protein constituents of the basement membranes may be involved in this process.
The distinctive geographic distribution of pseudoexfoliation is most consistent with founder effects caused by inheritance of genes responsible for this condition. High prevalence of this disease is found in Scandinavia, Russia, Nova Scotia, Scotland, northeastern United States, Saudi Arabia, Greece, and the African Bantu; the disease has a low prevalence in the Eskimo population, Germany, the United Kingdom, and the southern United States. Pedigrees affected by pseudoexfoliation have been reported, and studies of these suggest that the disease is inherited as a dominant trait with incomplete penetrance. The degree of genetic heterogeneity of the condition remains unknown. To date, loci that harbor genes responsible for this condition have not been found in the human genome.
Rieger’s syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye ( Fig. 212-2 ). Typical clinical findings may include posterior embryotoxon, iris hypoplasia, iridocorneal adhesions, and corectopia (see Chapter 230 ). Approximately 50% of affected individuals develop a high-IOP glaucoma associated with severe optic nerve disease. Although the elevation of IOP is likely to result from abnormal development of the anterior structures of the eye, a direct correlation between the severity of the anterior segment dysgenesis and the incidence of glaucoma has not been observed. Presumably, the structures that are involved in the elevation of IOP in these patients are not readily visible clinically.
Genetic heterogeneity of Rieger’s syndrome has been suggested by descriptions of affected individuals who have a variety of chromosomal abnormalities, which include deletions of chromosome 4 and of chromosome 13, a deletion of chromosome
Figure 212-2 Rieger’s syndrome. Slit-lamp view of a patient that shows the iris atrophy, iridocorneal adhesions, and corectopia that are typical clinical manifestations of the disease. The patient has also had a trabeculectomy for glaucoma.
10, a pericentric inversion of chromosome 6, and an isochromosome of chromosome 6. Genes for Rieger’s syndrome are established at chromosome loci 4q25, 13q14, and 6p25. Iris hypoplasia is the dominant clinical feature of pedigrees linked to the 6p25 locus, whereas pedigrees linked to 4q25 and 13q14 demonstrate the full range of ocular and systemic abnormalities found in these patients.
The genes responsible for Rieger’s syndrome loci mapped to 4q25 and to 6p25 have been identified. The chromosome 4q25 gene (RIEG1) codes for the bicoid homeobox transcription factor PITX2. Presumably, this gene plays an important role in the processes that result in normal eye development. Future studies designed to investigate the interaction of this gene with other genes involved in eye development, such as Pax6, are of great interest. The chromosome 6p25 gene codes for FOXC1, a member of the forkhead family of regulatory proteins. This protein also participates in the development of the anterior segment of the eye. A mouse that lacks the FOXC1 gene product has abnormal development of the anterior segment of the eye. Various anterior segment structures are abnormally formed in the FOXC1 deficit mouse, including the iris and Schlemm’s canal. The identification of other genes responsible for Rieger’s syndrome and anterior segment dysgenesis will also enable studies to determine whether these genes are part of a common developmental pathway or represent redundant functions necessary for eye development. The development of transgenic and knockout animals using these genes will allow important studies to correlate structure and function of the eye.
NAIL PATELLA SYNDROME.
Individuals with nail patella syndrome have abnormal development of finger and toe nails and the patellae. Some of these patients also develop glaucoma that may be associated with developmental abnormalities. A gene for this syndrome, LMX1B, has been idenetified.  This gene is a regulatory transcription factor and is likely to be involved in developmental processes in the eye.
The identification of genes that cause glaucoma is just an initial step in the establishment of the pathophysiology of the disorder. Studies to determine the normal role of these genes in the development and function of the eye are necessary to understand the foundation of the disease pathophysiology. To understand the normal role of the genes responsible for glaucoma, the specific proteins and classes of proteins they code for, when and where the genes are expressed, and how the expression is regulated must be determined.
Little is known about how an abnormal gene product results in a glaucoma phenotype and whether different mutations in the same gene can explain phenotypic variability. The identification of genes that cause glaucoma will allow the opportunity to determine whether the functions of these genes and their products are influenced by the action of other genes and/or environmental factors that can modify the disease phenotype.
The identification of genes and loci involved in disease enables studies to evaluate the clinical features of the disorder with respect to the molecular information. It will be possible to determine whether cases of glaucoma caused by a specific gene share common features that can be recognized clinically. Similarly, it will be possible to determine whether molecular subclasses of disease respond similarly to specific treatment modalities. The combined knowledge from genetic and clinical studies will lead to new methods of diagnosis and treatment that will improve the prognosis and quality of life of affected individuals.
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