Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

There are many other factors that may lead to IOP elevation (e.g., apoptosis of trabecular meshwork cells) and retinal ganglion cell death (e.g., extracellular matrix changes in the lamina cribrosa) in glaucoma. Some of these are summarized in Fig. 1A and B (19,20).

Juvenile Open-Angle Glaucoma

Juvenile open-angle glaucoma (JOAG) is an autosomal dominant, early onset form of POAG, often associated with highly elevated IOP with subsequent damage to the optic nerve and visual field. Affected eyes are often myopic. This disease usually begins between the ages of 4 and 35, often with a strong family history. JOAG generally responds poorly to drug or laser treatment and typically requires surgical intervention.

JOAG was first linked to chromosome 1q21–31 by Sheffield et al. in 1993 (21). Four years later, mutations were found in the responsible gene, the trabecular meshwork glucocorticoid response gene (TIGR, later renamed myocilin) (22). Of all cases of JOAG, approximately 10–20% are caused by mutations in the myocilin gene (23). There are now at least five loci mapped for JOAG (see Table 1).

Pigmentary Glaucoma

Pigment dispersion syndrome (PDS) is characterized by dispersion of melanin granules from the iris with deposition in the anterior segment of the eye, including the trabecular meshwork. It typically affects Caucasian individuals and has a predilection for young, myopic males. Approximately 15–35% of patients with PDS can develop glaucomatous optic nerve damage and/or visual field loss over a 15-year period (24,25).

Several investigators have demonstrated autosomal-dominant inheritance for PDS (26–28). In 1997, Andersen et al. described four autosomal-dominant PDS families and reported localization of a gene to chromosome 7q35–36 (29). The disorder is genetically heterogenous, and further studies are underway to determine whether additional loci exist and to find the gene(s) involved.

DBA/2J mice appear to develop a form of pigmentary glaucoma caused by mutations in the glyocoprotein (transmembrane) nmb gene, Gpnmb, and the tyrosinase-related protein 1 gene, Tyrp1. As both genes encode melanosomal proteins, it has been hypothesized that these mutations permit toxic intermediates of pigment production to leak from melanosomes. Supporting this, albino and hypopigmentation mutations inhibit development of glaucoma (30). However, a study examining glaucoma patients with PDS for DNA sequence variants in TYRP1 failed to find an association (31).

Bone marrow-derived cells and inflammatory processes appear to contribute to pigmentary glaucoma (32). The Gpnmb gene is expressed in dendritic cells that control immune responses. It appears that mutated Gpnmb disturbs ocular immune privilege and allows immune cells to attack the iris and propagate the iris disease that induces glaucoma. Interleukin-18 (IL-18) is an important regulator of innate and acquired immune responses and plays an important role in inflammatory/autoimmunity diseases. Using the DBA/2J mouse, Zhou et al. (33) demonstrated that the expression of the IL-18 protein and gene in the iris/ciliary body and level of IL-18 protein in the aqueous humor of DBA/2J mice are dramatically increased with age. This increase precedes

the onset of clinical evidence of pigmentary glaucoma, implying a pathogenic role of inflammation/immunity in this disease.

Pseudoexfoliation Glaucoma

Pseudoexfoliation (XFS) syndrome is characterized by accumulation of white ‘dandruff-like’ material on the lens capsule and in other anterior segment structures. XFS is the most common secondary form of open angle glaucoma worldwide.

XFS is an elastin-related microfibrillopathy (34). Zenkel et al. (35) suggest that the underlying pathophysiology is associated with an excessive production or reduced degradation of elastic microfibril components, enzymatic cross-linking processes, a proteolytic imbalance between matrix metalloproteinases and their inhibitors, and increased cellular and oxidative stress.

The genetic etiology of XFS and glaucoma in Iceland and Sweden was identified in a landmark study (36). Polymorphisms in the coding region of the gene lysyl oxidase-like 1 gene (LOXL1) are associated with XFS and glaucoma in these populations. LOXL1, located on chromosome region 15q24, is one of many enzymes that are essential for the formation of elastin fibers LOXL1 catalyze the process that enables tropoelastin monomers to cross-link and form elastin.

The disease-associated polymorphisms appear to account for virtually all XFS within the studied populations. Three single-nucleotide polymorphisms in the protein-coding portion of LOXL1 were specifically associated with XFS glaucoma risk. A person homozygous for both of the highest risk haplotypes was 700 times more likely than those homozygous for the low-risk variants to develop XFS glaucoma. There are likely to be other genes and environmental factors that play an important role for the development of XFS and the glaucoma that is associated with this syndrome. There may also be other important contributing factors in non-Scandinavian populations that remain to be determined (36).

Angle-Closure Glaucomas

Primary Angle-Closure Glaucoma

Angle-closure glaucoma is a leading cause of blindness among the Inuit, Mongolian and other Asian populations. It is far less common in Caucasians, native Americans, Australian Aborigines, and those of African ancestry (37).

Geographic and racial variation in PACG prevalence is most likely the result of structural differences of the eye in these populations. These differences appear to manifest in eyes with smaller more crowded anterior segments that predisposes to pupillary block and subsequent chronic or acute angle closure. These factors include shallow anterior chamber depth, thick lens, a more anterior lens position, small corneal diameter, shortened axial length of the globe, and small radius of corneal curvature (38). In addition, the iris insertion to the scleral wall is more anterior in Asians, slightly more posterior in African Americans, and most posterior in Caucasians (39).

Very few studies have been undertaken to explore the familial basis of this disorder. Hu found a sixfold increased risk for subjects with a family history of PACG in his population-based survey in Shunyi County, Beijing, which supports an inherited basis (40). A study of axial anterior chamber depth in twins (without PACG) indicated

that about 70% of the variance in dizygotic twins could be attributable to a genetic component (41). A biometric study showed a relatively shallow anterior chamber depth in sibs, children, nephews, nieces, and grandchildren of PACG probands (42). A heritability of 70% was found in this study, indicating that about two-thirds of the ageand sex-independent variation of anterior chamber depth is inherited.

Lowe has suggested that inheritance of a shallow anterior chamber is polygenic with a threshold effect so that the action of a large number of grouped or independently inherited genes results in anterior chamber shallowness (38). It has also been suggested that environmental triggers may alter anterior chamber depth and/or degree of pupillary block. These are associated with PACG including neural and/or humoral response to fatigue, mental stress, infection, and trauma. Alsbirk has proposed that in the Inuit population genes for a small, crowded anterior segment are the result of selection pressure to protect the cornea that is vulnerable to freezing in the Arctic climate (43).

Nanophthalmos

There is very little reported in terms of genetic susceptibility to secondary angleclosure glaucomas. The exception is nanophthalmos.

Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Nanophthalmic eyes often have an axial length below 20 mm and show considerable thickening of both the choroidal vascular bed and scleral coat.

Sundin et al. (44) have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in membrane-type frizzled-related protein (MFRP), a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the frizzled transmembrane receptors. MFRP appears primarily devoted to regulating axial length of the eye.

Another locus has been isolated for autosomal-dominant nanophthalmos on chromosome 11. Three pathogenic sequence alterations in VMD2 were identified in five families with nanophthalmos associated with ADVIRC (45). Some family members developed angle-closure glaucoma. VMD2 encodes bestrophin, a transmembrane protein located at the basolateral membrane of the RPE, that is also mutated in Best macular dystrophy (46). The data showed that VMD2 mutations caused defects of ocular patterning, supporting the hypothesized role for the RPE, and specifically VMD2, in the normal growth and development of the eye.

Developmental Glaucomas

Primary Congenital Glaucoma

Primary congenital glaucoma (PCG) is a relatively uncommon disease with a frequency ranging from 1/1250 (in Romanian gypsies) to 1/10,000 (47). Patients often present with enlarged corneas and globes (see Fig. 2). Symptomatic tearing, photophobia, and blepharospasm are frequently present. The anterior segment often reveals an anteriorly inserted iris, with a maldeveloped angle and trabecular meshwork (47).

Eyes of patients with congenital glaucoma are characteristically enlarged, a feature called buphthalmos meaning “ox eyed” (see Fig. 2). The eyes of infants and young

Fig. 2. Infant with congenital glaucoma and associated buphthalmos. Courtesy of Dr. Sharon Freedman.

children enlarge in the presence of elevated IOP in contrast to adult eyes that typically do not. The sclera and cornea of these young eyes are more elastic than that of adults, and typically enlarge with increased IOP. Enlargement of the cornea produces breaks in descemets membrane which are called Haab’s striae. The iris insertion is often very anterior, and trabecular meshwork specimens from patients with PCG demonstrate thickening of the juxtacanalicular area with layers of spindle cells and surrounding extracellular matrix (48).

Most cases of PCG are sporadic; in familial cases, autosomal recessive inheritance is most common. Two loci have been identified for the infantile form of congenital glaucoma: 2p21 (49) and 1p36 (50). The gene within the 2p21 locus, which accounts for the majority of familial cases, was identified in 1997 and encodes the protein, cytochrome P4501B1 (CYP4501B1) (51).

Other Developmental Glaucomas

Developmental glaucomas are secondary to morphological malformations of the anterior segment and are relatively rare. Importantly, however, developmental abnormalities of the ocular drainage structures are not always clinically detectable, and abnormal development may affect the metabolism and function of the drainage structures without disturbing morphology. Glaucomas and known genes associated with developmental disorders are listed in Table 1.

Anterior segment dysgenesis (ASD) is a spectrum of disorders arising from abnormal migration and differentiation of neural crest-derived cells (52). These include Axenfeld’s anomaly (anteriorly displaced Schwalbe’s line with no additional risk of glaucoma), iris hypoplasia and iridogoniodysgenesis (50–75% risk of associated glaucoma), Axenfeld–Rieger anomaly (variable findings ranging from iris adhesions to Schwalbe’s line to iris hypoplasia with corectopia and polycoria, associated with a 50% risk of glaucoma—Fig. 3), and Peter’s anomaly (which includes adhesion of the lens to the cornea). If systemic features such as redundant umbilical skin, dental,

PITX3, and FOXC1. PAX6 has also been reported in a small number of patients with varying ASD phenotypes.

Ocular and Systemic Diseases Associated with Glaucoma

A number of ocular disorders that have been linked are associated with open-angle forms of glaucoma as part of their phenotype. These are listed in Table 1.

In addition, a number of systemic disorders are associated with open-angle forms of glaucoma (e.g., nail patella syndrome and Marfan’s syndrome) and those for which the gene has been localized or identified are listed in Table 2.

COLLABORATION BETWEEN CLINICAL AND BASIC RESEARCHERS

A close collaboration between clinicians and basic scientists has fueled the pace of genetic discovery. Clinicians play an important role in identifying and recruiting patients for genetic and proteomic studies and in counseling patients once test results are available (53–55). As clinicians are usually the first to detect individuals or families with inherited disorders, the information clinicians provide about diagnosis, disease classification, and family history is invaluable. The ability to link genetic mutations and phenotypic characteristics relies on an accurate diagnosis and correct classification of individuals. The ability to determine genetic susceptibility for developing POAG or other inherited disorders will likely enable efficient and cost-effective population-based screening programs as well as novel therapeutic approaches to disease (1).

CONCLUSION

The glaucomas are a complex group of disease with considerable genetic heterogeneity. There are a large number of mapped locations for POAG and three genes that have been identified (MYOC, OPTN, and WDR36). However, the vast majority of the genetic contribution to this form of glaucoma as well as primary angle-closure glaucoma remains to be determined.

The identification of CYP1B1 gene for PCG, responsible for approximately half of cases, is a major improvement in our understanding of this devastating disorder.

Future studies in humans will provide an opportunity to correlate genotype with phenotype while animal studies will continue to unravel the complexity of biochemical networks that cause glaucoma in its various manifestations. This may enable earlier detection, a better understanding of the pathophysiology and natural history of disease, and ultimately the institution of more rational, targeted therapy.

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