Chapter 242

## Abstract

1. The glaucomas are a heterogeneous group of diseases that result in death of the optic nerve. Together, these disorders are the leading cause of irreversible blindness in the world. The glaucomas are categorized into open-angle, closed-angle, and congenital glaucoma based on the mechanism by which aqueous outflow is impeded in the anterior chamber of the eye. Primary open-angle glaucoma (POAG) accounts for the vast majority of glaucoma cases. Major risk factors for development of this disorder are age, race, elevated intraocular pressure, and family history. Genetic mapping studies have resulted in the identification of five POAG loci. A subset of POAG cases occurs at a young age and is known as juvenile onset primary open-angle glaucoma (JOAG), (MIM 137750). This disorder was mapped to and shown to be caused by mutations in a gene (GLC1A, MIM 137750) that codes for a 504-amino acid protein known as myocilin. Mutations in the GLC1A gene have been shown to account for nearly all cases of autosomal dominant JOAG, and 3 to 4 percent of cases of adult onset POAG. Glaucoma caused by GLC1A mutations is inherited as an autosomal dominant disorder with high penetrance and variable expressivity.

2. Normal tension glaucoma is a subtype of POAG that is defined by the presence of glaucomatous optic nerve changes and visual field loss in patients with normal intraocular pressure. This disorder is thought to occur because of polygenic or multifactorial inheritance. A locus (GLC1E) for this disorder has been reported on chromosome 10p14-p15 based on study of a single pedigree.

3. Pigmentary glaucoma (MIM 600510) is a form of open-angle glaucoma characterized by the presence of dense black pigment in the trabecular meshwork of the eye. The formation of glaucoma in patients with this disorder is thought to be secondary to the dispersion of melanosomes from the iris into the aqueous humor, and subsequently into the trabecular meshwork. Two loci thought to cause autosomal dominant inheritance of pigmentary glaucoma have been reported.

4. Exfoliative glaucoma is a common form of open-angle glaucoma in which increased intraocular pressure is secondary to deposition of a fibrillar material throughout the anterior segment of the eye. This disorder is a disease of the elderly. It has a high incidence in some populations, including Scandinavians and Navajo Indians. No genetic loci have been identified for this disorder.

5. Corticosteroids have been well documented as inducing elevated intraocular pressure in some patients. Susceptibility to steroid-induced glaucoma appears to have genetic components.

6. Closed-angle glaucoma is characterized by impedance of aqueous humor outflow secondary to the iris being displaced over the trabecular meshwork. This disorder can develop suddenly and, unlike other forms of glaucoma, results in recognizable symptoms including nausea, vomiting, headache, and severe eye pain.

7. The developmental glaucomas result from an abnormality of the iridocorneal angle present at birth that results in decrease aqueous outflow and increased intraocular pressure. The developmental glaucomas can occur as an isolated ocular abnormality, in which case it is known as primary congenital glaucoma (PCG), or they can occur in conjunction with a variety of other ocular and/or extraocular abnormalities. Primary congenital glaucoma has an incidence of about 1 in 10,000 live births. Many cases of PCG appear to be inherited as autosomal recessive traits. Two PCG loci have been reported. Recently, mutations in the CYP1B1 gene on chromosome 2 have been shown to cause PCG.

8. A number of abnormalities involving the anterior segment of the eye, including Rieger anomaly (MIM 180500), Axenfeld anomaly, and iris hypoplasia (MIM 137600), are associated with glaucoma. When extraocular findings, including dental hypoplasia and umbilical abnormalities, occur with these anterior chamber abnormalities, the disorder is known as Axenfeld-Rieger syndrome (MIM 601631). Axenfeld-Rieger syndrome is an autosomal dominant disorder, which is caused by a mutation in the PITX2/RIEG1 homeobox gene on chromosome 4q. A second Axenfeld-Rieger Syndrome locus has been reported on chromosome 13.

9. Several congenital glaucoma-related phenotypes transmitted in an autosomal dominant manner have been mapped to chromosome 6p25. These phenotypes include Rieger anomaly, Axenfeld anomaly, and iridogoniodysgenesis (MIM 601631). These disorders are caused by mutations in the FKHL7 gene. A number of other genetic eye disorders can lead to congenital glaucoma, including Peter's anomaly (MIM 106210), aniridia, and posterior polymorphous corneal dystrophy (MIM 122000).

10. Current methods of screening for glaucoma are inadequate. Identification of genes involved in glaucoma will lead to molecular screening methods that should reduce the incidence of blindness resulting from glaucoma. A careful family history should be obtained from patients with glaucoma, and genetic counseling should be made available.

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