51

Juvenile Open-Angle Glaucoma

Janey L. Wiggs, MD, PhD

Primary open-angle glaucoma (POAG) that develops in patients younger than 40 years of age has been called juvenile-onset POAG (JOAG) or early-onset POAG.^1–4 This disorder is less common than adult-onset POAG and typically is associated with severely elevated intraocular pressure (IOP) that frequently requires surgical therapy. Affected individuals have a clinically normal anterior segment, without features of anterior segment dysgenesis. The normal development of the angle structures in patients with JOAG suggests that the elevation of IOP occurs as a consequence of a molecular abnormality that may be more amenable to gene-based therapies than the anatomically abnormal angle that is the consequence of defective ocular development.

The age of onset for JOAG is variable, and although the disease typically develops between 3 and 20 years of age, the disease can be first diagnosed decades later. Family history of glaucoma is frequently found in patients with JOAG; however, the age of onset may vary considerably among family members.⁵ Juvenile glaucoma has been previously classified as true juvenile glaucoma, neglected infantile (congenital) glaucoma, pre senile glaucoma, and angle-closure glaucoma. The discussion in this chapter refers to the form of juvenile glaucoma previously classified as true juvenile glaucoma. The dis ease process is characterized by a severe high-pressure glaucoma that can result in significant damage to the optic nerve leaving affected individuals with little useful vision early in life. Although early-onset glaucoma may be a component of chromosome syndromes and other systemic disorders,⁶ there are no consistent systemic findings in patients with true JOAG.

Characteristic ocular features often include a high incidence of myopia.⁷ Affected eyes do not show signs of buphthalmos. The cornea does not demonstrate breaks in Descemet’s membrane. Gonioscopy typically shows a nor mal appearance to the angle structures. There is no evidence of increased pigment deposition in the angle or other findings consistent with the pigment dispersion syndrome. Some patients with JOAG may have an increased number of iris processes, some of which have an anterior insertion crossing the scleral spur and posterior trabecular meshwork. However, this is not a consistently identified finding, and these patients do not have any of the other features of developmental glaucoma, including posterior embryotoxon.¹ Patients with JOAG do not have a Barkan membrane covering the angle as is typical of patients affected by congenital glaucoma. One histopathologic study⁸ suggested that a thick compact tissue on the anterior chamber side of Schlemm’s canal was present in 10 cases of juvenile glaucoma. In these 10 patients, the mechanism of glaucoma was postulated to be a developmental immaturity of the trabecular meshwork.⁸ Other specific anatomical abnormalities have not been identified in patients with juvenile glaucoma.

Patients affected by JOAG may be successfully treated medically but frequently require surgical intervention for adequate IOP control. Medical treatment with latanoprost⁹ has been shown to be particularly effective in JOAG patients. Patients have also been treated effectively by goniotomy,¹⁰ trabeculectomy,¹¹ viscocanalostomy,¹² and valve implants.¹³ For some JOAG patients with myocilin mutations, genotype-phenotype correlations can help guide therapeutic decisions based on expected disease prognosis.

JOAG is commonly inherited as an autosomal dominant trait. The early onset of disease leads to the formation of large multigenerational families that are suitable for linkage analyses. Five of the 29 open-angle glaucoma genetic loci are primarily associated with JOAG: GLC1A, GLC1J, GLC1K, GLC1M, and GLC1N.4,14–16 Myocilin is the gene located in the GLC1A region, and mutations in these genes account for 10% to 20% of cases of JOAG and also up to 5% of adult-onset POAG.^17–19 Disease-causing mutations (both early- and late-onset glaucoma) have been found primarily in the third axon that codes for the olfactomedin-like portion of the protein.^18–22 Mutations in the protein appear to cause misfolding of the nascent polypeptide chain, leading to accumulation of precipitated protein in the endoplasmic reticulum and subsequent cell death.^23–26 The loss of the myocilin protein due to null alleles or gene deletion does not cause glaucoma.^27–29 A transgenic mouse containing one of the most severe human mutations (Tyr437His) has a glaucoma phenotype.³⁰ Aggregation of mutant myocilin has recently been shown to be inhibited in vitro by small molecule chemical chaperones,^31,32 a result that may lead to future therapies for individuals with glaucoma caused by myocilin mutations.

Myocilin mutations may cause early- (before 10 years of age), middle- (between 10 and 30 years of age), and late-onset (older than 40 years of age) POAG. There are more than 50 different disease-associated myocilin mutations, and the majority are missense changes rather than insertion/deletion mutations or nonsense mutations.¹⁹ Families affected with glaucoma caused by a myocilin mutation may have a consistent age of onset or may show significant intrafamilial variability. The penetrance of the condition is felt to be high, although formal penetrance studies have not been completed. Myocilin mutations that are consistently associated with severe early-onset disease include Pro370Leu^33,34 (Figure 51-1) and Tyr437His.³⁵ The Gln368Stop mutation is primarily associated with adult-onset (older than 40 yeras of age) disease.^36,37 Several mutations are associated with an intermediate phenotype³⁸ including the Thr377Met mutation.^39,40

Myocilin is currently the only gene known to cause JOAG glaucoma, and the fact that mutations in this gene account for at most 10% of early-onset POAG cases^17,18 suggests that JOAG is a genetically heterogeneous disease and that other genes are likely to be responsible for this disorder. Genome-wide linkage studies have revealed new loci for JOAG: GLC1J (9q22)⁴; GLC1K (20p12)⁴; GLC1M (5q22)¹⁶; and GLC1N (15q).¹⁵ The causative genes located in GLC1J and GLC1K have not yet been identified; however, the size of the GLC1K locus has been refined.⁴¹ An important candidate gene, neuregulin, has been excluded from GLC1M,¹⁶ and the region defined by GLC1N contains the LOXL1 gene known to contribute to exfoliation syndrome.¹⁵ Current evidence suggests that LOXL1 does not contribute to glaucoma independent of exfoliation syndrome and that another gene in this region is likely responsible for early-onset glaucoma.⁴² GLC1I, a genomic region associated with early adult-onset POAG, is also located on chromosome 15 and may overlap with GLC1N.⁴³ The identification of new JOAG genes will help define the underlying pathophysiology of the condition as well as lead to the development of DNA-based screening tests and novel therapeutics.

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