Glaucoma is characterized by progressive loss of retinal ganglion cells resulting in a loss of peripheral vision and a characteristic excavative atrophy of the optic nerve, resulting in blindness if untreated.
1,2 Primary open angle glaucoma (POAG) is characterized by onset during adulthood, an open angle of normal appearance, and glaucomatous optic nerve head damage in the absence of an identifiable secondary cause.
2 Increased intraocular pressure (IOP) secondary to reduced aqueous outflow through the filtration angle is the most important risk factor for the development of POAG and is frequently, although not invariably, associated with the disease.
3 –5 Increased IOP is the only modifiable factor.
6 –8 Other risk factors for POAG include African ethnicity, positive family history, increasing age (older than 40 years), thin central corneal thickness, myopia, and low diastolic perfusion pressure.
5,9,10 Glaucoma is the leading cause of irreversible blindness worldwide,
11 with POAG the most prevalent form and the second leading cause of blindness in the United States and Europe.
4,12 On average, POAG affects 2% of people older than 40 years with an incidence that increases with age, reaching a prevalence of 6% in white populations, 16% in black populations, and 3% in Asian populations in persons older than 70.
13 In England and Wales, POAG is responsible for 10% of the certification for visual impairment and 11% of the certification for severe visual impairment, and it accounts for more than 1 million hospital visits per year in the National Health Service of England and Wales.
14,15 Approximately 50% of POAG patients have a positive family history, and first-degree relatives of an affected person are at threefold to ninefold increased risk for the disease.
1,5,16 Pedigrees with familial POAG displaying an autosomal dominant pattern of inheritance with incomplete penetrance and variable expressivity have been described.
17 The variable and complex phenotype suggests POAG has a multifactorial etiology and is likely to involve the interaction of one or more genes with environmental factors.
18 Sixteen loci have been reported for POAG (GLC1A-P),
19 although not all have been replicated and only two causal genes—myocilin
MYOC (
GLC1A) and optineurin
OPTN (
GLC1E)—have been identified.
3 Sequence variants in WD-repeat domain 36
WDR36 (
GLC1G) have been reported as a cause of POAG
20,21 but have been excluded by others,
22,23 and the locus remains controversial.
24 Similarly, sequence variants in
NTF4 (
GLC1O) have been reported
25,26 and excluded
27,28 as a cause of POAG. Mutations in
MYOC are the most common cause of POAG but still only account for 4% of adult-onset cases and 6% to 36% of juvenile-onset cases.
29,30 Mutations in
OPTN are a rare cause of POAG and probably account for <1% of cases.
18