Exfoliation syndrome was described as early as 1917, and has been the subject of intense investigation since. It has long been known to be prevalent in Nordic populations, and has more recently been found to be present in many other populations throughout the world. The association of the disorder with the development of elevated intraocular pressure (IOP) and secondary open-angle glaucoma is widely known.
Using a powerful new technique known as genome-wide association or whole genome association, researchers at deCODE Genetics, Inc. in Iceland along with researchers at the University of Iceland and Uppsala University, Sweden have identified two different mutations in the lysyl oxidase-like 1 gene (LOXL1) that are associated with more than 99% of cases of exfoliative glaucoma (XFG) in Icelandic and Swedish populations.1
Genome-wide Association
The new gene hunting technique is performed by scanning the entire genome of an individual for up to 900,000 single-nucleotide polymorphisms (SNPs) simultaneously, using special chips that can be read in an automated fashion. SNPs are variations in the DNA sequence that occur in the population. DNA samples of large numbers of subjects, with and without the disease in question, are evaluated with the aim of identifying specific SNPs that are frequently present in subjects with the disease and significantly less frequently present in those without. Once such an association is detected, the DNA in the region of the relevant SNP(s) can be studied in more detail in hopes of tracking down the disease-associated gene(s).
deCODE Genetics, Inc. is a gene hunting corporation that has an enormous number of DNA samples in its databank. In the XFG study, investigators screened the genomes of 195 glaucoma subjects, 75 of whom had XFG. For controls, they used over 14,000 subjects from their existing databank. The researchers discovered two different mutations in the LOXL1 gene on chromosome 15 that confer a risk for XFG, but not primary open-angle glaucoma (POAG). For further verification, this association was then replicated in a population of Swedish control, POAG, and XFG subjects. Exfoliation syndrome (the presence of the characteristic exfoliation material in the absence of glaucomatous optic neuropathy) was found to be as strongly associated with both of these LOXL1 mutations, suggesting that the risk of developing XFG is conveyed entirely through the development of exfoliation syndrome.
The product of the gene LOXL1 catalyzes a reaction that leads to the spontaneous cross-linking of tropoelastin. Ultimately, this leads to the formation of mature elastin polymer fibers. Elastin is an important structural element throughout the body, including the optic nerve head and lens zonules. It is thought that the disease-associated LOXL1 mutations lead to either decreased expression of the gene or decreased activity of its enzyme product. Over the life of an individual, the reduced LOXL1 activity ultimately leads to the visible accumulation of the exfoliation material and its consequences with respect to intraocular pressure elevation in some individuals.
The abnormal exfoliative material present on the lens capsule, lens zonules, ciliary processes, iris, and other structures in the anterior segment can be observed during slit lamp biomicroscopy. The material has typically been described as an abnormal fibrillar extracellular material. This material’s precise composition had not been known, though the presence of elastin and abnormal elastin-like material had been previously described.2
Mechanisms for the development of glaucoma in exfoliation syndrome
Exfoliation syndrome may confer an increased risk for the development of glaucoma by two totally separate mechanisms: (1) by causing an elevation in IOP; and (2) by rendering the optic nerve, specifically the lamina cribrosa, more susceptible to the damaging effects of elevated IOP.
Elevated IOP in exfoliation syndrome may occur because the abnormal exfoliative material in the anterior chamber may flow into and obstruct the trabecular meshwork (TM) or Schlemm’s canal. Additionally, the material may be produced in the TM itself, thereby decreasing outflow facility.
In the course of one recent study, the Early Manifest Glaucoma Trial, patients with ocular hypertension with and without exfoliation syndrome were identified as part of a population-based survey. It was found that the presence of exfoliation syndrome represents an independent risk factor for progression to glaucoma among eyes with ocular hypertension, independent of central corneal thickness and baseline intraocular pressure.3 This finding suggests that the presence of exfoliation syndrome may somehow render the optic disc more susceptible to glaucomatous damage. This is a compelling notion. Ophthalmologists know that exfoliation syndrome is associated with an increased risk of zonular rupture during cataract surgery – the lens zonules are structurally compromised. It seems intuitive to extend this to the possibility that the lamina cribrosa may have a similar structural weakness in eyes with exfoliation syndrome since elastin is present in both structures.4,5
Investigators have previously identified the presence of severe elastosis of the connective tissue in the lamina cribrosa in human cadaver eyes with exfoliation glaucoma.6 Those investigators correctly postulated that the mechanism for the glaucomatous optic neuropathy in these eyes may be the result of abnormalities in elastin synthesis. The question that remains is whether abnormal elastin metabolism at the lamina cribrosa is part of the glaucomatous process or whether the damage occurs exclusively as a result of elevated IOP caused by deposition of the exfoliative material in the outflow pathways. In another important recent report, investigators demonstrated that there is decreased expression of LOXL2 in healthy African-Americans. This gene encodes another enzyme that is involved in the post-translational modification of elastin, possibly explaining the increased risk for the development of glaucoma in persons of African ancestry.5
In summary, mutations in a single gene, LOXL1, seem to be responsible for nearly all cases of exfoliation syndrome and XFG. The exact mechanism by which the two LOXL1 mutations cause glaucoma is unclear, but likely involves the abnormal synthesis of elastin fibers. Once the mechanism is more clearly elucidated, it may be possible to use targeted therapeutic approaches, either pharmacologic or genetic, to alter the disease course in affected individuals or even those at future risk of developing the disease.
References:
1 Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 317:1397-400, 2007
2 Li ZY, Streeten BW, Wallace RN. Association of elastin with pseudoexfoliative material: an immunoelectron microscopic study. Current Eye Research. 7:1163-72, 1988
3 Grodum K, Heijl A, Bengtsson B. Risk of glaucoma in ocular hypertension with and without pseudoexfoliation. Ophthalmology. 112:386-90, 2005
4 Streeten BW, Licari P. The zonules and the elastic microfibrillar system in the ciliary body. Investigative Ophthalmology & Visual Science. 24:667-81, 1983
5 Urban Z, Agapova O, Hucthagowder V, et al. Population differences in elastin maturation in optic nerve head tissue and astrocytes. Investigative Ophthalmology & Visual Science. 48:3209-15, 2007
6 Netland PA, Ye H, Streeten BW, Hernandez MR. Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma. Ophthalmology. 102:878-86, 1995
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