AMD
Age-related macular degeneration (AMD) is a common complex disorder characterized by chronic and progressive degeneration of photoreceptors, the underlying retinal pigment epithelium (RPE), Bruch’s membrane and, possibly, the choriocapillaries in the macula. Clinical and pathological features of AMD include thickened Bruch’s membrane, drusen formation, pathological changes of the RPE, photoreceptor atrophy, choroidal neovascularization (CNV) and/or fibroglial tissue in the macula. These alterations result in the loss of central visual acuity. It is an age-related process and usually develops after a person reaches 50 years [1].
AMD is divided clinically into 2 subtypes: 80% of patients have “dry” AMD, the hallmarks of which include 1 or more of the following: the presence of cellular debris (drusen) in or under the retinal pigment epithelium (RPE), irregularities in the pigmentation of the RPE, or geographic atrophy (GA). Twenty percent of patients have exudative or “wet” AMD characterized by serious detachment of the RPE or choroidal neovascularization (CNV), or both. Severe vision loss is associated most often with geographic atrophy or exudative disease [2].
Susceptibility to AMD is a multi-factorial trait involving both genetic and environmental factors. Several genes – CFH, ARMS2, CFB, C2 have now been associated with the development of age-related macular degeneration. Polymorphisms in these genes can increase or decrease the risk for AMD. SNPs (single nucleotide polymorphisms) in CFH (complement factor H) and ARMS2 (age-related maculopathy susceptibility 2, also known as LOC387715) capture a substantial fraction of AMD risk and permit the identification of individuals at high risk of developing AMD [3].
CFH on chromosome 1q32 is a critical regulator of the complement cascade in innate immunity and associated inflammatory processes. It has been suggested that the CFH protein encoded by the at-risk CFH haplotype(s) may have attenuated complement inhibitory function. CFH variants associated with AMD (rs1061170, rs1410996) may put RPE and choroidal cells at sustained risk for alternative pathway-mediated complement attack [4].
LOC387715/ARMS2 on chromosome 10q26 is a hypothetical gene encoding mitochondrial protein associated with oxidative stress. It has been proposed that SNP rs10490924 altering the function of the putative mitochondrial protein LOC387715/ARMS2 enhances the susceptibility to ageing-associated degeneration of macular photoreceptors [3].
Variations in CFB (complement factor B) and C2 (complement component 2) can decrease the risk for AMD. CFB and C2 on chromosome 6p21 are in LD. CFB plays an essential role in alternative pathway complement activation, C2 is essential to activation of the classical complement pathway. Genetic variants rs641153 and rs4151667 of CFB gene and rs9332739 variant of C2 gene have been associated with a significantly reduced risk of AMD [5].
The test developed by Asper Biotech is based on the evaluation of single nucleotide polymorphisms (SNPs) in genes associated with AMD. The AMD risk assessment test enables analysis of 3 SNPs in genes CFH and ARMS2 that have been associated with higher risk for disease-onset. The test also enables to detect 3 SNPs in genes CFB and C2 that are associated with reduced risk of disease.
Test is recommended for patients with known cases of AMD in the family and close relatives of patients with increased risk. AMD increased risk assessment enables prevention and early diagnosis of the disease.
Early detection and diagnosis of AMD is important to delay progression of disease. There is no effective treatment available for “dry” AMD, vitamin supplements with high doses of antioxidants, lutein and zeaxanthin, have been suggested to slow the progression of disease. “Dry” AMD can develop into “wet” AMD.
For “wet” AMD the treatment is available for maintaining existing vision or regression of vision loss. Vascular endothelial growth factor (VEGF) is a cytocine that has angiogenic and vascular permeability effects which have been implicated in the pathogenesis of macular diseases, including AMD. Inhibiting the actions of VEGF has been proposed as a possible treatment modality for macular disease, which results in visual loss secondary to ocular angiogenesis. New drugs, called anti-angiogenics or anti-VEGF (anti Vascular Endothelial Growth Factor) agents, can cause regression of the abnormal blood vessels and improvement of vision when injected directly into the eye.
References:
[1] de Jong PT. Age-related macular degeneration. N Engl J Med 2006; 1471-1485. [PubMed:17021323]
[2] Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M. Mutation of the Stargardt Disease Gene (ABCR) in Age-Related Macular Degeneration. Science 1997; 1805-7. [PubMed:9295268]
[3] Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16227-32. [PubMed: 17884985]
[4] Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32.[PubMed: 15870199]
[5] Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006;38:1055–1059.[PubMed: 16936732]
ORPHANET: www.orpha.net
OMIM ® – Online Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov
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