Thompson & Thompson Genetics in Medicine, 8th Edition

Case 3. Age-Related Macular Degeneration (Complement Factor H Variants, MIM 603075)



• Complex inheritance

• Predisposing and resistance alleles, at several loci

• Gene-environment (smoking) interaction

Major Phenotypic Features

• Age at onset: >50 years

• Gradual loss of central vision

• Drusen in the macula

• Changes in the retinal pigment epithelium

• Neovascularization (in “wet” form)

History and Physical Examination

C.D., a 57-year-old woman, presents to her ophthalmologist for routine eye examination. She has not been evaluated in 5 years. She reports no change in visual acuity but has noticed that it takes her longer to adapt to changes in light level. Her mother was blind from age-related macular degeneration by her 70s. C.D. smokes a pack of cigarettes per day. On retinal examination, she has many drusen, yellow deposits found beneath the retinal pigment epithelium. A few are large and soft. She is told that she has early features of age-related macular degeneration, causing a loss of central vision that may progress to complete blindness over time. Although there is no specific treatment for this disorder, smoking cessation and oral administration of antioxidants (vitamins C and E and beta-carotene) and zinc are recommended as steps she can take to slow the progression of disease.


Disease Etiology and Incidence

Age-related macular degeneration (AMD, MIM 603075) is a progressive degenerative disease of the macula, the region of the retina responsible for central vision, which is critical for fine vision (e.g., reading). It is one of the most common forms of blindness in older adults. Early signs occur in 30% of all individuals older than 75 years; approximately one quarter of these individuals have severe disease with significant visual loss. AMD is rarely found in individuals younger than 55 years. Approximately 50% of the population-attributable genetic risk is due to a polymorphic variant, Tyr402His, in the complement factor H gene (CFH). In contrast, polymorphic variants in two other genes in the alternative complement pathway, factor B (CFB) and complement component 2 (C2), significantly reduce the risk for AMD (see Chapter 10).

In addition to the polymorphisms in the three complement factor genes, mutations at other loci have been implicated in a small percentage of patients with AMD, and they are classified as ARMD1 to ARMD12, depending on the susceptibility gene. In 7 of 402 patients with AMD, different heterozygous missense mutations were identified in the FBLN5 gene encoding fibulin 5, a component of the extracellular matrix involved in the assembly of elastin fibers. All patients had small circular drusen and retinal detachments. AMD was also seen among relatives of patients with Stargardt disease, an early-onset recessive form of macular degeneration seen in individuals homozygous for mutations in the ABCA4 gene. The affected relatives were heterozygous for ABCA4 mutations. Other ARMD genes include FBLN6, ERCC6, RAXL1, HTRA1, ARMS2, C3, TLR4, CST3, and CX3CR1. Mutations at each of these loci account for only a small proportion of the large number of individuals with AMD.


The pathobiology of AMD is characterized by inflammation. The current view is that inflammatory insults characteristic of aging have a greater impact in the retina of individuals predisposed to AMD because of reduced activity of the alternative complement pathway in limiting the inflammatory response. The inflammation damages the photoreceptors of the macula, causing retinal atrophy. AMD is further divided into “dry” (atrophic) and “wet” (neovascular or exudative) types. Early AMD is usually dry. Dry AMD is characterized by large soft drusen, the clinical and pathological hallmark of AMD. Drusen are localized deposits of extracellular material behind the retina in the region of the macula. Although small “hard” drusen, which are small granular deposits commonly found in normal retinas, are not associated with macular degeneration, large soft drusen are strongly linked with AMD and are harbingers of retinal damage. As AMD progresses, there is thinning and loss of retinal tissue in focal or patchy areas. In approximately 10% of patients, retinal pigment epithelium remodeling occurs at the site of large, soft drusen. There is invasion of the subretinal space by new blood vessels (neovascularization) that grow in from the choroid. These vessels are fragile, break, and bleed in the retina, resulting in wet AMD.

Drusen contain complement factors, including complement factor H (CFH). Given that CFH is a negative regulator of the alternative complement cascade and that the Tyr402His variant is less capable of inhibiting complement activation, Tyr402His appears to be a functional variant that predisposes to AMD. Importantly, the CFH variants confer increased risk for both the wet and dry forms, suggesting that these two manifestations of the disease have a common basis.

The Leu9His and Arg32Gln variants in factor B and the Glu318Asp and intron 10 variants of complement component 2 reduce the risk for AMD substantially (odds ratios of 0.45 and 0.36, respectively). The mechanism by which the variants in the factor B and complement component 2 genes decrease the risk for AMD is not yet known but is also likely to occur through their effect on complement activation.

Although it is clear that environmental factors contribute to AMD, the only nongenetic risk factor identified to date is smoking. Interestingly, smoking significantly decreases serum levels of CFH. The reason for the epidemic of AMD in developed countries is unknown.

Phenotype and Natural History

AMD leads to changes in the central retina that are readily apparent by ophthalmoscopy (Fig. C-3). Patients complain of loss of central vision, making reading and driving difficult or impossible. Visual loss is generally slowly progressive in dry AMD. In contrast, the bleeding from neovascularization can lead to retinal detachment or bleeding under the retina and cause rapid vision loss. Peripheral vision is usually preserved.


FIGURE C-3 A, Funduscopic image of numerous large, soft drusen in and around the region of the fovea (dryage-related macular degeneration). B,Neovascularization and scarring in the region of the fovea (arrow). C, Area of thinning and loss of retinal tissue at the fovea (“geographical atrophy”; arrow), which tends to protect against neovascularization. See Sources & Acknowledgments.


There is no specific treatment for the dry type of AMD. Smoking cessation is strongly indicated. Large clinical trials have suggested that for individuals with extensive intermediate-sized drusen or one large drusen, the use of antioxidants (vitamins A and E, beta-carotene) and zinc may slow progression of disease. Beta-carotene should probably not be used by smokers because some studies suggest it increases the risk for lung cancer and coronary heart disease.

For wet-type AMD, thermal laser photocoagulation, photodynamic therapy, and intravitreous injection of a vascular endothelial growth factor inhibitor (pegaptanib) may slow the rate of visual loss.

Inheritance Risk

The role of both genetic and environmental influences is demonstrated by twin studies showing concordance in monozygotic twins of 37%, far below the 100% expected for a purely genetic trait but still significantly greater than the 19% concordance in dizygotic twins, indicating there is a prominent genetic contribution to the disorder. First-degree relatives of patients are at a 4.2-fold greater risk for disease compared with the general population. Thus AMD falls into the category of a genetically complex disease. Despite ample evidence for familial aggregation in AMD, most affected individuals are not in families in which there is a clear mendelian pattern of inheritance.

Questions for Small Group Discussion

1. How could mutations in a complement factor account for a disease limited to the eye?

2. Suggest other types of proteins that could be implicated in AMD.

3. Discuss possible reasons that ABCR mutations account for such a small proportion of AMD if they are the main cause of Stargardt disease.

4. How would antibodies against vascular endothelial growth factor help in wet-type AMD? Suggest other diseases for which this treatment might be effective alone or in conjunction with other therapies.


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Kourlas H, Schiller DS. Pegaptanib sodium for the treatment of neovascular age-related macular degeneration: a review. Clin Ther. 2006;28:36–44.

Ratnapriya R, Chew EY. Age-related degeneration—clinical review and genetics update. Clin Genet. 2013;84:160–166.