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  Disease summary:

  
  
  
  
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    The “macula” is the central portion of the retina, where the greatest density of cone photoreceptors provides clear central vision. With increasing age, the macula is susceptible to disruption of the normal cellular architecture.

    
    
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    In the early stages, toxic metabolic waste products, especially metabolites of the retinal photopigments, accumulate in the retinal pigment epithelial cells immediately beneath the retinal photoreceptors. Accumulations of photoreceptor debris overwhelm the cellular transport mechanisms and form extracellular deposits known as “drusen” between the retinal pigment epithelium and the underlying basement membrane. While small, isolated drusen are essentially innocuous, larger, coalescent drusen indicate a high risk of atrophic breakdown of the retinal pigment epithelium and the underlying capillary bed, the choriocapillaris. This often takes the form of sharply demarcated atrophic patches, referred to as “geographic atrophy” or “dry” macular degeneration. The overlying retinal photoreceptors cease to function, resulting in central scotomas and loss of visual acuity. In some cases, the underlying vascular bed reacts to the atrophic process by the elaboration of vascular membranes which proliferate under the retinal pigment epithelium, or between the retinal pigment epithelium and the retina. These neovascular membranes are prone to extravasation into the extracellular space, causing macular edema, as well as subretinal hemorrhage, again leading to loss of central vision. This “wet” or “exudative” macular degeneration is much less frequent than “dry” macular degeneration, but accounts for most cases of severe visual loss from macular disease.

    
    
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    Age-related macular degeneration (AMD) (or macular degeneration, for short) is a leading cause of acquired blindness in developed countries, accounting for 54% of legal blindness in the United States.

    
    
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    There is a strong racial predilection: prevalence among adults age 45 to 85 is 5.4% among Caucasians, 4.6% among ethnic Chinese, 4.3% among Hispanics, 2.4% among African Americans. The prevalence increases rapidly in all ethnic groups after age 80.

  
  
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  Differential diagnosis:

  
  
  
  
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    Geographic atrophy: hereditary macular dystrophies (Stargardt disease, retinitis pigmentosa, cone and cone-rod dystrophy, central areolar pigment epithelial dystrophy), congenital retinal abnormalities (coloboma, Leber congenital amaurosis), traumatic injuries, retinal drug toxicity.

    
    
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    Exudative maculopathy: diabetic retinopathy with macular edema, central serous chorioretinopathy, juvenile retinoschisis, myopic retinal degeneration, Best vitelliform dystrophy, serpiginous choroiditis, familial exudative vitreoretinopathy, epiretinal membranes with macular pucker.

    
    
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    Diagnosis is based on ophthalmoscopic appearance, then confirmed by fluorescein angiography to identify subretinal neovascularization, and optical coherence tomography imaging (OCT) to confirm and measure macular edema.

  
  
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  Monogenic forms:

  
  
  
  
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    No single-gene cause of age-related macular degeneration is known. Candidate genes which may contribute to risk for AMD include APOE (apolipoprotein E—found in drusen, affects lipid transport), and genes for several Mendelian disorders somewhat akin to AMD: ABCA4—Stargardt disease; TIMP3—Sorsby fundus dystrophy; VMD2—Best vitelliform dystrophy; Fibulin-3—Malattia leventinese, RDS-peripherin—pattern dystrophies; A4917G—a mitochondrial DNA polymorphism; TLR4—toll-like receptor 4.

  
  
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  Family history:

  
  
  
  
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    Comparison of prevalence of AMD between parents and children is difficult, as information about parents is frequently unavailable by the time their children are old enough to be at significant risk for AMD. After controlling for race and other known risk factors for AMD, the odds ratio (OR) for AMD in the siblings of patients with AMD compared with siblings of unaffected probands is between 3.6 and 10.3, depending on the stage of disease.

  
  
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  Twin studies:

  
  
  
  
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    Concordance for AMD in twin studies has ranged from 90% to 100% in monozygotic twins, compared with about 40% in dizygotic twins.

  
  
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  Environmental factors:

  
  
  
  
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    Smoking increases the risk of AMD 3.5-fold. Dietary supplementation with antioxidant vitamins and zinc is weakly protective against AMD in patients at high risk.

  
  
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  Genome-wide association studies:

  
  
  
  
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    Linkage signals have been demonstrated to 1q25-31 (CFH) and 10q26 (ARMS2/HTRA1). Association signals have been confirmed to ABCA4, CFI, C2-CFB, and C3.

    
    
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    The locus associated with AMD at or near 1q31 is the gene for complement factor H (CFH). Unfavorable single-nucleotide polymorphisms (SNPs) at this locus and other complement factor loci are associated with ORs for development of AMD of 2.0 to 4.0.

    
    
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    Two genes at 10q26, LOC387715 (of unknown function), and HTRA1 have been associated with AMD. Variations in alleles of these two loci account for as much as 63% of the variation in risk for AMD, with ORs in combination as great as 57.6.

  
  
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  Pharmacogenomics:

  
  
  
  
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    Data are very preliminary. Specific SNPs of CFH and LOC387715 have been associated with small variations in the degree of protection against AMD by nutritional supplements, and frequency of injections of antivascular endothelial growth factor (anti-VEGF) treatments (see later).

The diagnosis of AMD is based on ophthalmoscopic findings and clinical imaging.

Findings of dry AMD include

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  Clumping and irregularity of the macular pigment epithelium

  
  
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  Drusen

  
  
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  Geographic atrophy of the macular pigment epithelium

  
  
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  Abnormal transmission of “choroidal flush” during early phases of fluorescein angiography (“window defects”)

Findings of wet AMD include

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  Macular edema

  
  
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  Turbid or cloudy subretinal fluid

  
  
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  Subretinal hemorrhage

  
  
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  Progressive intensification and spreading of subretinal fluorescence during late phases of fluorescein angiography