Macular Degeneration, Age-Related - AMD

Diagnosis

Indications for Testing

  • Macular degeneration on retinal examination

Laboratory Testing

  • Genetic testing may predict likelihood of disease progression in patients with AMD or predict risk in family members

Differential Diagnosis

Clinical Background

Age-related macular degeneration (AMD) is a degenerative retinal disease resulting in progressive central vision loss. AMD is the leading cause of blindness in older adults (>60 years) in North America and Europe.

Epidemiology

  • Prevalence – 1.75 million affected in U.S. (estimate from Eye Disease Prevalence Group)
    • 52-64 years – 1.6%
    • 65-74 years – 11%
    • >74 years – 28 %
  • Age – peak is >65 years
  • Sex – M<F
  • Ethnicity – Caucasians (highest risk)

Inheritance

  • Usually multifactorial
  • Two single nucleotide polymorphisms (SNP), Y402H and A69S, are independent risk factors for the development or progression of AMD; together, they account for approximately 70% of AMD risk
    • Y402H (c.1277T>C) is in the complement H factor (CHF) gene where histidine is substituted for lysine
    • A69S (c.205G>T) is located in the age-related maculopathy susceptibility 2 (ARMS2) gene, also known as LOC387715
  • Heterozygosity for either A69S or Y402H predicts a nearly threefold (95% Cl: 2.5-3.3) and a twofold (95% Cl: 2.0-2.6) increased risk for AMD, respectively
  • Heterozygosity for both Y402H and A69S is reported to cause a nearly sixfold (95% Cl: 4.4-7.7) increased risk for AMD
  • Homozygosity for either A69S or Y402H increases the risk for AMD by more than eightfold (95% Cl: 6.0-10.9) and more than sevenfold (95% Cl: 5.3-9.5), respectively
  • Homozygosity for both Y402H and A69S predicts a 57-fold (95% Cl: 37.2-89.0) increased risk for AMD

Risk Factors

Pathophysiology

  • Dry AMD
    • Early AMD
      • Spectrum of changes observed before the overt loss of vision
        • Drusen – fatty waste products of photoreceptor cells that accumulate within the retinal pigment beneath the macula, hypo- and hyperpigmentation of macula
    • Late AMD
      • Neovascularization and geographic atrophy observed
  • Wet AMD
    • Abnormal vessel growth beneath the macula, leaking blood and fluid into the macula

Clinical Presentation

  • Mild to severe visual impairment
  • Central vision blurring
  • Blind spots (scotomas)
  • Contralateral eye likely to be affected at some point

Treatment

  • Anti-VEGF (vascular endothelial growth factor) therapies
  • Thermal laser photocoagulation and photodynamic therapy

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Macular Degeneration, Age-Related, 2 DNA Markers 0051674
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Predict the likelihood of disease progression in individuals affected with early-stage AMD

Provide incentive for lifestyle modification in individuals with high-risk genotypes

Determine risk for AMD in individuals with a positive family history

Not recommended for nonsymptomatic patients <18 years

Detects only the two most common genetic variants associated with AMD

The variants tested are associated with risk for AMD but may not be causal for the disorder

Analytical sensitivity may be compromised by rare primer- or probe-site mutations

Counseling and informed consent are recommended for genetic testing