At What Age Does Age-Related Macular Degeneration Start?

Abstract

Patients presenting to an ophthalmologist with macular drusen at a young age is not an uncommon scenario in medical retina clinics. These young patients want to be informed regarding their future visual prognosis, possible impact on occupation or activities of daily living, and most importantly, any prospect of treatment. What criteria could contribute to an ophthalmologist's confidence in diagnosing early-onset age-related macular degeneration (AMD) as opposed to the early features of an inherited macular dystrophy, such as Doyne retinal dystrophy/Malattia Leventinese or Sorsby fundus dystrophy? In this issue of JAMA Ophthalmology, de Breuk et al 1 report the findings of a genotype-phenotype study in patients with early-onset macular drusen. The authors have used the term early-onset drusen maculopathy (EODM) to describe younger (≤55 years) patients with macular drusen and compared 89 patients with EODM with 91 patients diagnosed with AMD who were 65 years or older.Strikingly, the study shows that approximately 45% of these patients with EODM developed geographic atrophy or choroidal neovascularization in at least 1 eye by the mean age of 56.4 years, with associated visual impairment. Approximately 30% of patients in the EODM cohort carried a rare complement factor H (CFH) genetic variant, compared with approximately 8% of patients with AMD. Patients with EODM tended to carry fewer common variants that are known to predispose to maculopathy in patients with AMD. 2 However, these patients showed a considerable enrichment in genetic risk attributable to rare genetic variation. Rare genetic variants, particularly located in protein-coding regions of genes, tend to have very large effects, inversely proportional with their allele frequency. 3 The presence of rarer risk variants located within the same genes in patients with EODM intriguingly may suggest an explanation for the early onset of symptoms compared with the AMD cohort.This study demonstrates a shared genetic and phenotypic profile between EOMD and AMD. Therefore, is EOMD a separate disease from AMD or does it suggest that AMD exists in individuals younger than 55 years? The findings described here 1 suggest that patients presenting with an AMD phenotype who are younger than 55 years have a similar genetic basis for the disease, albeit with more rare variants, and as such, have an early-onset form of AMD.A lower genetic risk score for common AMD genetic risk variants was observed in the EOMD cohort. While the genes involved are the same for both the EOMD and AMD cohorts, the differences in phenotypic expression probably represent a reflection of the genetic architecture, ie, individuals with a