Early-onset drusen maculopathy: Ideal candidate for development of complement gene therapy

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Reviewed by Carel B. Hoyng, MD, PhD

Carel Hoyng, MD, PhD, discussed early-onset drusen maculopathy (EODM), which is part of the age-related macular degeneration (AMD) phenotype that occurs in individuals under 55 years of age. Hoyng, professor of ophthalmology, Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands, presented his ideas at the Angiogenesis, Exudation, and Degenerative conference sponsored by Bascom-Palmer Eye Institute, Miami.

He suggested that EODM may be an ideal candidate for development of complement gene therapy due to the high-impact genetic variants.

AMD develops as the result of genetic and environmental factors, with aging an important component. He addressed studying the genetic mechanism of AMD by removing the impact of age by amassing a cohort of young patients (EODM subjects). He also suggested reducing the effect of the environment by studying multiple families and by reducing the environmental effect by studying multiple families with multiple affected subjects.

He pointed out that there is a higher proportion of positive genetic risk in late and early AMD. The genetic risk score is a tool that can estimate the cumulative contribution of genetic factors to the development of AMD and can predict progression in patients who do not have a high number of drusen.

He cited a study¹ in which he and his research team set out to identify genotypic and phenotypic characteristics of patients with EODM. “We determined the contribution of 52 AMD associated variants by calculating a genetic risk score and performed a comprehensive analysis of rare variants in complement genes. The phenotypic characteristics were assesed by grading fundus photographs for the presence of different features, such as drusen type, location and area, pigment, and the presence of end-stage disease,” he explained.

The study included 89 patients aged 55 years and younger with EODM. A second group of 91 patients aged 65 years and older with AMD also was included to compare the genotypic and phenotypic characteristics.

When they analyzed the genetic characteristics in both groups, the researchers found that the genetic risk score was higher in AMD patients. Hoyng explained that, although the median genetic risk score was lower in EODM, there is a large overlap, meaning that there is a shared genetic basis.

“When analyzing the complement genes, we identified rare variants in the complement factor H (CFH) gene in a large proportion, ie 30.3%, of the patients with EODM patients, in contrast to 7.7% in patients with AMD. More than 70% of the identified CFH variants in patients with EODM were found in the first 7 complement control protein domains of factor H,” he reported.

Some typical phenotypic characteristics in the EODM group were large colloid drusen, temporal drusen, and extensive extramacular drusen. He related that 44.9% of patients with EODM developed advanced macular degeneration in 1 or both eyes at a mean age of 56.4 years. Patients with EODM more often had a large macular drusen area compared to those with AMD (14.8% vs 5.5%, OR 4.6, P=0.008).

Rare variants can have a large impact on outcomes at the end stage of patients with EODM.The three most important phenotypic characteristics of CFH rare variant carriers are larger drusen areas, increased drusen nasal to the optic disc, and increased drusen with a crystalline appearance.

Importance of genetic testing

Undergoing genetic test will create awareness of the disease potential in families at risk. It also will facilitate changes in lifestyle and provide the ability to distinguish between dystrophies and AMD. In addition, patients may be eligible candidates for therapeutic trials.

Potential carriers of rare variants in the complement genes are individuals with an early age of onset, have 2 or more affected first-degree family member, more than 100 hard drusen or more than 50 soft drusen, drusen that are nasal to the optic disc, and extensive geographic atrophy. Three of more of these criteria is the guideline to suggest genetic testing in The Netherlands.

In addition to the age of onset of EODM, the phenotypic and genotypic overlap between AMD and EODM, and the rare CFH variants found frequently in patients with EODM, Hoyng also suggested that EODM seems to be an early manifestation of AMD rather than a separate disease entity, and rare variants in the CFH gene may contribute to an earlier onset.

Future research that addresses the functional characterization of rare CFH variants will allow for better interpretation of their clinical relevance. The current findings support targeting the complement system and sequencing the CFH gene for upcoming AMD treatments supplementing factor H, Hoyng concluded.

Reference

1. de Breuk A, Heesterbeek TJ, Bakker B, et al. Evaluating the occurrence of rare variants in the complement factor H gene in patients with early-onset drusen maculopathy. JAMA Ophthalmol. 2021;139:1218-1226; 1. doi: 10.1001/jamaophthalmol.2021.4102.