Author: Ángela González Alonso (Spain)
Co-authors: Gerardo Pedro García García, Angi Lizbeth Mendoza Moreira, Belén Figuerola García, Lucía Moreno Castro, David Gijón Carretero, Juan José Pérez-Santonja
Aged-related macular degeneration (AMD) is a progressive, chronic disorder affecting the macula and is the leading cause of non-reversible vision impairment worldwide in people over 50 years. Degenerative changes in Bruch's membrane provide a pro-angiogenic environment that can promote choroidal neovascularization (CNV). Anti-Vascular Endothelial Growth Factor (Anti-VEGF) agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation may occur. Genetic testing for neovascular AMD is not routinely performed. Nevertheless, in cases of poor response to standard therapy, aggressive forms of AMD or doubts in the diagnosis it can be a useful resource to guide us in management. We report two cases of bilateral neovascular AMD with no response to Anti-VEGF therapies in which genetic testing was conducted, both presenting a complex inheritance pattern.
Department of Ophthalmology, University General Hospital of Alicante, Alicante, Spain. Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.
Clinical examination of the patients included: • Best-corrected visual acuity (BCVA) in decimal scale. • Slit lamp biomicroscopy of the anterior segment. • Intraocular pressure measurement by handheld rebound tonometer (Icare Finland Oy, Vantaa, Finland). • Indirect biomicroscopic examination of the ocular fundus with a 90-diopter lens and a Goldmann fundus contact lens (Volk Optical, Mentor, USA). • Retinography and fundus autofluorescence (FAF) image with a field of view of 45 degrees of the retina (DRI OCT Triton, Topcon, Tokyo, Japan). • Spectral domain optical coherence tomography (SD-OCT) of the macula and optic nerve head (DRI OCT Triton, Topcon, Tokyo, Japan). • Massive parallel DNA next-generation-sequencing (NGS) technique using a gene panel of 64 genes associated with AMD and inherited macular dystrophies with drusen.
The first patient, a 78-year-old woman was admitted in 2014 due to visual impairment in the right eye (RE). BCVA was 0.7/0.9 and fundus examination showed a neuroepithelial detachment (NED) in the RE. SD-OCT revealed a round-oval polyp attached to NED, being the diagnosis of polypoidal choroidal vasculopathy (PCV) made. In 2018 the disease became bilateral. The patient was non-responder to anti-VEGF therapy in both eyes because her BCVA did not improve by 1 ETDRS line and the foveal thickness not decreases as a result of the multiple anti-VEGF injections performed. BCVA was 0.2/0.2 in 2020. Genetic testing revealed two heterozygous mutations: variant c.1169G>A; p. (Arg390His) in the IMPG2 gene and c.1500G>A; p. (Arg500=) in the ABCA4 gene. The second patient, a 69-year-old male, was referred in 2018 due to visual loss in the left eye (LE). BCVA was 0.8/0.1. In the examination, signs compatible with PCV in the LE were observed, becoming bilateral one year later. He was also non-responder to neither anti-VEGF therapy nor photodynamic therapy (PDT). BCVA in 2020 was 0.4/0.15. Genetic study revealed two heterozygous mutations: variant c.1413C>T; p. (Ser471=) in the EFEMP1 gene and c.499C>T; p. (Pro167Ser) in the C9 gene.
We report two cases of non-responder to anti-VEGF therapy patients with a devastating course of AMD. Both exhibited heterozygous mutations in genes related to AMD and macular dystrophies. Heterozygous variants in IMPG2 gene have been detected in patients with adult-onset vitelliform macular dystrophy (AVMD) and autosomal dominant inheritance (AD). The mutation c.1169G>A; p. (Arg390His) -a variant of unknown significance (VUS) - detected in our first patient suggests AVMD. AVMD can be confused with AMD because of the presence of small macular lesions that may be complicated by CNV. On the other hand, we consider variant c.1500G>A; p. (Arg500=) in ABCA4 gene likely benign. Concerning the second patient, variant c.1413C>T; p. (Ser471=) in EFEMP1 gene is a VUS linked to Doyne honeycomb retinal dystrophy, with AD inheritance, and the heterozygous variant c.499C>T; p. (Pro167Ser) in the C9 gene confers an increased risk for AMD. Doyne retinal dystrophy may be confused with AMD because of the presence of drusen and evolution to CNV. Differentiation between AMD and other disorders is crucial as accurate diagnosis can affect prognosis and genetic counselling as well as for preventive and therapeutic strategies. Genetic testing should be considered in non-responder to anti-VEGF therapy AMD patients.
The authors declare that there has not a financial interest in the subject matter or receives money from any mentioned company.