Purpose: To describe an atypical phenotype of retinal dystrophy in the setting of a heterozygous missense mutation (CRX-RD). Methods: The case is a 71-year-old woman previously diagnosed with advanced, non-neovascular, nonexudative age-related macular degeneration (AMD) who presented with longstanding blurry vision for consideration of intravitreal anti-complement factor therapy. Results: Ophthalmic examination showed geographic atrophy (GA) in both eyes, without evidence of drusen or drusenoid deposits. Genetic panel testing revealed a pathogenic, heterozygous missense mutation in CRX, the NM_000554.6(CRX) variant c.128G>A (p.Arg43His) (RCV001228802.6). Although CRX-RD is known to have phenotypic heterogeneity, cases with macular atrophy most commonly display bullseye maculopathy or benign concentric annular macular dystrophy. Conclusions: This case presenting with bilateral GA is consistent with a novel phenotype associated with a pathogenic variant of CRX and is an atypical presentation of RD simulating AMD.

The peripherin gene (PRPH2) mutation is associated with photoreceptor cell dysfunction as well as in several inherited retinal dystrophies. The PRPH2 mutation c.582-1G>A is a rare variant reported in retinitis pigmentosa and pattern dystrophy. Here Case 1 was of a 54-year-old woman with bilateral atrophy of the perifoveal retinal pigmentary epithelium and choriocapillaris with central foveolar respect. Autofluorescence and fluorescein angiography revealed perifoveal atrophy of the retinal pigmentary epithelium with an annular window effect without the "dark choroid" sign. Case 2 (mother of Case 1) presented with extensive atrophy of the retinal pigmentary epithelium and choriocapillaris. PRPH2 was evaluated and the c.582-1G>A mutation was identified in heterozygosity. An advanced adult-onset benign concentric annular macular dystrophy diagnosis was thereby proposed. The c.582-1G>A mutation is poorly known and not present in all common genomic databases. This case report is the first one to report a c.582-1G>A mutation associated with benign concentric annular macular dystrophy. Mutações do gene da periferina (PRPH2) estão associadas à disfunção das células fotorreceptoras e estão envolvidas em várias distrofias retinianas hereditárias. A mutação c.582-1G>A do gene PRPH2 é uma variante rara, relatada na retinite pigmentosa e nas distrofias em padrão. O caso 1 foi de uma mulher de 54 anos com atrofia bilateral do epitélio pigmentar da retina perifoveal e da coriocapilar, com acometimento foveolar central. A autofluorescência e a angiofluoresceinografia revelaram atrofia perifoveal do epitélio pigmentar da retina, com efeito de janela anular, sem o sinal da “coroide escura”. O caso 2 (mãe) apresentava extensa atrofia do epitélio pigmentar da retina e da coriocapilar. Foi feito um estudo do gene PRPH2, que identificou a mutação c.582-1G>A em heterozigose. Foi proposto um diagnóstico de distrofia macular anular concêntrica benigna de início adulto em estágio avançado. A mutação c.582-1G>A é pouco conhecida e não está presente em todos os bancos de dados genômicos usuais. Este é o primeiro relato de caso publicado de uma mutação c.582-1G>A associada à distrofia macular anular concêntrica benigna.

Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP. Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role. Exome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments. This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Background Historically, CRX mutations have been associated with cone-rod dystrophy, cone dystrophy, Leber's congenital amaurosis, and retinitis pigmentosa. There is recent emerging evidence of an adult-onset macular dystrophy phenotype. We review the published literature and discuss the first case of heterozygous CRX R90 W macular dystrophy. Materials and Methods The patient received serial ophthalmic examination and imaging. Genetic testing was performed by MyRetinaTracker with the use of a retinal dystrophy panel. Results A 55-year-old Caucasian male patient without a prior medical history presented for evaluation of decreased vision in the right eye. Visual acuity was 20/32 both eyes, and his fundus examination was notable for an incomplete ring-shaped macular atrophy with foveolar sparing in both eyes. Fundus autofluorescence was notable for hypo-autofluorescence of the ring and fluorescein angiography for transmission hyperfluorescence. Full-field ERG and EOG were normal, while mfERG showed central depression. His lesion was clinically diagnosed as benign concentric annular macular dystrophy, but genetic testing revealed a heterozygous mutation in CRX (c.268 C > T, p.R90 W). A three-generation family tree did not reveal other members with known macular dystrophy. Given the lack of documentable autosomal dominant inheritance and the presence of a CRX mutation, the patient's diagnosis was revised to adult-onset macular dystrophy. Conclusions We believe this to be the first case of adult onset macular dystrophy associated with heterozygous CRX R90 W mutation.