Background: North Carolina Macular Dystrophy (NCMD) is a non-progressive inherited macular dystrophy characterized by marked phenotypic variability. The genetic etiology of NCMD remains largely unknown, and only a limited number of families have been reported in Europe. Methods: We performed an in-depth investigation of an Italian family affected by NCMD using an integrated approach that combined SNP-array analysis, whole-exome sequencing, and long-read whole-genome sequencing. Additionally, we conducted a comprehensive review of NCMD-related literature. Results: We identified a novel 98 Kb duplication involving both PRDM13 and CCNC genes in a three-generation kindred, where the proband exhibited severe macular alterations, while all other affected family members presented with a milder clinical phenotype. A review of the literature suggests different genotype-phenotype correlations and similar penetrance for duplications and single-nucleotide variants (SNVs) in described families. Specifically, smaller duplications may be associated with more severe phenotypes, while SNVs exhibit high phenotypic variability. Conclusions: In this study, we describe the first NCMD Italian family, in which the integration of second- and third-generation sequencing methods enabled the identification of a novel pathogenic PRDM13 and CCNC duplication, thereby expanding the mutational spectrum of NCMD. Overall, these findings, together with the literature review, highlight the importance of selecting appropriate genetic testing approaches that allow the detection of non-coding variants and CNVs and thus enable accurate diagnosis and effective clinical management of patients and their families.

North Carolina Macular Dystrophy (NCMD) is an autosomal dominant, congenital, completely penetrant non-progressive macular malformation. The NCMD phenotype is highly variable even within the same family (Fig. 21.1). Grade 1 individuals have few drusen centrally while grade 2 can appear with confluent drusen to central vitelliform lesions. Grade 3 appears as dramatic choroidal excavations and coloboma like lesions (Small 1989; Small et al. 1991, 2022a). There can be some vision decline secondary to the development of choroidal neovascular membranes (CNVMs) (Bakall et al. 2018). Patients who develop CNVMs are the subjects who experience progressive moderate to severe vision impairment, typically confined to one eye. In grade 3 lesions, the CNVMs and resulting fibrosis typically occur along the temporal edge of the "coloboma" and do not affect the visual acuity. Peripheral drusen are variably reported.

Macular colobomata (MCs) are excavated chorioretinal lesions found in subjects with systemic diseases and syndromes, positive family history, congenital toxoplasmosis, North Carolina Macular Dystrophy, and other retinal dystrophies. Case report. A full-term-born, otherwise healthy 18-year-old female patient with no known family history of ocular conditions presented bilateral MCs, peripheral spotty hypopigmentation, and compromised cone and rod function. Genetic testing showed the pathogenic homozygous variant NM_001029883.3:c.3604C>T (p(Arg1202*)) of C2ORF71/PCARE, a ciliary gene previously associated with RP and cone-rod dystrophy, but not previously found in cases of MCs. Further studies are needed to elucidate the genotype/phenotype correlation and the pathogenesis of MCs in retinal dystrophies.

A diagnosis of age-related macular degeneration (AMD) may have a significant impact on a patient's life. Therefore, it is important to consider differential diagnoses, as these can differ considerably from AMD regarding prognosis, inheritance, monitoring and therapy. Differential diagnoses include other macular diseases with drusen, drusen-like changes, monogenic retinal dystrophies, as well as a wide range of other, often rare macular diseases. In this review, clinical examples are presented that illustrate alternative diagnoses to AMD and when these should be considered. These include, amongst others, patients with autosomal dominant drusen, Sorsby fundus dystrophy, pachydrusen, late-onset Stargardt disease, extensive macular atrophy with pseudodrusen (EMAP), pseudoxanthoma elasticum (PXE), North Carolina macular dystrophy, mitochondrial retinopathy, benign yellow dot maculopathy, dome- or ridge-shaped maculopathy, or macular telangiectasia type 2. Die Diagnose der altersabhängigen Makuladegeneration (AMD) kann einen Einschnitt im Leben von Patienten bedeuten. Vor diesem Hintergrund ist es wichtig, Differenzialdiagnosen in Erwägung zu ziehen, da diese sich hinsichtlich Prognose, Vererblichkeit, Kontroll- und Therapiebedarf beträchtlich von der AMD unterscheiden können. Differenzialdiagnosen sind vor allem andere Makulaerkrankungen mit Drusen, drusenähnlichen Veränderungen, weitere monogene Netzhautdystrophien sowie ein breites Spektrum weiterer, oftmals seltener Makulaerkrankungen. In dieser Übersicht werden anhand klinischer Beispiele Befundkonstellationen gezeigt, bei denen eine Differenzialdiagnose der AMD in Erwägung gezogen werden sollte. Unter anderem beinhaltet dies Patienten mit autosomal-dominanten Drusen, Sorsby-Fundusdystrophie, Pachydrusen, spät beginnendem Morbus Stargardt, extensive makuläre Atrophie mit Pseudodrusen (EMAP), Pseudoxanthoma elasticum (PXE), North-Carolina-Makuladystrophie, mitochondriale Retinopathie, Benign Yellow Dot Maculopathy, kuppel- oder leistenförmige Makulopathie und makuläre Teleangiektasien Typ 2.

To describe a novel case of secondary multiple evanescent white dot syndrome in a patient with North Carolina Macular Dystrophy. The patient was evaluated with ultra-widefield color and autofluorescence imaging, fluorescein angiography, and spectral-domain optical coherence tomography. A 43-year-old man with longstanding blurred vision in both eyes acutely developed glare in the right eye after an upper respiratory illness. He had chorioretinal atrophy in both eyes consistent with North Carolina Macular Dystrophy, which was later confirmed by genetic testing. He also had white spots in the macula of the right eye consistent with secondary multiple evanescent white dot syndrome. The diagnosis of secondary multiple evanescent white dot syndrome was confirmed with fundus autofluorescence and fluorescein angiography, and a negative infectious workup. His symptoms and the retinal lesions had resolved by 11 weeks and after a short course of oral corticosteroids. Prior studies have suggested a link between disruption of the retinal pigment epithelium/Bruch membrane complex and secondary multiple evanescent white dot syndrome. This report describes the first case of secondary multiple evanescent white dot syndrome after North Carolina Macular Dystrophy and provides further support for this association.