Fine central macular dots associated with childhood‐onset Stargardt Disease

Extensive phenotypic variability has been reported in ABCA4-related retinal disease since the discovery that mutations in the ABCA4 gene underlie Stargardt disease (STGD) (Allikmets et al. 1997). This report describes four cases with fundus features of fine macular dots associated with STGD. Four female cases from three families were recruited; two siblings were from one consanguineous family (case 1, 11 years and case 2, 9 years) and two cases from two additional families (case 3, 11 years and case 4, 11 years). After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8 and 6 years old, respectively. LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Fundus photography identified symmetrical yellowish-white fine dots at the central macula in all cases; in three (cases 1, 2 and 3), there were also numerous peripheral yellowish-white flecks (Fig. 1). Autofluorescence (AF) imaging showed well-defined dots of high AF signal corresponding to the macular dots seen clinically in all cases (Fig. 1). Additional foci of high or low signal extending to the peripheral retina were observed in cases 1, 2 and 3. In addition, case 1 had a ring of increased AF signal at the macula surrounding the area with the dots. Optical coherence tomography (OCT) detected gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing (Fig. 1). Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4). To our knowledge, this is the first report of cases with fine central macular dots in STGD. Three cases also had typical peripheral flecks, and two ABCA4 mutations were identified in each of two probands. Hence, both the clinical and molecular findings are in keeping with a diagnosis of STGD. Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle (Weleber et al. 2011; Sergouniotis et al. 2012). ABCA4 encodes a transmembrane rim protein that is involved in transport of retinoids. These common clinical features suggest that the fine macular dots may be caused by visual cycle dysfunction. Interestingly, a broadened peak of the presumed ELM was observed in two cases with fine central macular dots. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD (Burke et al. 2013). In our two cases, good visual acuity could support their suggestions, whilst the ONL was thinned and the ISe band was missing or severely diminished at the fovea.