A nonconsanguineous family (MOL0632) of Ashkenazi-Jewish ancestry (
Fig. 1A) was recruited for this study. The 9-year-old asymptomatic index case (IV:1) was found to have foveal changes on a routine eye examination (
Figs. 2A, B, E, F), and subsequently further evaluation and testing was performed on her and on other family members. Visual acuity of the index case was normal (
Table 1), and her fundus showed signs compatible with subclinical, early (previtelliform) stages of Best disease, including yellow foveal spots (
Figs. 2A, E) that are more readily seen on infrared imaging (
Figs. 2B, F) and show very minimal hyperautofluorescence (
Figs. 2C,G). Horizontal spectral OCT scans through the fovea show the physiologic hyporeflective cleft that characterizes the outer segment/RPE complex in the subfoveal region and are normal (
Figs. 2D, H). Full-field ERG testing revealed normal light-adapted cone ERG responses and supernormal dark-adapted rod and mixed cone-rod ERG amplitudes with normal implicit times (the cause and significance of the elevated dark-adapted ERG responses are not clear; the hypermetropia that is present may partially account for this). The EOG Arden ratio, however, was severely reduced, with practically no light rise (
Table 1). Panel D-15 color vision testing did not reveal any deficiencies. Based on these findings, she was clinically diagnosed with Best disease. After her diagnosis, her younger brother (IV:4) was referred for examination. At the age of 2.5 years, visual acuity (using a picture cube) was 0.8 in each eye, but maculopathy was already clearly evident (
Figs. 2I–N). Interestingly, foveal changes were more prominent than in his older sister, and spectral OCT shows significant subfoveal deposits located between the RPE and Bruchs membrane (
Figs. 2K, N). ERG testing under anesthesia (using a short protocol, without full dark adaptation) was within normal limits (
Table 1). Because of the young age of the patient, EOG testing as well as more detailed retinal imaging could not be performed. Clinical evaluation of the father at 40 years of age (III:4) revealed normal retinal appearance and function including a normal fundus examination (
Figs. 3A, B), OCT (
Figs. 3C, D), color vision, and EOG. Fundus findings, color vision, and EOG were also normal in the 34 year-old mother (III:3) of the affected children. After the molecular genetic work-up (detailed below), we also performed clinical evaluation of the two grandmothers (II:1 and II:3). In both, EOG, FFERG, and color vision were within normal limits (
Table 1). Individual II:1 (
Fig. 1A), at age 62, had a practically normal fundus examination, with mild extramacular RPE changes manifesting as deep, pale yellow spots that showed some staining on late-phase FA images (
Figs. 3E, F). In contrast, individual II:3 (
Fig. 1A), at age 61, had marked macular changes compatible with moderate to severe dry (nonneovascular) AMD, including large soft drusen (some of them confluent) that are clearly evident on fundus color photos (
Figs. 3H, I) and spectral OCT imaging (
Fig. 3J). Interestingly, the deceased mother of this patient (individual I:1) was also reported to manifest severe AMD, causing legal blindness in her early sixties.