CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

Abstract

Purpose: To investigate the Stargardt disease phenotype associated with an unusually common and "extremely hypomorphic" ABCA4 variant, p.N1868I.

Methods: The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of disease were recorded for all 27 patients, 18 of whom had multiple visits. When available, fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, full-field electroretinograms, Goldmann visual fields, and fluorescein angiography were included. Five families with multiple affected members were analyzed.

Results: The median age at symptom onset was 41.5 years, and 3 p.N1868I patients had not developed visual symptoms as of the most recent eye examination. Median best-corrected visual acuity in the better-seeing eye at baseline was 20/25, and the median duration from symptom onset to legal blindness was 25 years. The five families described in this study demonstrated clinically significant intrafamilial variability, and affected family members who did not share the p.N1868I variant had relatively more severe phenotypes.

Conclusion: This study demonstrates the consistency of foveal sparing, the variation in age at onset, the intrafamilial variability, and the prognosis with regard to visual acuity in p.N1868I-associated Stargardt disease.

Fig. 1

Pedigrees illustrating the segregation of multiple ABCA4 variants and discordant Stargardt disease phenotypes in five families. Affected individuals are represented by filled shapes (black = classic Stargardt disease or cone-rod dystrophy; gray = hypomorphic Stargardt disease; square = male; circle = female). The index patient or affected proband of each family is indicated by a white arrow. Affected individuals were observed across successive generations in three families (Families 1, 2, and 4; A, B, and D), with the patients possessing the p.N1868I variant having consistently later subjective onset than affected family members without that variant. Some phenotypic discordance was found among p.N1868I patients, even between patients with identical ABCA4 genotypes; this was especially notable in Family 2 (see main text and Figure 2). Family 3 (C) segregated c.5603A>T (p. N1868I) in both a single allele and a complex allele (in cis with c.5461–10T>C). The proband in Family 3 was diagnosed with Stargardt disease with onset in childhood; his mother (I:2, Patient #7) was biallelic for ABCA4, with p.N1868I and p.P1380L, and is indicated by a question mark to denote uncertainty whether she will develop overt Stargardt disease. Two affected sisters (Family 5, E; Patients #20 and #19) with the genotype p.N1868I/c.5196+1G>A were both found to have late-onset Stargardt disease with similar phenotypes.

Fig. 2

Near-infrared autofluorescence, measuring the presence of melanin, in four different patients from Family 2. Panel A (proband, Patient #4, age 61 years) shows a bull’s eye-like ring of hypoautofluorescence representing RPE atrophy, with inhomogeneity (dark spots) primarily at the temporal border representing flecks, and a small island of foveolar sparing. Panel B (sister of proband, Patient #3, age 62 years) shows a large macular lesion with visibility of choroidal vessels representing at least RPE and choriocapillaris atrophy, with hyperautofluorescent and hypoautofluorescent flecks at the borders of the lesion and a very small island of foveolar sparing. Panel C (daughter of proband, Patient #6, age 30 years) shows hypoautofluorescence centrally with a ring of homogeneous hyperautofluorescence and no definite foveal sparing (although BCVA in this eye was 20/70 at this visit, suggesting some foveal function). Panel D (also daughter of proband, Patient #5, age 27 years) shows an incomplete ring of subtle hyperautofluorescence.

Fig. 3

Macular SD-OCT line profiles, derived from SD-OCT b-scans. Reflectivity (arbitrary units; normalized to the RPE) is plotted as a function of retinal depth. The gray regions represent the range of normal and the two profiles (red and blue) are from two p.N1868I patients. The top-left panel shows measurements performed within a 1° region centered at the fovea (filled arrows), whereas the topright panel shows measurements from the nasal and temporal parafovea (0.5–5.5° from the fovea, broad arrow outlines). Below the graphs are the horizontal SD-OCT b-scans of the right macula in both p.N1868I patients, neither of whom had definite flecks or atrophy on ophthalmoscopy, with the measured regions of the fovea and parafovea demarcated by vertical lines. Note that Patient #7 had essentially normal line profiles, whereas the ELM of Patient #5 was hyperreflective relative to the control subjects in the parafovea. The ellipsoid zone (EZ) was similar to controls in both patients. Near-infrared autofluorescence in the right eye from Patient #7 is displayed in the lower right corner, showing no definite abnormalities; this is in contrast to the subtle NIR-AF changes found in Patient #5 (Figure 2D).

Fig. 4

Spaghetti plot showing BCVA in the better eye of all 27 p. N1868I patients, with the initial visit at time zero. Patients with only one visit are represented as dots. Note that in the first few years, none of the patients were worse than 20/50, but in later years, a number of patients (N = 6) did go on to lose foveal vision and were worse than 20/100 in the better eye.

Fig. 5

Fundus photographs of macular lesions and fundus fleck distributions found in ABCA4 p.N1868I patients. Panel A (Patient #23) shows Stage 1 fundus flecks with subtle bull’s eye hypopigmentation. Panel B (Patient #11) shows a bull’s eye-appearing lesion with Stage 2 flecks with a relatively sparse distribution. Panel C (Patient #25) shows an incomplete bull’s eye with several round areas of parafoveal hypopigmentation becoming confluent. Panel C also shows both nonpigmented and pigmented Stage 2 flecks. Panel D (Patient #14) shows Stage 3 (primarily resorbed flecks) and macular atrophy with a relatively spared fovea.

Fig. 6

Peripheral lesions in two patients with ABCA4 p.N1868I Stargardt disease. In the near-periphery of the left eye shown in Panel A (Patient #25), there are nonpigmented flecks in the macula and near-periphery, as well as reticular degeneration-like deep pigment in the mid-periphery. Panel B (Patient #10, right eye) shows a hypertrophic, highly pigmented lesion temporally.

Fig. 7

Goldmann visual fields of the right eyes in two patients with ABCA4 p.N1868I Stargardt disease. In both examples, the peripheral boundaries are normal to the II4e target. Panel A (Patient #26) shows a central relative scotoma to the II2e (filled in red), but only paracentral loss to II4e (filled in blue); the peripheral boundaries to the II4e and II2e targets are normal. Panel B (Patient #14) shows the most advanced visual field loss among the 27 p. N1868I patients, yet the peripheral sensitivity is still largely spared. There is a large central scotoma to all targets, including V4e (the largest and brightest available target). Peripherally, the II4e and larger targets are essentially normal; only the II2e target is considerably constricted.