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 20/25−2, 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.

Author Response: Penetrance of theABCA4p.Asn1868Ile Allele in Stargardt Disease

“…Reduced penetrance in a disease with a highly variable age of onset arguably is difficult to substantiate as disease may develop later in life. However, the age of onset of recently described cohorts of patients harboring p.Asn1868Ile [2][3][4] (Fig. ) shows a normal distribution with a peak incidence between 30 and 50 years, and 49/57 (86%) of p.Asn1868Ile cases show STGD1 symptoms before the age of 60 years.…”

“…c.768G>T), 6 which was found as a trans allele in three p.Asn1868Ile cases. 3 As the allele frequency of this complex allele is not present in SE-NL nor in nFE ExAC, we did not include it in our calculations. Fourth, in the commentary it was stated that modifiers should only be mentioned if these have actually been identified, such as cis-modifiers for c.5603A>T. Although we cannot exclude the possibility that as yet unrecognized variants in cis with c.5603A>T partly explain the reduced penetrance mentioned above, we consider our findings in STGD1 families, a likely sex imbalance of the cases, and the calculations above, strongly indicate that modifiers do play a big role.…”

Progressive Choriocapillaris Impairment in ABCA4 Maculopathy Is Secondary to Retinal Pigment Epithelium Atrophy

“…[1][2][3] The typical presentation involves yellow, pisciform flecks along with macular atrophy that leads to central vision loss. [3][4][5] Nevertheless, STGD exhibits extensive clinical heterogeneity, readily apparent in fundus imaging and presentation. For example, patients can present with disease onset early in adulthood (adult-onset) or late in adulthood (late-onset), both of which are usually associated with milder disease, whereas early-onset (early or before teenage years) is associated with more severe disease.…”

“…For example, patients can present with disease onset early in adulthood (adult-onset) or late in adulthood (late-onset), both of which are usually associated with milder disease, whereas early-onset (early or before teenage years) is associated with more severe disease. 4,[6][7][8] Imaging of the posterior pole has become an essential tool for the clinician in the diagnosis and monitoring of retinal dystrophies, including STGD. Short-wavelength fundus autofluorescence (SW-AF) is an important imaging modality for STGD, as the areas of retinal pigment epithelium (RPE) atrophy that characterize the disease are readily observed as areas of hypoautofluorescence.…”

“…For example, patients can present with disease onset early in adulthood (adult-onset) or late in adulthood (late-onset), both of which are usually associated with milder disease, whereas early-onset (early or before teenage years) is associated with more severe disease. 4 , 6 – 8 …”