Author: Julie De Zaeytijd (Belgium)
Co-authors: Frauke Coppieters, Marieke De Bruyne, Dimitri Roels, Caroline Van Cauwenbergh, Elfride De Baere, Bart Leroy
Purpose
Longitudinal, detailed phenotypic analysis in a 7-generation Belgian family with autosomal dominant late-onset retinal degeneration (L-ORD) due to the c.562C>A p.(Pro188Thr) variant in the C1QTNF5 gene, using a mixed cross-sectional and longitudinal approach.
Setting/Venue
Twenty-six patients (21 - 81 years) with a mean follow-up time of 8 years (range 1-37 years).
Methods
Extensive ophthalmic work-up including psychophysical, electrophysiological testing and multimodal imaging.
Results
Sequencing of the C1QTNF5 gene detected c.562C>A p.(Pro188Thr). SNP-based haplotyping revealed a common haplotype of 9.7 – 11.4 Mb, and genealogical investigation identified a common ancestor, rendering c.562C>A p.(Pro188Thr) a Belgian founder variant. Best-corrected visual acuity (BCVA) and visual fields were maintained up to 50 to 55 years (n=8), with a gradual decline but conservation of functional central vision between 55 to 65 years (n=15), followed by a steep decrease in overall visual function beyond 65 years (n=9). Classic anterior segment findings in L-ORD of abnormally long, anteriorly-inserted lens zonules were absent in most patients (n=24/26). In contrast, findings of iris transillumination and sphincter pupillae atrophy with poor dilation were novel. Patients presented with three completely different initial fundus phenotypes: adjoining pavingstone-like atrophic patches (type 1) (n=6/20); tiny yellow-white subretinal dots (type 2) (n=8/20); or larger yellow, thick, round sub-RPE drusenoid deposits (type 3) (n=4/20). Two patients had a mixed phenotype (type 1 and 2). Although different in presentation phenotype, patients eventually all progressed to a common panretinal atrophy with diffuse intraretinal pigment migration beyond the age of 65. Progression pace, and thus visual prognosis, differed depending on presentation phenotype. Specifically, type 2 appears to have the more benign course.
Conlusions
Phenotypic analysis showed 3 distinct presenting phenotypes with a considerable intrafamilial variability both in age of onset of clinical signs, as well as in disease progress, with a fair visual potential (> 20/40) until the seventh decade. This study provides novel insights into clinical signs and symptoms, as well as visual prognosis, emphasizing the phenotypic heterogeneity of L-ORD.
Financial Disclosure
Member of Advisory Boards for Novartis, Bayer, Abbvie
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