Peter Charbel Issa1, Carolyn Tysoe2, Richard Caswell3. 1. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, UK. Electronic address: study-enquiries@outlook.com. 2. Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 3. Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Institute of Biomedical and Clinical Science, University of Exeter School of Medicine, Exeter, UK.
Abstract
PURPOSE: To describe patients with late-onset Pseudoxanthoma elasticum (PXE) associated with a likely hypomorphic ABCC6 variant. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing and molecular modeling. RESULTS: Three patients with first vision symptoms over the age of 80 years showed age-related macular degeneration (AMD)-like fundus changes. However, features characteristic for PXE, including discrete angioid streaks and reduced fluorescence on late-phase indocyanine green angiography, prompted genetic testing which revealed the c.1171A>G variant in combination with a large deletion in ABCC6 in each case. None of the patients had obvious skin changes or cardiovascular disease atypical for their age. Comparative molecular modeling supported the hypothesis that c.1171A>GABCC6 acts as a hypomorphic variant. CONCLUSIONS: Late-onset PXE extents the spectrum of ectopic calcification disorders caused by mutations in ABCC6 and may clinically be limited to the eye, mimicking AMD. Patients may be identified based on specific ocular changes, whereas skin and cardiovascular changes may remain ambiguous. The study provides evidence for a role for hypomorphic ABCC6 variants in the pathogenesis of PXE.
PURPOSE: To describe patients with late-onset Pseudoxanthoma elasticum (PXE) associated with a likely hypomorphic ABCC6 variant. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing and molecular modeling. RESULTS: Three patients with first vision symptoms over the age of 80 years showed age-related macular degeneration (AMD)-like fundus changes. However, features characteristic for PXE, including discrete angioid streaks and reduced fluorescence on late-phase indocyanine green angiography, prompted genetic testing which revealed the c.1171A>G variant in combination with a large deletion in ABCC6 in each case. None of the patients had obvious skin changes or cardiovascular disease atypical for their age. Comparative molecular modeling supported the hypothesis that c.1171A>GABCC6 acts as a hypomorphic variant. CONCLUSIONS: Late-onset PXE extents the spectrum of ectopic calcification disorders caused by mutations in ABCC6 and may clinically be limited to the eye, mimicking AMD. Patients may be identified based on specific ocular changes, whereas skin and cardiovascular changes may remain ambiguous. The study provides evidence for a role for hypomorphic ABCC6 variants in the pathogenesis of PXE.