Abstract
Background and aimsPseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. MethodsABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. ConclusionsPXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.
Highlights
Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder characterized by the fragmentation and calcification of the elastic fibers of the skin, the peripheral arteries and Bruch’s membrane in the eyes [1]
PXE is caused by pathogenic variants in the ABCC6 gene, overlapping phenotypes due to variants in the ENPP1 and GGCX genes have been reported [5]
289 clinically confirmed PXE patients were included from 243 families
Summary
Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder characterized by the fragmentation and calcification of the elastic fibers of the skin, the peripheral arteries and Bruch’s membrane in the eyes [1]. In the skin, this results in pseudoxanthomas and severe skin loosening due to reduced elasticity [1]. Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability
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