Hereditary Disorders of Cardiovascular Calcification

Abstract

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.

Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort

“…To this end, recent studies of genetic disorders of ectopic mineralization have disclosed several causal genes that have provided new insights into the mechanisms of ectopic mineralization processes in general. 2,3 Among the hereditary ectopic mineralization disorders, pseudoxanthoma elasticum (PXE) (Online Mendelian Inheritance in Man [OMIM] 264800) is the most common orphan disease with a prevalence of approximately 1:50,000.…”

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum

“…Arterial calcification is a feature of aging, atherosclerosis, chronic kidney disease, and diabetes [1]. A few monogenic disorders are characterized by an early-onset of vascular calcification affecting the arterial media [2][3][4]. These diseases include pseudoxanthoma elasticum (PXE), the most frequent one, generalized arterial calcification of infancy (GACI), 2 of 11 and arterial calcification due to deficiency of CD73 (ACDC).…”

“…These diseases include pseudoxanthoma elasticum (PXE), the most frequent one, generalized arterial calcification of infancy (GACI), 2 of 11 and arterial calcification due to deficiency of CD73 (ACDC). These three conditions promote a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in soft tissues and arteries [2][3][4].…”

“…PXE results from biallelic mutations of the ABCC6 gene, encoding for ABCC6 (ATPbinding cassette, subfamily C member 6), a transmembrane ABC transport protein expressed mainly in the liver and the kidney. PXE patients are affected by vascular (arterial), retinal, kidney, and skin calcifications [2,3,[5][6][7]. ABCC6 promotes adenosine triphosphate (ATP) externalization in the blood, where ATP is hydrolyzed by the ectonucleotide pyrophosphatase phosphodiesterase-1 (ENPP1), inducing systemic pyrophosphate and adenosine monophosphate (AMP) release.…”

“…ABCC6 and ENPP1 are actually the main source of systemic pyrophosphate, limiting ectopic hydroxyapatite crystalline deposits in arteries and other tissues. Patients with PXE, as well as Abcc6 −/− mice, have a reduced plasma pyrophosphate level which explains at least partly their mineralization disorder [2][3][4]6,7].…”