Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

A randomized controlled trial of oral phosphate binders in the treatment of pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare connective tissue disorder involving fragmentation and mineralization of elastic fibers predominantly in the skin, eyes, and cardiovascular system. OBJECTIVE: The objective of this study was to assess the efficacy of sevelamer hydrochloride on the reversal of elastic fiber calcification and clinical lesions of PXE. METHODS: This was a randomized, double-blind, placebo-controlled, two-part prospective study. In the first year, 40 patients with PXE were randomized to receive either sevelamer hydrochloride (800 mg by mouth three times daily) or placebo in a 1:1 ratio. In the second year, all patients received sevelamer hydrochloride (800 mg by mouth three times daily). RESULTS: In the first year, the placebo and treatment groups' mean calcium scores decreased from 29.52 to 15.97 (41.93% mean improvement) and 27.48 to 16.75 (38.37% mean improvement), respectively. In the second year, the mean calcium scores decreased to 13.36 (53.94%) and 14.03 (51.35%) in these groups. The mean clinical score in the placebo group decreased from 6.25 to 6.05 at year 1 (2% improvement) whereas the mean clinical score in the sevelamer hydrochloride group decreased from 7.10 to 6.55 (7% improvement). In year 2, the scores in the original placebo and sevelamer hydrochloride groups decreased to 5.33 (14% improvement) and 5.72 (19% improvement), respectively. LIMITATIONS: Magnesium stearate in our placebo and active drugs may have played a confounding role in this study, contributing to the small differences observed in these two groups. CONCLUSION: Sevelamer hydrochloride produced a reduction in both calcification levels and clinical scores; however, this difference was not statistically significant compared with placebo. Future clinical studies should examine the inhibitory role and potential therapeutic effect of magnesium in PXE.

Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE).

In recent years it has become clear that, mechanistically, biomineralization is a process that has to be actively inhibited as a default state. This inhibition must be released in a rigidly controlled manner in order for mineralization to occur in skeletal elements and teeth. A central aspect of this concept is the tightly controlled balance between phosphate, a constituent of the biomineral hydroxyapatite, and pyrophosphate, a physiochemical inhibitor of mineralization. Here, we provide a detailed analysis of a zebrafish mutant, dragonfish (dgf), which is mutant for ectonucleoside pyrophosphatase/phosphodiesterase 1 (Enpp1), a protein that is crucial for supplying extracellular pyrophosphate. Generalized arterial calcification of infancy (GACI) is a fatal human disease, and the majority of cases are thought to be caused by mutations in ENPP1. Furthermore, some cases of pseudoxanthoma elasticum (PXE) have recently been linked to ENPP1. Similar to humans, we show here that zebrafish enpp1 mutants can develop ectopic calcifications in a variety of soft tissues - most notably in the skin, cartilage elements, the heart, intracranial space and the notochord sheet. Using transgenic reporter lines, we demonstrate that ectopic mineralizations in these tissues occur independently of the expression of typical osteoblast or cartilage markers. Intriguingly, we detect cells expressing the osteoclast markers Trap and CathepsinK at sites of ectopic calcification at time points when osteoclasts are not yet present in wild-type siblings. Treatment with the bisphosphonate etidronate rescues aspects of the dgf phenotype, and we detected deregulated expression of genes that are involved in phosphate homeostasis and mineralization, such as fgf23, npt2a, entpd5 and spp1 (also known as osteopontin). Employing a UAS-GalFF approach, we show that forced expression of enpp1 in blood vessels or the floorplate of mutant embryos is sufficient to rescue the notochord mineralization phenotype. This indicates that enpp1 can exert its function in tissues that are remote from its site of expression.