Insights into Pathomechanisms and Treatment Development in Heritable Ectopic Mineralization Disorders: Summary of the PXE International Biennial Research Symposium-2016

Abstract

Pseudoxanthoma elasticum is a prototype of heritable ectopic mineralization disorders, with phenotypic overlap with generalized arterial calcification of infancy and arterial calcification due to CD73 deficiency. Recent observations have suggested that the reduced inorganic pyrophosphate/phosphate ratio is the cause of soft connective tissue mineralization in these disorders. PXE International, a patient advocacy organization, supports research in part by sponsoring biennial research symposia on these disorders; the latest meeting was held in September 2016 at Thomas Jefferson University, Philadelphia. This report summarizes the progress in pseudoxanthoma elasticum and other ectopic mineralization disorders, as presented in the symposium, with focus on translational aspects of precision medicine toward improved diagnostics and treatment development for these currently intractable disorders.

Figure 1. Clinical features and histopathology of ectopic mineralization in pseudoxanthoma elasticum

(a, b) Cutaneous findings consist of discrete yellowish papules that coalesce into inelastic, leathery plaques on the predilection sites, such as the side of the neck. (c, d) Histopathology of the affected skin reveals accumulation of pleomorphic elastotic material that becomes progressively calcified (left panel, Verhoeff-van Giesson elastic stain; right panel, von Kossa calcium stain). (e) Eye involvement is signified by angioid streaks reflecting breakage in the calcified Bruch’s membrane (arrows). These breaks allow neovascularization from the underlying capillaries to the retina (arrowheads) leading to loss of visual acuity and blindness unless treated. (f) Extensive mineralization of arterial vasculature, as illustrated by left renal artery, can result in nephrogenic hypertension, intermittent claudication and occasionally early myocardial infarcts and strokes (aadapted from Li et al., 2014a).

Figure 2. Schematic illustration of the generation of PPi and Pi, and heritable diseases featuring perturbations in the promineralization/antimineralization networks

Loss-of-function mutations in the ABCC6, ENPP1, NT5E, and ALPL genes cause autosomal recessive pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), arterial calcification due to CD73 deficiency (ACDC), and infantile hypophosphatasia (HOPS), respectively. ABCC6, a putative transmembrane transporter, mediates ATP release from hepatocytes to extracellular space where ATP is converted to PPi and AMP by ENPP1, a membrane-bound pyrophosphatase/phosphodiesterase; CD73 converts AMP to Pi and adenosine, the latter one being an inhibitor of tissue nonspecific alkaline phosphatase (TNAP), an extracellular, yet membrane-associated protein, that hydrolyzes PPi to Pi. Deficiencies in ABCC6, ENPP1, and CD73 proteins lead to reduced plasma PPi levels and PPi/Pi ratio, thereby promoting hydroxyapatite mineralization in peripheral tissues. TNAP deficiency is associated with severe hypophosphatasia and defective bone mineralization due to significantly increased plasma pyrophosphate levels. ANKH is a transmembrane protein that transports PPi across the plasma membrane and stimulates the elaboration of extracellular PPi from intracellular stores. Loss of ANKH function in patients and in progressive ankylosis mice leads to decreased extracellular PPi and increased hydroxyapatite deposition in articular cartilage (ank phenotype). Gain-of-function mutations in ANKH gene can cause calcium pyrophosphate deposition disease (CPPD) due to excess extracellular PPi. The PPi/Pi balance is, therefore, critical for prevention of ectopic mineralization and maintenance of normal skeletal mineralization. Please note that these reactions do not necessarily take place in the same cell. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; EC, extracellular; IC, intracellular; PPi, inorganic pyrophosphate.