Daniela Quaglino, Federica Boraldi and Giulia Annovi

Daniela Quaglino by SINGER-POLIGNAC

Pseudoxanthoma elasticum: more than an elastic fiber disorder

Daniela Quaglino, Federica Boraldi and Giulia Annovi

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder mainly affecting skin, eyes and the cardiovascular system due to progressive mineralization of elastic fibres in the presence of normal levels of calcium and phosphorus in blood and urine. Because PXE is characterized by calcification of elastic fibres, genes involved in the synthesis and assembly of the elastic fibre network (namely elastin, elastin-associated microfibrillar proteins, lysyl oxidase) were initially considered as primary candidates for mutations. Failure in demonstrating their pathogenetic role led to the discovery that the ABCC6 gene (16p.13.1) is actually the main site of mutations in PXE. So far, more than 300 different mutations have been reported in ABCC6, a gene that encodes for a transmembrane protein (MRP6), whose physiological substrate is still elusive, although it has been suggested that it may be involved in the transport of complex conjugated molecules. In spite of the high level of ABCC6 expression, liver and kidney do not suffer from mutations in this gene. By contrast, tissues as skin, retina and vessel walls, which are deeply altered in PXE, express very low levels of MRP6.

These findings raised a still puzzling dilemma concerning the pathogenesis of PXE: how do mutations in a gene expressed primarily in the liver result in the mineralization of a certain number of elastic fibres in peculiar areas of the body? Furthermore, elastic fibers, given their almost absent turnover, can be regarded as a mirror of body homeostasis, thus reflecting changes in complex metabolic pathways and being the result of more general matrix alterations? From in vivo and in vitro studies, it has been shown that, although the dramatic involvement of the elastic component, other abnormalities characterize the PXE phenotype. Patients, for instance, exhibit altered levels of circulating factors such as proteoglycans, lipoproteins and mineralization inhibitors (i.e. fetuin-A and Matrix Gla Protein). Moreover, a number of plasma molecules have been shown to be modified by effects of an altered redox balance that, directly through and epigenetic regulation or indirectly due to the high amount of oxidised proteins and lipids, might have relevant consequences on soft connective tissue cells. Consistently, numerous in vitro studies undoubtedly highlighted the permanently modified phenotype of mesenchymal cells and the active role of these cells in the pathogenesis of ectopic calcifications.

Nevertheless, a clear understanding of PXE pathogenesis is further complicated by the fact that the age of disease onset and the expression of clinical symptoms are highly variable and marked phenotypic variations have been observed in affected siblings bearing the same ABCC6 mutation. Although there is no evidence of involvement of other genes in the pathogenesis of PXE, however, a number of modifying factors, both genetic and environmental, have been suggested to play a role in the phenotypic expression of the disease. Moreover, even though no other phenotypes are known to be associated with mutations in the ABCC6 gene, PXE-like clinical features, including aberrant mineralization of elastic fibres, have been reported in a number of apparently unrelated acquired and genetic clinical conditions.

Among the acquired conditions, PXE-like cutaneous changes may be associated with multiple pregnancy, in longstanding end-stage renal disease, L-tryptophan induced eosinophilia myalgia syndrome and amyloid elastosis as well as after D-penicillamine treatment, cutaneous exposure to calcium salts and salpeter. In these cases, mineralization of skin is the result of metabolic abnormalities affecting calcium and/or phosphate homeostasis or of direct deposition of mineral salts on collagen or elastic fibres.

Unexpectedly, PXE-like cutaneous changes have also been found in approximately 20% of patients with beta-thalassemia and sickle cell anaemia, that are well known severe congenital forms of anemia resulting from the deficient or altered synthesis of haemoglobin chains. In addition, the recent observation that a PXE-like phenotype can be observed in patients with pronounced deficiency of the vitamin K-dependent clotting factors raised the intriguing and exciting possibility that there might additional pathway/s, independent of ABCC6, leading to the PXE phenotype.

Therefore, Pseudoxanthoma elasticum represents a very interesting example for investigating the complexity that regulates molecular pathways and the influence of metabolism on the extracellular matrix of several organs/systems.

Data from the lab of the presenting Author result from research studies supported by PXE International, PXE Italia Onlus and Fondazione Cassa di Risparmio di Modena (EctoCal).