Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an autosomal recessive connective tissue disorder in which fragmentation and calcification of elastic fibres results in skin (yellowish papules, skin laxity in flexural areas of the body), ocular (angioid streaks, subretinal neovascularisation and hemorrhage) and cardiovascular symptoms (occlusive artery disease). Caused by mutations in the ABCC6 gene (ATP-binding Cassette C6), PXE has always been regarded a paradigm for soft tissue calcification and ectopic mineralization diseases. An emerging amount of evidence suggests the presence of a disease spectrum encompassing PXE and a number of related phenotypes. Examples include the PXE-like syndrome with generalized cutis laxa and a coagulation defect (OMIM# 610842), caused by mutations in the gamma-carboxylase (GGCX) gene, the PXE phenocopies seen in haemoglobinopathies and acquired phenotypes such as PXE-like papillary dermal elastolysis. The recent descriptions of overlap phenotypes between PXE and PXE-like further strengthen the hypothesis of a disease spectrum.
The PXE phenotype is characterized by significant variability in disease severity. Although it was attempted to delineate genotype-phenotype correlations, it has proven difficult to find a clinically relevant relationship. The impossibility to predict the natural course in an individual patient hampers the use of individualized follow-up and leaves patients and their families with many uncertainties. To meet these limitations, it is assumed that modifier genes may play an important role in PXE. Unfortunately, to date very few modifier genes with clinical utility have been identified.
Since the identification of ABCC6 as the causal gene for PXE in 2000, more than 300 mutations have been described and progress has been made in the characterization of the ABCC6 transporter. Novel insights have emerged on ectopic mineralization and extracellular matrix homeostasis in PXE and in general. Among the classic theories are the metabolic hypothesis, with vitamin K and vitamin K-dependent calcification inhibitor deficiency and the role of an as yet unidentified serum factor and the cellular hypothesis encompassing the role of mitochondrial dysfunction and chronic oxidative stress. Novel findings and observations - such as the involvement of BMP-related pathways and the potential role of extracellular nucleotides and adenosine - endeavor to bridge the space between the rare ectopic mineralization diseases and ECM calcification in more common disorders such as atherosclerosis or chronic kidney disease. Despite growing insights in the clinical diversity and pathophysiological mechanisms of this disease spectrum, a significant number of questions remain. Physiologically, the identity of the substrate(s) of the ABCC6 transporter remains, 12 years after its identification, still puzzling; also the relation between deficiency of this transporter and the histological hallmark of PXE - calcification - is a mystery. The cellular mechanisms leading to ectopic mineralization are only just being unravelled and it can be hoped for that pathways relevant for common diseases such as atherosclerosis or age-related macular degeneration may in part also be of interest for the PXE spectrum. Clinically, the delineation of the phenotype of heterozygous carriers of one ABCC6 mutation and the identification of modifier genes are just some of the challenges that lie ahead. Finally, as knowledge increases, it will become more and more important to visualize how the clinical and pathophysiologiacl features of PXE, the related elastinopathies and ectopic mineralization disorders and ECM calcification in common diseases correlate with each other.
Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an autosomal recessive connective tissue disorder in which fragmentation and calcification of elastic fibres results in skin (yellowish papules, skin laxity in flexural areas of the body), ocular (angioid streaks, subretinal neovascularisation and hemorrhage) and cardiovascular symptoms (occlusive artery disease). Caused by mutations in the ABCC6 gene (ATP-binding Cassette C6), PXE has always been regarded a paradigm for soft tissue calcification and ectopic mineralization diseases. An emerging amount of evidence suggests the presence of a disease spectrum encompassing PXE and a number of related phenotypes. Examples include the PXE-like syndrome with generalized cutis laxa and a coagulation defect (OMIM# 610842), caused by mutations in the gamma-carboxylase (GGCX) gene, the PXE phenocopies seen in haemoglobinopathies and acquired phenotypes such as PXE-like papillary dermal elastolysis. The recent descriptions of overlap phenotypes between PXE and PXE-like further strengthen the hypothesis of a disease spectrum.
The PXE phenotype is characterized by significant variability in disease severity. Although it was attempted to delineate genotype-phenotype correlations, it has proven difficult to find a clinically relevant relationship. The impossibility to predict the natural course in an individual patient hampers the use of individualized follow-up and leaves patients and their families with many uncertainties. To meet these limitations, it is assumed that modifier genes may play an important role in PXE. Unfortunately, to date very few modifier genes with clinical utility have been identified.
Since the identification of ABCC6 as the causal gene for PXE in 2000, more than 300 mutations have been described and progress has been made in the characterization of the ABCC6 transporter. Novel insights have emerged on ectopic mineralization and extracellular matrix homeostasis in PXE and in general. Among the classic theories are the metabolic hypothesis, with vitamin K and vitamin K-dependent calcification inhibitor deficiency and the role of an as yet unidentified serum factor and the cellular hypothesis encompassing the role of mitochondrial dysfunction and chronic oxidative stress. Novel findings and observations - such as the involvement of BMP-related pathways and the potential role of extracellular nucleotides and adenosine - endeavor to bridge the space between the rare ectopic mineralization diseases and ECM calcification in more common disorders such as atherosclerosis or chronic kidney disease. Despite growing insights in the clinical diversity and pathophysiological mechanisms of this disease spectrum, a significant number of questions remain. Physiologically, the identity of the substrate(s) of the ABCC6 transporter remains, 12 years after its identification, still puzzling; also the relation between deficiency of this transporter and the histological hallmark of PXE - calcification - is a mystery. The cellular mechanisms leading to ectopic mineralization are only just being unravelled and it can be hoped for that pathways relevant for common diseases such as atherosclerosis or age-related macular degeneration may in part also be of interest for the PXE spectrum. Clinically, the delineation of the phenotype of heterozygous carriers of one ABCC6 mutation and the identification of modifier genes are just some of the challenges that lie ahead. Finally, as knowledge increases, it will become more and more important to visualize how the clinical and pathophysiologiacl features of PXE, the related elastinopathies and ectopic mineralization disorders and ECM calcification in common diseases correlate with each other.