What causes Pseudoxanthoma Elasticum (PXE)?

From the Guidelines

Pseudoxanthoma elasticum (PXE) is primarily caused by mutations in the ABCC6 gene, which encodes a protein involved in cellular transport, leading to abnormal mineralization and fragmentation of elastic fibers in various tissues. The condition is associated with genetic disorders, including connective tissue diseases with abnormal collagen and hyperelasticity, such as Ehlers-Danlos syndrome, osteogenesis imperfecta, congenital hip dysplasia, nail patella syndrome, and hyper-immunoglobulin E syndrome associated with eczema and atopy 1. PXE is typically inherited in an autosomal recessive pattern, meaning a person must inherit two defective copies of the gene (one from each parent) to develop the condition. Key factors that contribute to the development of PXE include:

• Genetic mutations in the ABCC6 gene
• Abnormal mineralization and fragmentation of elastic fibers
• Association with connective tissue diseases and other genetic syndromes
• Autosomal recessive inheritance pattern The disease typically manifests in adolescence or early adulthood, though symptoms can appear at any age, and is characterized by yellowish papules on the skin, visual problems due to retinal changes, and cardiovascular complications from blood vessel damage 1. Less commonly, mutations in other genes such as ENPP1 and GGCX have been associated with PXE-like conditions. It is essential to consider the genetic and biochemical factors contributing to PXE to provide appropriate management and treatment options, prioritizing the patient's morbidity, mortality, and quality of life 1.

From the Research

Causes of Pseudoxanthoma Elasticum

• Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system 2.
• The disease is characterized by elastic fibre mineralisation and fragmentation, and is caused by mutations in the ABCC6 gene 2, 3, 4, 5.
• At least one ABCC6 mutation is found in about 80% of patients, and these mutations can be missense, nonsense, frameshift mutations, or large deletions 2.
• The inheritance pattern of PXE is autosomal recessive, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disease 2, 3, 4, 5.
• The ABCC6 gene encodes a protein that is a member of the large ATP-dependent transmembrane transporter family, and is expressed predominantly in the liver and kidneys 2.
• The physiological substrates of ABCC6 remain to be determined, but it is thought that PXE should be considered a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres 2.

Genetic Mutations

• A total of 59 distinct mutations in the ABCC6 gene have been identified, including 32 missense, eight nonsense, and six likely splice-site point mutations 4.
• Some mutations are relatively frequent, such as three nonsense mutations, a splice donor site mutation, and a large deletion comprising exons 23-29 4.
• Most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, suggesting that these chromosomes originate from single founder mutations 4.
• The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype 4.

Disease Mechanism

• The disease mechanism of PXE is thought to involve the progressive mineralization and fragmentation of elastic fibers in the skin, retina, and blood vessels 5.
• This leads to the characteristic cutaneous features of the disease, as well as morbidity related to the degree of extracutaneous involvement 5.
• The disease is progressive with phenotypic variability, and there is no definite genotype-phenotype correlation 5.