Connective tissue
Brian J Pollard, Gareth Kitchen in Handbook of Clinical Anaesthesia, 2017
Pseudoxanthoma elasticum (PXE) is a systemic disorder of elastic and collagen tissue in which there is progressive calcification and degeneration of elastin fibres and the supportive collagen matrix in skin and mucous membranes. Similar processes may affect the arterial system, leading to arterial occlusion and ischaemia. Ocular and myocardial involvement may also occur. The condition is caused by a mutation in the ATP-binding cassette subfamily C member 6 (ABCC6) gene, inherited in either an autosomal dominant or recessive pattern. Diagnosis is usually confirmed by skin biopsy. The prevalence of PXE is estimated to be between 1 in 50,000 and 1 in 200,000 adults. The disease occurs at any age and, although average life expectancy is normal, premature death in childhood is a recognised risk. Acceleration of symptoms may occur during pregnancy. The majority of patients with PXE who undergo anaesthesia and surgery have an uncomplicated course and outcome. Those with severe cardiovascular involvement are at greater risk, as are those suffering complications such as gastrointestinal haemorrhage, requiring emergency surgery.
Stroke and Transient Ischemic Attacks of the Brain and Eye
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue related to mutations in the ABCC6 (adenosine triphosphate [ATP] binding cassette subtype C number 6) gene, which primarily affects the skin, retina, and cardiovascular system. It is characterized pathologically by elastic fiber mineralization and fragmentation (so-called “elastorrhexia”), large artery calcifications and stenosis, and clinically by substantial heterogeneity in age of onset and the extent and severity of organ system involvement. The diagnosis relies on clinical features and the histologic demonstration of abnormal, calcified elastic fibers in the dermis through the use of special stains.
Disorders of bone and connective tissue
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Most cases of pseudoxanthoma elasticum follow autosomal recessive inheritance, but a few apparently dominant families have been described, mostly with milder clinical features. Asymptomatic individuals may be detected by the presence of angioid streaks in the retina. Most cases are caused by homozygous or compound heterozygous mutations in ABCC6, leading to calcification of elastic fibres in skin, the arterial wall and the retina; the apparently dominant families mostly represent examples of pseudo-dominant inheritance.
Pseudoxanthoma elasticum and retinitis pigmentosa: dual diagnosis of recessive conditions with ophthalmological consequences
Published in Ophthalmic Genetics, 2020
Disha Katiyar, Peter Davies, Himanshu Goel
Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disease with variable systemic manifestations that are a result of mineralisation and fragmentation of elastic fibres (1). The prevalence of PXE is estimated to be between 1:25 000 and 1:100 000 (2). Pathogenic mutations in ABCC6 (OMIM 603234) are associated with PXE. ABCC6 (Chr16p13.1) encodes for multidrug resistance protein six (MRP6) which is a part of the ATP-binding cassette family (2). The highest level of ABCC6 expression is in the liver and kidney cell membranes; for this reason, it is theorised that PXE is a metabolic disease caused by abnormal levels of molecules which play a role in the synthesis of the extracellular matrix (1). Since connective tissue is present throughout the body, the disease manifests with skin, eye and cardiovascular features.
Coquille d’oeuf in young patients affected with Pseudoxantoma elasticum
Published in Ophthalmic Genetics, 2019
Vittoria Murro, Dario Pasquale Mucciolo, Dario Giorgio, Andrea Sodi, Federica Boraldi, Daniela Quaglino, Gianni Virgili, Stanislao Rizzo
Five young PXE patients (2 males and 3 females) were investigated. Mean age was 16 years (range 12–20 years) from three different families. P2 and P3 were brother and sister whereas P4 and P5 were twins. Positive Skin biopsy was available for four patients (P1, P3, P4, P5), patient P2 did not perform the biopsy exam. Analysis of genetic features revealed that P1 was heterozygous for only one rare sequence variant in the ABCC6 gene (c.1132C>T, p.Gln378*) (9), but additional analyses on other genes that have been recently associated to Pseudoxanthoma Elasticum (i.e. GGCX and ENPP1) (10) revealed, in ENPP1, the functional polymorphism c.517A>C, p.Lys173Gln (11). The other patients were compound heterozygous for two pathogenic sequence variants in the ABCC6 gene. In particular, P2 and P3 were carriers of the stop codon variant c.3490C>T, p.Arg1164* (12) and of the splicing mutation c.3736-1G>A (13), whereas P4 and P5 were carriers of the splice site mutation c.2247 + 1G>A (14) and of the missense mutation c.3661C>T, p.Arg1221Cys (15). All patients were asymptomatic, and the visual acuity was 20/20 in both eyes. Fundus examination showed retinal abnormalities in all patients.
A novel tumor-homing TRAIL variant eradicates tumor xenografts of refractory colorectal cancer cells in combination with tumor cell-targeted photodynamic therapy
Published in Drug Delivery, 2022
Zhao Li, Tianshan She, Hao Yang, Tao Su, Qiuxiao Shi, Ze Tao, Yanru Feng, Fen Yang, Jingqiu Cheng, Xiaofeng Lu
The chemotherapeutic MDR of cancer cells is predominantly attributed to overexpressed chemical efflux pumps, such as ABC transporters. To investigate the expression of ABC transporters in tumor tissues derived from CRC patients, public RNA-seq data obtained from TCGA and GTEx were analyzed by GEPIA. As shown in Figure 1(A) and Supplementary Figure S1, bioinformatics analysis demonstrated that the tumor tissue levels of ABC transporters, including ABCB1, ABCB7, ABCC1, ABCC2, ABCC3, ABCC4, ABCC6, ABCC10, ABCC11, and ABCG1, were significantly higher than those in normal tissues, suggesting the MDR of CRC cells. In fact, cytotoxicity assays revealed that CRC cells, such as COLO205, HCT116, LS174T, and HT29, showed resistance (IC50 > 1000 nM) to all tested chemical drugs, including cisplatin, vincristine, doxorubicin, and bortezomib (Figure 1(B)). Interestingly, bioinformatics analysis also demonstrated that death receptors, including DR4 and DR5, were overexpressed in CRC tumor tissues (Figure 1(A)), suggesting the potential of TRAIL as an anticancer agent for CRC. In fact, TRAIL showed robustly (ICs50 < 10 nM) cytotoxicity in CRC cells, including COLO205, HCT116, and LS174T cells overexpressing DR5 and/or DR4 (Figure 1(C, D)), indicating that TRAIL might overcome the chemotherapeutic MDR of CRC cells. Nevertheless, due to the low expression of death receptors, some CRC cells, such as HT29, showed moderate resistance (IC50s > 50 nM) to TRAIL (Figure 1(C, D)), suggesting the need to improve the cytotoxicity of TRAIL in these cells.
Related Knowledge Centers
- Protein
- Atherosclerosis
- Pseudoxanthoma Elasticum
- Gene
- Atp-Binding Cassette Transporter
- Multiple Drug Resistance