Elsevier

Survey of Ophthalmology

Volume 48, Issue 4, July–August 2003, Pages 424-438
Survey of Ophthalmology

Current research
Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update

https://doi.org/10.1016/S0039-6257(03)00053-5Get rights and content

Abstract

Pseudoxanthoma elasticum is an autosomally inherited disorder that is associated with the accumulation of mineralized and fragmented elastic fibers in the skin, Bruch's membrane in the retina, and vessel walls. The ophthalmic and dermatologic expression of pseudoxanthoma elasticum and its vascular complications are heterogeneous, with considerable variation in phenotype, progression, and mode of inheritance. Using linkage analysis and mutation detection techniques, mutations in the ABCC6 gene were recently implicated in the etiology of pseudoxanthoma elasticum. ABCC6 encodes the sixth member of the ATP-binding cassette transporter and multidrug resistance protein family (MRP6). In humans, this transmembrane protein is highly expressed in the liver and kidney. Lower expression was found in tissues affected by pseudoxanthoma elasticum, including skin, retina, and vessel walls. So far, the substrates transported by the ABCC6 protein and its physiological role in the etiology of pseudoxanthoma elasticum are not known. A functional transport study of rat MRP6 suggests that small peptides such as the endothelin receptor antagonist BQ123 are transported by MRP6. Similar molecules transported by ABCC6 in humans may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. One of these sites is Bruch's membrane. This review is an update on etiology of pseudoxanthoma elasticum, including its clinical and genetic features, pathogenesis, and biomolecular basis.

Section snippets

The skin and mucosal membranes

Skin lesions are frequently seen in PXE patients and were initially described in 1881 by Rigal110 and in 1896 by Darier.27 In 1929 Groenblad and Strandberg recognized the combination of skin and eye abnormalities for the first time.52., 132.

The most common presentation of skin lesions involves ivory to yellowish-colored, raised papules varying in size from 1–3 mm. The papules may have a linear or reticular arrangement and may coalesce into plaques.125 Sometimes larger confluent areas with

The skin

The classic histological picture of PXE skin is elastin abnormality in the mid-epidermis with normal morphology in the papillary and deep dermal layers.87

The elastin band undergoes swelling, granular degeneration, and fragmentation; splitting and curling of elastin fibers gives it the appearance of an iron wool scouring pad upon Von Kossa staining.75., 90., 117. In the abnormal granular elastin matrix, calcium depositions (CaCO3and CaPO4) were found.87 In addition, the presence of proteoglycans

Classification of PXE

From the previous sections describe, it may be clear that the diagnosis of PXE may be quite difficult. Neither the skin lesions nor the AS by themselves are pathognomonic. Von Kossa staining in skin biopsies will probably more often solve a diagnostic problem than demonstration of AS, because the differential diagnosis of elastin changes in a skin biopsy contains fewer disorders than the differential diagnosis of AS (Table 2). The comet-like tails in the retina seem to be pathognomonic for PXE

Mode of inheritance

The majority of PXE patients are sporadic cases. In PXE families with a discernible mode of inheritance, AR inheritance is much more common than AD segregation.102., 103., 104., 144. In PXE families, multiple affected siblings are common, but multigenerational transmission is rare. Initially, some investigators have attempted to subtype PXE based both on phenotypic expression and inheritance. Pope et al suggested, on the basis of the phenotype alone, that there are two AD and two AR forms of

Transport function of ABCC6 in relation to PXE

At present, the relationship between biomolecules transported by ABCC6 and the PXE disease phenotype is not clear. Given the high expression of ABCC6 in kidney and liver, it is possible that PXE is in fact a heritable systemic disorder.142 In this scenario, a primary defect of ABCC6 in liver and kidney could result in abnormal levels of ABCC6 substrates in the blood, which could affect the elastic fiber assembly at specific sites in the body. On the other hand, (lower) ABCC6 expression also has

Future prospects

The recent progress in the identification of the gene for PXE is a significant step. New insights in the etiology of the disease have opened up new research avenues, but many questions remain. The functional consequences of mutations in ABCC6 gene are not yet understood. It is essential to obtain additional genetic mutation and phenotypic data for a complete overview of all mutations that lead to PXE. With these data, further insight will be gained in the genotype–phenotype relationship and the

Method of literature search

Medline, PubMed, and OVID search of relevant literature spanning the period 1966 to January 2002 was performed. Search terms were the following: ATP-binding cassette transporter, (autosomal dominant) angioid streaks, Bruch's membrane, classification, differential diagnosis, elastic fibers, hereditary angioid streaks, pseudoxanthoma elasticum, photoreceptor, retina, and retinal pigment epithelium. Additional references included standard textbooks on biology and biochemistry of the eye as well as

Acknowledgements

The authors acknowledge with gratitude Ms. S. Terry (PXE International Committee) for her support and helpful comments. We would like to thank. L. Kornet, PhD, for stimulating comments. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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