Begrijpen en Behandelen van Pseudoxanthoma Elasticum Huidziekten

PUTATIVE PATHOMECHANISMS

Table I

Anti-Mineralization Factor with a Potential Role in the Pathogenesis and/or Treatment of Pseudoxanthoma Elasticum

* Those proteins marked with an asterisk are known to undergo vitamin K-dependent γ-glutamyl carboxylation [Berkner, 2008]

Utilization of the Abcc6 −/− mouse model of PXE has confirmed the presence of chronic oxidative stress as reflected by reduced total antioxidant capacity and the presence of enhanced protein oxidation and lipid peroxidation markers [Li et al., 2008]. However, an antioxidant diet containing vitamins C and E, selenium and N-acetylcysteine, while counteracting the oxidative stress, did not modify the process of aberrant mineralization of connective tissues in these mice. Thus, these animal studies do not support the possibility that ingestion of antioxidants may be directly beneficial in counteracting the disease process in PXE, but carefully controlled clinical trials on patients with PXE could potentially provide an unequivocal answer. At the same time, it should be noted that the progression of the phenotype in patients with PXE often parallels the development of chronic, age-associated diseases, such as arteriosclerosis and age-associated macular degeneration, resulting in a combination of clinical manifestations. Thus, treatments suggested to be beneficial in ameliorating age-associated complications in general, such as antioxidants, could also be beneficial for patients with PXE.

An interesting observation, with potential pathomechanistic implications, is offered by patients with mutations in the GGCX gene, with the development of skin findings reminiscent of PXE [Vanakker et al., 2007, Li et al., 2009a]. The GGCX gene encodes a vitamin K dependent enzyme, γ-glutamyl carboxylase, which catalyzes γ-carboxylation of glutamyl residues in a number of proteins (Gla proteins), including several coagulation factors and a number of extracellular matrix proteins, such as MGP ( Table 1 ) [Berkner, 2008]. The carboxylation reaction is required for activation of these proteins, and as a result of deficient γ-glutamyl carboxylation of clotting factors, these patients demonstrate vitamin K-dependent coagulation factor deficiency manifesting with a bleeding disorder. The action of γ-glutamyl carboxylase is dependent on reduced vitamin K as a cofactor [Berkner, 2008]. Based on the similarity of cutaneous findings in PXE and patients with GGCX mutations in both alleles, it has been suggested that the ABCC6 deficiency in PXE patients may result in reduced concentrations of vitamin K or its derivatives in serum causing reduced activation of anti-mineralization proteins, such as MGP [Borst et al., 2008, Vanakker et al., 2010]. In fact, the ratio of active (carboxylated) compared to inactive (undercarboxylated) forms of MGP have been shown to be reduced in the tissues of patients with PXE and in PXE mouse model [Gheduzzi et al., 2007, Li et al., 2007], suggesting a critical role for vitamin K in pathogenesis of PXE. While this hypothesis is currently being tested in different model systems of PXE, it was first reported at this conference that feeding of Abcc6 −/− mice with high doses of vitamin K1 or K2 or systemic injection of vitamin K3-glutathione conjugate into these mice had no effect on the level of tissue mineralization [Jiang et al., 2011, Brampton et al., 2010]. The results in the mouse model therefore suggest that supplementation of the diet of PXE patients with vitamin K may not be effective and will require further study.

MODEL SYSTEMS

Soon after the first demonstrations of mutations in the ABCC6 gene in human patients with PXE, transgenic knockout mice were developed through targeted ablation of the Abcc6 gene [Gorgels et al., 2005, Klement et al., 2005]. These Abcc6 −/− mice recapitulate many of the features of human PXE, including autosomal recessive inheritance with full penetrance and delayed onset of mineralization which becomes evident by histopathologic examination around 5-6 weeks of age. Similar to findings in humans, the PXE mice demonstrate deposition of mineral complexes in the skin, the retina and arterial blood vessels, in addition to widespread evidence of mineralization in other tissues as well. A characteristic feature of Abcc6 −/− mice is the early and progressive mineralization of the connective tissue capsule surrounding vibrissae [Klement et al., 2005]. Consequently, assessment of the degree of mineralization of vibrissae during the development and growth of the mice by histopathology coupled with computerized morphometric analysis, and by direct chemical assay of calcium and phosphate, serves as a biomarker that can be quantitated to follow the progression of mineralization in these mice [Jiang et al., 2007]. Thus, the Abcc6 knockout mice have provided a useful preclinical model system to explore the pathomechanisms of PXE and to test potential treatment modalities.

One of the limitations of the mouse model is the long developmental lifespan and relatively slow onset of the disease. In addition, establishment and maintenance of mouse colonies is time consuming and costly. In search for complementary, and perhaps more expedient model systems to study heritable skin diseases in general, the zebrafish was examined as an alternate [Li et al., 2011b]. The zebrafish, a freshwater vertebrate, has nearly the same complement of genes as mammals, and assembly of the zebrafish genome database is essentially complete. The zebrafish embryos develop rapidly outside of the mother’s body, so that the organ development, including skin, which is essentially complete at 5-6 days post fertilization, can be visualized by optical means.

Diagnosis and Classification

In developing a classification for a disease, such as PXE, there are several considerations. For example, the diagnostic criteria should be specific based on diagnostic findings, they should be sensitive and not limited to a minority of patients, and they should be easily detectable and quantitatively measurable. Such criteria should also show high inter-observer reliability, should have been validated, and should be applicable to different age groups. Such criteria are necessary for the development and standardization of clinical trials, understanding the histopathology and correlate the phenotypic findings with pathogenetic observations, thus helping to translate the meaning of the molecular data. The presence of diagnostic criteria is also important for disease registries to produce meaningful and comparable data.

The early attempts to devise a classification system for PXE date back to 1970s, when Pope described four subtypes based on clinical findings and the proposed mode of inheritance, autosomal dominant vs. autosomal recessive, in a cohort of 121 patients [20]. One of the difficulties with this classification was that the clinical signs were not particularly well delineated. Furthermore, with the advent of molecular genetics and identification of the mutant genes, it has been demonstrated that the inheritance of PXE is exclusively autosomal recessive, and there is no autosomal dominant form of this disease [21,22]. In 1988, Neldner proposed that histopathological diagnosis of a lesion on the neck or a flexural area should be an inclusion criterion, but this approach eliminates potential cases without characteristic skin lesions or with atypical histopathology [1]. In 1992, a Consensus Conference proposed classification of patients into two major categories, based on histopathology and clinical findings in the skin and the eyes. A combination of these criteria allowed classification of patients either into “certain PXE” (Category I) or “uncertain PXE” (Category II) [23]. Vanakker et al. in 2008 classified PXE patients into “definite”, “probable” and “probably not” categories, based on skin evaluation and ophthalmologic examination [24].

Pseudoxanthoma elasticum huidziekten

Bei Pseudoxanthoma elasticum (PXE) handelt es sich um eine seltene, erbliche Erkrankung, die auf einem Defekt des sog. ABCC6-Proteins beruht und vor allem die Haut, die Augen und das Herz-Kreislauf-System betrifft.

Im Jahre 1929 brachten die schwedische Augenärztin Groenblad und der schwedische Hautarzt Strandberg das Auftreten von gefäßähnlichen Streifen der Netzhaut im Auge mit den PXE-typischen Hautveränderungen in Verbindung. Seitdem wird „Groenblad-Strandberg Syndrom“ auch gleichbedeutend mit Pseudoxanthoma elasticum verwendet.

PXE ist eine seltene, erbliche Erkrankung mehrerer Organe, bei der es zu einer Anreicherung verkalkter und gebrochener elastischer Fasern in der Haut, einer der vielen Hüllen des Augapfels (der Bruch-Membran) und den Gefäßwänden kommt. Klinisch fallen v. a. Herz- und Gefäßkomplikationen, Hautveränderungen und Veränderungen des Augenhintergrunds auf.

Die Erkrankung wird häufig erst spät durch Auftreten von Augenkomplikationen diagnostiziert, auch wenn schon seit einigen Jahren oder Jahrzehnten ungewöhnlich ausgeprägte Herz- und Gefäßprobleme und nicht-symptomatische Hautveränderungen bekannt sind.