controls, longer time to maximal cold-induced flow reduction, and longer recovery time (Hollo´ et al., 1998). These findings have been summarized in a recent editorial (Irkec, 2006).

Electron microscopy reveals aggregates of XFM in heart, lung, liver, kidney, gall bladder, and meninges in patients with ocular XFS (Schlo¨tzerSchrehardt et al., 1992; Streeten et al., 1992). In addition to the vascular abnormalities described above, an increasing number of associations with specific systemic disorders is being reported, including transient ischemic attacks, hypertension, angina, myocardial infarction, stroke, asymptomatic myocardial dysfunction, Alzheimer’s disease, and hearing loss (Hagadus et al., 1989; Repo et al., 1995; Mitchell et al., 1997; Linne´r et al., 2001; Cahill et al., 2002; Shaban and Asfour, 2004; Aydogan Ozkan et al., 2006). Some of these associations have been disputed and there is yet no clear evidence of increased mortality in patients with XFS, which one might expect with these associations, nor has there been shown a clear-cut association of XFS with a systemic disease with conclusive evidence of a functional deficit caused by the presence of XFS.

Pathogenesis of exfoliation syndrome

The pathologic process is characterized by the chronic accumulation of an abnormal fibrillar matrix product, which is either the result of an excessive production or insufficient breakdown or both, and which is regarded as pathognomonic for the disease, based on its unique light microscopic and ultrastructural criteria (Naumann et al., 1998).

Immunohistochemical, biochemical, and molecular biologic data give strong support to the elastic microfibril theory of pathogenesis, first proposed by Streeten et al. (1986) on the basis of histochemical similarities between XFM and zonular fibers and which explains XFS as a type of elastosis affecting elastic microfibrils. The characteristic fibrils, composed of microfibrillar subunits surrounded by an amorphous matrix comprising various glycoconjugates, contain predominantly epitopes of elastic fibers, such as elastin, tropoelastin, amyloid P, vitronectin, and

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components of elastic microfibrils, such as fibrillin- 1, microfibril-associated glycoprotein (MAGP-1), and latent TGF-b binding proteins (LTBP-1 and LTBP-2) by immunohistochemistry (Ritch and Schlo¨tzer-Schrehardt, 2001). Recently, a direct analytical approach by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been accomplished and showed XFM to consist of the elastic microfibril components fibrillin-1, fibulin-2, and vitronectin, the proteoglycans syndecan and versican, the extracellular chaperone clusterin, the cross-linking enzyme lysyl oxidase, and other proteins, confirming many of the previously reported immunohistochemical data (Ovodenko et al., 2007). The currently proposed pathogenetic concept of XFS describes the condition as a specific type of stressinduced elastosis, an elastic microfibrillopathy, associated with the excessive production of elastic microfibrils and their aggregation into typical mature fibrils by a variety of potentially elastogenic cells (Schlo¨tzer-Schrehardt and Naumann, 2006).

A set of genes primarily involved in extracellular matrix metabolism and in cellular stress was found to be differentially expressed in anterior segment tissues of XFS eyes [Zenkel, 2005 # 14541] (Zenkel et al., 2006), suggesting that the underlying pathophysiology of XFS is associated with excess production of elastic microfibril components, enzymatic cross-linking processes, overexpression of the transforming growth factor (TGF-b1), a proteolytic imbalance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), increased cellular and oxidative stress, and an impaired cellular stress response (Schlo¨tzer-Schrehardt et al., 2003; Ho et al., 2005; Ro¨nkko¨et al., 2007). Growth factors, particularly TGF-b1, increased cellular and oxidative stress, an impaired cellular protection system, and the stable aggregation of misfolded stressed proteins appear to be involved in this fibrotic process (Koliakos et al., 2001). Due to an imbalance between MMPs and TIMPs and extensive crosslinking processes involved in fiber formation, the pathologic material is not properly degraded but progressively accumulates within the tissues over time.