Pseudoxanthoma elasticum - Genetics, pathophysiology, and clinical presentation

Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed.

Keywords: ABCC6; Bruch's membrane; PXE; Pseudoxanthoma elasticum.

Figure 1 –. Pyrophosphate pathway.

Ectopic tissue mineralization in PXE is a complex process involving not only ABCC6, but also ENPP1, CD73 and TNAP. See Chapter 4 ‘Disease mechanism’ for a detailed description.

Figure 2 –. Overview of ocular characteristics in Pseudoxanthoma elasticum.

Fundus photography (A), infrared reflectance imaging (B) and short-wavelength fundus autofluorescence (C) of an eye with PXE. In the mid-periphery, comet tail lesions (D) can be found. Their tail points towards the posterior pole. Around the optic disc, breaks in bruch’s membrane can be found (E, blue arrowhead), that radiate towards the periphery. The streaks never cross peau d’orange (F), which is the border of calcified and uncalcified Bruch’s membrane. This transition zone is better visible in IR-imaging (G), where the mottled aspect in the central border (i.e., uncalcified BrM to transition zone) is best appreciable.

Figure 3 –. Facultative ocular findings in Pseudoxanthoma elasticum.

On Funduscopy (A, C) several common and facultative findings in PXE are visible. Optic disc drusen affecting all quadrants of the optic nerve head are present. On short-wave fundus autofluorescence (B, D, E) optic disc drusen are strongly hyperautofluorescent (D). Additionally, pattern dystrophy-like changes can be found around the vessel arcades (E).

Figure 4 –. Zones of calcification.

The diagram illustrates the current knowledge on fundus alterations in pseudoxanthoma elasticum, combining observable changes across various imaging methods. In the initial stages of the disease, a (possibly predetermined) region exhibiting Bruch’s membrane (BM) calcification, characterized by a speckled appearance referred to as peau d’orange, is already evident. Gradually, this area undergoes a progression of more cohesive BM calcification, manifesting as an augmented fundus reflex. Over time, a discernible pattern emerges in the form of reduced indocyanine green angiography (ICGA) fluorescence, initiating in the macula and extending centrifugally. This model was initially proposed by Charbel Issa et al. and was modified by Risseeuw et al.

Figure 5 –. Histology of ocular alterations in Pseudoxanthoma elasticum (PXE).

The flatmount of a human donor eye (A) shows the spatial distribution of alterations in eyes with PXE. Centrally, late stages including atrophic areas and choroidal neovascularization (white arrow) is visible. Angioid streaks (white arrowheads) radiate towards the periphery, where they terminate around the Peau d’orange (peripheral pink area). Electron microscopy (B-D) reveals an altered ultrastructure of Bruch’s membrane, highlighting HAP deposits with the elastic and collagen layers.

Figure 6 –. Vascular calcification in Pseudoxanthoma elasticum.

Non-contrast computer tomography (CT) scan with 3D reconstruction of the femoral area shows multiple lesions of calcification within the femoral artery. Due to the slow course of the disease, collaterals compensate the restrictions resulting in delayed symptoms in patients with PXE. Vascular imaging often shows widespread alterations in only mildly affected patients.

Figure 7 –. Skin alterations in Pseudoxanthoma elasticum.

Dermal alterations are often best and first visible at the back of the neck. The inner sides of the elbows and other intertriginous areas are affected. The mucosa of the inner lip can be altered with whitish lesions.

Figure 8 –. Vascular calcification in Pseudoxanthoma elasticum.

Non-contrast computer tomography (CT) scan with 3D reconstruction of the femoral area shows multiple lesions of calcification within the femoral artery. Due to the slow course of the disease, collaterals compensate the restrictions resulting in delayed symptoms in patients with PXE. Vascular imaging often shows widespread alterations in only mildly affected patients.