Pseudoxanthoma Elasticum: A Novel Mutation in the ABCC6 Gene That Affects Eye Manifestations of the Disease

INTRODUCTION

Pseudoxanthoma elasticum (PXE) is an inherited disorder with multiple systemic manifestations involving the skin, vascular system, and Bruch's membrane of the eye. Histopathology has demonstrated the mineralization and fragmentation of elastic fibers in these tissues. Of interest, 43 mutations in the ABCC6 gene have been noted in approximately 80% of patients with PXE.1 This particular gene encodes an adenosine triphosphate–binding cassette protein.

Ocular involvement has been noted in most patients, with a typical sequence of findings that includes peau d'orange appearance of the retinal pigment epithelium (RPE), angioid streaks, peripapillary atrophy, retinal drusen, and, ultimately, comet-like tails. Although there are no known deleterious effects noted from peau d'orange appearance and comet-like tails, the visual prognosis associated with angioid streaks is poor. It has been noted that 75% of those with angioid streaks develop disciform macular scars.2

Bruch's membrane is an elastin- and collagen-rich membrane and is the attachment site for the RPE; it also functions in the bidirectional transport of nutrients and metabolites between the RPE and choriocapillaris. Angioid streaks are ruptures in pathologically thickened and calcified Bruch's membrane; breaks in Bruch's membrane lead to atrophy of the overlying RPE and photoreceptors.

Most patients with PXE have been noted to have sporadic mutations, including 43 mutations of the ABCC6 gene. The disease has been localized to an 820-kilobase region of chromosome 16p13.1.3 Adenosine triphosphate–binding cassette proteins are involved in signal transduction, protein secretion, drug and antibiotic resistance, and the antigen presentation cascade. The physiologic function of ABCC6 remains unclear, although it has been proposed that the protein functions in the regulation of the extracellular matrix movement between the inner retina and the photoreceptor RPE–Bruch's membrane complex.4 Faulty active transport of anions could affect the transport properties and distribution of molecules, thereby producing pathology in Bruch's membrane. Of note, ABCC6 is highly expressed in the liver and kidney, while less expression can be found in tissues affected by PXE.

RESULTS

The ocular findings noted during the clinical examinations of 28 subjects included the following: peau d'orange appearance (4 patients), angioid streaks (5 patients), choroidal neovascular membranes (4 patients), peripapillary atrophy (11 patients), comet-like tails (1 patient), and retinal drusen (4 patients) (Table 1). A statistically significant association between the presence of peau d'orange appearance (P  =  0.0016), angioid streaks (P < 0.0001), and choroidal neovascular membranes (P  =  0.0016) was discovered with respect to the R39G mutation of the ABCC6 protein (Table 2).

DISCUSSION

R1138W is an established mutation in a large intracellular loop of ABCC6 in which mutants are often identified. To our knowledge, no specific ophthalmic associations with the R39G gene of interest have been reported previously. If the R39G mutation could be evaluated further, it might provide insight into the pathogenesis of angioid streaks and, ultimately, related choroidal neovascular membranes, as discovered in PXE. Further studies could similarly evaluate angioid streak formation in other known systemic diseases such as Ehlers-Danlos syndrome, Paget disease, and sickle cell anemia. Effective therapy remains challenging.5

Although the statistics of this study demonstrated significant findings, 28 patients were included, and the study thereby lacked power. In addition, only 2 of the known mutations of ABCC6 protein were explored. It would be helpful to repeat the study to look at all known mutations and to evaluate any associations.