Fundus Autofluorescence in X-Linked Retinoschisis



Fundus Autofluorescence in X-Linked Retinoschisis


Irena Tsui

Stephen H. Tsang



X-linked retinoschisis (XLRS), also known as juvenile retinoschisis, is the most common cause of macular degeneration in young men (1,2), with an incidence between 1:5000 and 1:25,000 (3). Rarely, a homozygous female from a consanguineous marriage can be affected. The disease occurs in all races, with the highest prevalence in Finland (4).

Patients with XLRS have a highly variable clinical course. Patients present most commonly as school-aged boys who fail vision-screening examinations (60%) because of strabismus (30%) or vitreous hemorrhage (1,2,5). The classic “spoke wheel” appearance may be present in the fovea (3), but eventually nonspecific macular atrophy occurs in adulthood (6). Therefore, the diagnosis can be missed when patients present late or atypically.

RS1, the gene responsible for XLRS, is located on chromosome Xp22 and encodes the protein retinoschisin. It is not known to be expressed anywhere else in the body besides the retina and there are no systemic associations with XLRS. To date, there are 132 different pathogenic mutations known to cause XLRS (7). RS1 gene defects have complete penetrance, but the phenotypic expression of the disease is variable (8) and there is no known genotype-phenotype correlation (9,10).

In children and young adults with XLRS, the differential diagnosis includes uveitic macular edema, myopic foveal schisis, and other inherited retinal diseases such as enhanced S-cone syndrome (ESCS)/Goldmann-Favre, congenital stationary night blindness, Stargardt disease, and familial exudative vitreoretinopathy. Adults with XLRS usually progress to macular atrophy, and the major differential diagnosis is age-related macular degeneration (AMD).


MOLECULAR BASIS AND PATHOLOGY OF XLRS

The cellular location of retinoschisin in the retina is a controversial issue. It was initially thought that retinoschisin is secreted by photoreceptors and ganglion cells. Specifically, it was first found in the photoreceptor inner segment microsomal and synaptic compartments (11, 12, 13).

In a more recent study using an epitope unmasking protocol, retinoschisin immunoreactivity was also found in the plasma membrane of inner retinal cells in addition to photoreceptors and ganglion cells (14). Since retinoschisin has not been conclusively detected in Müller cells (14,15), the long-standing hypothesis that Müller cells contribute to the pathogenesis of XLRS has yet to be verified experimentally.

In a mouse model of XLRS, loss of retinoschisin led to disrupted synaptic interactions between photoreceptors and bipolar neurons in the outer plexiform layer (OPL) (15,16). During development of XLRS mice, failure of centrifugal displacement of
dendrites and synapses, as well as other inner retinal neurons and synapses, was thought to be responsible for the splitting of the putative fibers of Henle (14).

Improvement of the electronegative electroretinography (ERG) b-wave was found in adult RS1-deficient mice treated with adeno-associated virus (AAV) carrying the wild-type gene (16). A single injection of AAV-RS1 resulted in sustained RS1 expression and functional rescue. This demonstrated that even when loss of retinoschisin was long-standing, function could be recovered (16).

There is only one human pathology specimen of a patient with XLRS. In this 19-year-old man’s enucleated eye, reduced levels of retinoschisin immunoactivity were observed in both the macula and the peripheral retina compared to a normal eye of an age-matched control (17). Clinically, about 50% of XLRS patients manifest peripheral retinoschisis, and some also have bridging vessels from the inner to the outer layer. Traction on these bridging vessels causes vitreous hemorrhage.


IMAGING AND DIAGNOSTIC TECHNIQUES

The classic foveal schisis seen in XLRS is best visualized at the slit lamp using red-free illumination. Similarly, red-free photos demonstrate the cavities better than color fundus photography (Fig. 11C.1A).

In XLRS, optical coherence topography (OCT) shows cystic spaces in the macula at the level of the retinal nerve fiber layer and inner nuclear layer, corresponding to the schisis cavities (Fig. 11C.1B). However, similar findings are observed in cystoid macular edema. As in other diseases with macular thickening, there is no correlation between foveal thickness and visual acuity in XLRS. Macular atrophy, which is often observed in late stages of XLRS, is another nonspecific finding on OCT. In the presence of vitreous hemorrhage, OCT is of limited value because the signal cannot penetrate dense vitreous opacities.

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Aug 29, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Fundus Autofluorescence in X-Linked Retinoschisis
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