careful follow-up of all patients suspected of being affected. Although the genetic linkage has been identified, generalized genetic testing is not yet available.

fiber layer. Although JXRS is a rare condition, it affects all races and is the most common form of juvenile macular degeneration.

Careful follow-up of patients with WGN is imperative given the progressive nature of the disease. Treatment of retinal tears should be considered, and prompt diagnosis and treatment, if indicated, of retinal detachment are important.

Retinal detachments may be treated with conventional scleral buckling, [21, 22] or given the possibly abnormal vitreoretinal interface, more aggressive combined scleral buckle and vitrectomy surgery may be considered. Brown and Tasman reported successful retinal reattachment in three patients necessitating vitrectomy after failed scleral buckling [20].

13.2.11 Complications and Associations

Classically, WGN is not associated with complex rhegmatogenous retinal detachment. Visual decline is associated with progressive chorioretinal atrophy [21]. Patients may require cataract surgery at an early age and have mild to moderate myopia. WGN is not associated with systemic findings.

13.2.12 Social and Family Impact

WGN can have a major impact on a family and on society. Given the autosomal dominant genetic inheritance and the progressive nature of the disorder, a family can have multiple affected family members who may expect visual decline. This may lead to diagnosis of other asymptomatic family members. The decision to closely follow or offer prophylactic laser treatment is controversial.

Haas first described JXRS clinically in 1898 [26]. It is also known as congenital hereditary retinoschisis, congenital vitreous veil, cystic disease of the retina in children, and juvenile retinoschisis [27].

13.3.3Overview with Clinical Significance

The clinical findings in patients with JXRS vary from family to family and within a family; however, the hallmark clinical findings are macular schisis (Figs. 13.3, 13.4), peripheral retinal schisis, and vitreous veils (figure “X-linked schisis”). Characteristic macular changes cause decreased vision. All patients have some type of macular changes; however, these may be subtle [28]. The macula appears “spoke-like” with radiating retinal striae and not uncommonly pigmentary alterations. The appearance is sometimes best appreciated under red-free viewing (Fig. 13.3). Although the macula may have a cystoid appearance, no leakage is visible on fluorescein angiography (Fig. 13.5) [29].

Peripheral retinoschisis is present in 70% of eyes [30, 31], most commonly inferotemporally (Fig. 13.4 (d)). In JXRS, the retinal splitting occurs at the nerve fiber layer [32], as opposed to degenerative adult

13.3 Juvenile X-Linked Retinoschisis

13.3.1 Introduction

Juvenile X-linked Retinoschisis (JXRS) is a bilateral ocular condition occurring in males with stellate maculopathy and peripheral retinal schisis of the nerve

Fig. 13.3 Red free photo showing foveal schisis characteristic of JXRS

Fig. 13.4  Fundus photo of the right (a) and left (b) eye of a young male child with X-linked schisis showing large schisis cavity extending into the macula. Note the vitreous hemorrhage present in the left eye (b). The patients elder brother is shown with similar schisis cavity in his right eye (c) but only peripheral schisis is present in the left eye (d)

Fig. 13.5  Fluorescein angiogram of young male child with X-linked retinoschisis. Early (a) and late (b) frames of the angiogram are shown which are devoid of leakage

a

c

a

b

d

b

retinoschisis where the break splitting occurs at the outer plexiform layer. The schisis cavity may not be present at birth; however, the peripheral schisis cavity may become more elevated or may be the source of complications in JXRS [33]. The inner wall of the schisis cavity is thin, inner retinal holes occur, and thinned retina may result in floating retinal vessels leading to recurrent vitreous hemorrhage (Fig­ . 13.4 (b)) [33, 34]. The peripheral vitreous has the appearance of vitreous veils. Holes in the outer retinal layer (outer retinal holes) may lead to rhegmatogenous retinal detachment. Tractional and exudative retinal detachments may also occur. Macular ectopia with nasal or temporal dragging may lead to decreased vision. Extension of the peripheral schisis cavity into the macula may also cause decreased vision.

13.3.4  Classification

None available

13.3.5  Genetics

JXRS occurs only in an X-linked pattern and is a leading cause of juvenile macular degeneration in males. Only male patients are affected. Females are carriers with no clinical manifestation of the disease. Linkage studies localized the gene responsible for JXRS to the distal short arm of the X chromosome (Xp22.1–p22.3) [35–37]. The gene RS1, formerly known as XLRS1, was identified by positional cloning, [38] and the gene

product, known as retinoschisin, by amino acid homology belongs to the family of proteins implicated in cell adhesion [38, 39].

Different RS1 mutations cause a wide range of phenotypic variability in males with JXRS and the female carriers (The Retinoschisis Consortium 1998; Pimenides et al. 2004; Rodriguez et al. 2005). Mutations in RS1 can promote protein misfolding or failure of secretion, failure of oligomerization, or failure of surface binding or cell: cell interactions due to mutations in the conserved discoidin domain. On the other hand, there does not appear to be a strong correlation between genotype and phenotype in JXRS patients with RS1 mutations, and there is a fairly uniform clinical presentation although age of onset and severity do vary (The Retinoschisis Consortium 1998; Pimenides et al. 2004).

The disease gene underlying JXRS has been mapped totheshortarmoftheX-chromosome(Xp22.2–Xp22.1). The retinoschisin (RS1) gene has six exons and five introns and covers a span of approximately 30 kbp (kilo base pairs) (Sauer et al. 1997). RS1 encodes a protein called retinoschisin, which is a 224-amino acid protein (24 kD). RS1 contains a dominant and C-terminal discoidin domain that is highly conserved in a family of extracellular or transmembrane proteins. These proteins are involved in molecular interactions that take place on the surface of cells and form cellular adhesions or cell–cell interactions. RS1 is expressed and secreted by photoreceptors and bipolar cells (Molday et al. 2001). There is a 23-amino acid N-terminal secretory signal in the primary peptide, which is cleaved off to form the mature 23 kD protein. Over 130 mutations are known to occur in the gene. Databases for RS1 mutations are found on the Retina International Mutations Database (http://www.retina-international. com/sci-news/mutation.htm), RetNet (http://www.sph. uth.tmc.edu/Retnet/), and the Retinoschisis Consortium site (http://www.dmd.nl/rs/index.html).

13.3.6  Pathophysiology

The disease results in anatomical changes in the macula and peripheral retina that include microcystic changes in the fovea and macula and intraretinal splitting to form schisis cavities in the peripheral retina. It was a long-held view that the cysts and schisis cavities in JXRS were due to a failure of Muller glial cells that provided transretinal structural and physiological

support for the retina. The classical lesions of JXRS are a pinwheel-shaped arrangement of inner retinal cystic cavities surrounding the fovea, and larger schisis cavities in the midperipheral and usually inferior retina (Tantri et al. 2004). Histopathology and clinicopathologic data show that the splitting of the retina occurs within the nerve fiber layer [32]. Deficiency of RS1 causes a generalized disruption of retinal laminar architecture with loss of integrity of the outer plexiform and inner nuclear layers and profound loss of photoreceptors. Structural delamination of the inner retina is a characteristic of JXRS, and “vitreous veils” of inner retina separated from bulk retina appear in the clinical retinal anatomic exam. While the disease is often stationary and benign, marked loss of central vision can result from foveal lesions, and severe complications can arise from larger retinal schisis cavities including retinal detachment, vitreous hemorrhage, and neovascular glaucoma. Macular cystic cavities found in youth often disappear to leave only an altered foveal reflex in adults.

Electrophysiologic data show selective reduction of the b-wave flash electroretinogram (ERG) and markedly reduced oscillatory potentials initially implicating a primary diffuse bipolar cell and Muller cell abnormality [40]. Retinoschisin has been localized within the outer plexiform layer at the synapse between photoreceptors and bipolar cells (Takada et al. 2004). This localization of RS1 to the synapse coincides in development with the natural appearance of the b-wave of the ERG, indicating the importance of RS1 to synaptic architecture and maintenance. Breakdown of the photoreceptor: bipolar synapse is a characteristic feature of JXRS and is indicated by a loss of b-wave in the ERG of affected individuals (Sieving et al. 2006).

Retinoschisin, the protein product of the gene responsible for JXRS, is an oligomeric disulfide-linked protein complex with a discoidin-like domain [39, 41]. Retinoschisin is expressed and secreted by rod and cone photoreceptors and likely bipolar cells, and it interacts with the surface of these cells [41]. It may function as a cell adhesion complex in order to stabilize the structure of the retina. RS1 is a discoidin domain containing protein that is expressed and secreted by photoreceptors, bipolar cells, and ganglion cells and acts to form a matrix of extracellular contacts throughout the outer and inner retina (Reid et al. 1999; Molday et al. 2001; Takada et al. 2004; Tantri et al. 2004). RS1 is first expressed early in retinal development (Takada et al. 2004). Strongest expression is in

the photoreceptor cells. RS1 localizes throughout both the inner and outer retina with greatest immunocytochemical staining in the region of outer plasmamembrane surfaces of photoreceptor inner segments and bipolar cells (Molday et al. 2001). Retinoschisin forms disulfide-linked octamers within the intracellular compartment prior to secretion (Wu et al. 2003, 2005). The highly conserved discoidin domain, which is also found in clotting factors and other proteins, occupies about 75% of the total protein sequence. Most human RS1 mutations occur within this domain. The role of the secreted protein appears to be in establishing and maintaining cell: cell interactions among photoreceptors, bipolar cells, and Müller glia and inner retinal neurons extending up to the ganglion cells that are essential for retinal tissue architecture and stability, and which are paramount to proper function (SteinerChampliaud et al. 2006; Takada et al. 2004; Molday et al. 2001; Tantri et al. 2004). Müller glial cells play a role in distributing RS1 throughout the retina through a process of transcytosis (Reid et al. 1999, 2003; Reid and Farber 2005). While RS1 appears to be synthesized by all retinal neurons during development (Takada et al. 2004), other experiments have shown that retinoschisin synthesized and secreted into the subretinal space by photoreceptors is endocytosed by apical microvilli of Müller cells, which then transport it internally and secrete it throughout the inner and outer retina at its focus sites in the mature retina (Molday et al. 2001; Takada et al. 2004; Reid and Farber 2005; Steiner-Champliaud et al. 2006). This may be a mechanism to supplement retinoschisin expression throughout the retina. RS1 is a peripheral membrane protein that interacts with the anionic phospholipid head charges on the outer surface of the membranes in a divalent ion dependent fashion (Vijayasarathy et al. 2007). There is evidence that the discoidin domain of RS1 can form interactions with extracellular collagen matrix, which would be important for anchoring cells within the extracellular space of the retina. When there is a deficiency of the secreted protein proper cell: cell interactions and likely cell: matrix interactions cannot occur, which set the stage for the clinically evident retinal lesions of XLRS. A recent study has shown that RS1 forms protein: protein interactions with Na+/K+ ATPase in the surface membranes of retinal neurons (Molday et al. 2007). This suggests that RS1 may also serve a signaling or physiological role in addition to its apparent role in forming cell: cell and cell: substrate interactions.

13.3.7  Incidence

JXRS is rare. The highest frequency of the disease has been noted in Finland with an incidence of 44 cases per million population (Rudanko et al. 1993). The frequency in the general population is between 1/7,000 and 1/2,800 (The Retinoschisis Consortium 1998; Tantri et al. 2004).

13.3.8  Natural History and Prognosis

(Signs, Symptoms, Timing, etc.)

Males with JXRS present at early school age with difficulty reading. The clinical findings may be subtle at first and may be most noticeable on red-free viewing of the macula. Patients may present earlier with strabismus or leukocoria if early retinal detachment occurs. Vision is usually mildly to moderately affected in childhood with slow progression. More than 50% of patients have vision worse than 20/70 [27].

The progressive macular changes can be visualized in childhood. In adults, the foveal changes or characteristic macula schisis may not be apparent; clinical examination may only show a poor foveal reflex and RPE changes.

13.3.9  Diagnosis and Diagnostic Aids

The diagnosis of JXRS is based on clinical exam. The examination of family members may be helpful if other members are found to be affected. Clinical photography of the macula with red-free viewing shows a characteristic stellate maculopathy with the appearance of cystoid macular edema; however, no leakage is noted on fluorescein angiography. An ERG may be helpful since reduced b-wave and oscillatory potentials can be found in patients even if no peripheral schisis cavity is present [40]. Carriers can be determined with peripheral blood samples since the gene, RS1, responsible for JXRS has been cloned. Optical coherence tomography of JXRS has been used to delineate foveal schisis not evident by biomicroscopy [42].

The differential diagnosis for JXRS includes retinopathy of prematurity (ROP), Goldmann-Favre Disease, Retinitis Pigmentosa, and Familial Exudative ­Vitreo­retinopathy (FEVR).