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Clinicopathologic Reports, Case Reports, and Small Case Series |

Hereditary X-Linked Juvenile Retinoschisis: A Review of the Role of Müller Cells FREE

Cornelia M. Mooy, MD, PhD; L. Ingeborgh van den Born, MD; Seerp Baarsma, MD; Dion A. Paridaens, MD; Thea Kraaijenbrink, MSc; Arthur Bergen, PhD; Bernhard H. F. Weber, PhD
Arch Ophthalmol. 2002;120(7):979-984. doi:.
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Hereditary X-linked retinoschisis (RS) is the most common cause of juvenile macular degeneration in males1,2 and may lead to vitreoretinal degeneration characterized by cystic spoke-wheel maculopathy, peripheral retinoschisis, alterations of the vitreous body, and a reduced b wave on the electroretinogram. Its prevalence ranges from 1:5000 to 1:25 000.3,4 The condition is usually bilateral and affects males only. Males with juvenile RS usually seek treatment because of diminished vision at school age, followed by progressive visual deterioration later in life. Peripheral retinoschisis is found in 50% of patients and may be limited to the inferior temporal quadrant. Breaking of the inner schisis layer may lead to unsupported retinal vessels in the vitreous cavity, called a "congenital vascular veil."5 There have been few reports on the histopathologic characteristics of RS.611 The principal feature in all these cases was a large schisis cavity originating from the nerve fiber layer (NFL). Several theories concerning the pathogenesis of RS have been postulated. First, findings on fluorescein angiography led to a vascular theory of RS development12 because of delayed development of the retinal and choroidal vasculature in which the retina outgrows its blood supply infratemporally. Vascular changes might play a role in the evolution of the schisis,13 and RS may be complicated by neovascular glaucoma.14 Second, Schepens15 believed that the primary abnormality was vitreous traction on the inner retinal surface caused by inadequate growth or shrinkage of the cortical vitreous. The histologic characteristics of RS in a male infant with congenital retinal detachment and splitting in the inner retina but no schisis16 and in 2 male infants with congenital hereditary RS17 supported the theory of a vitreoretinal developmental anomaly. Third, based on pathological findings, several authors postulated that juvenile RS arises from a basic inherited defect in probably the innermost portion of the cytoplasm of Müller cells.7,10,11 Current molecular genetic and immunohistochemical findings contradict the theory of a primary defect in the Müller cells18 and suggest an abnormality that interacts with a Müller cell receptor or components of the extracellular matrix.19 Based on immunohistochemical analysis with a RS1-specific antibody applied to the enucleated eye of a relatively young patient with RS, we support the theory that photoreceptors appear to be the cells primarily involved in the pathologic characteristics of RS.

At age 5 months, our patient was diagnosed as having X-linked juvenile RS. At age 19 years, his right eye was enucleated. The enucleated eye was fixed in 4% formaldehyde solution in a 0.1M phosphate buffer. After horizontal sectioning, the eye was embedded in paraffin. Sections (5-µm) were incubated with polyclonal antibody glial fibrillary acid protein (DAKO, Glostrup, Denmark) (dilution, 1:1200; incubation, 30 min at room temperature; peroxidase-antiperoxidase method). The monoclonal antibodies vimentin (BioGenex, San Ramon, Calif), and fibronectin (DAKO) and neurofilaments (Sanbio, Uden, the Netherlands) were applied using the avidin-biotin complex method (dilution, 1:3200, 1:1200, and 1:300, respectively; incubation, 10 min). Prior to incubation with vimentin and neurofilaments, slides were pretreated for 15 minutes in citrate buffer (microwave); prior to fibronectin incubation, slides were pretreated with pronase for 10 minutes. The RS1 antibody was provided by one of us (B.H.F.W.) and is identical to the RS1 antibody described in Molday et al.18 Raising the RS1 antibody and the specificity have been described previously.18 In short, the amino peptide LSSTEDEGEDPWYQKAC, corresponding to aa22-39 of the human RS1 precursor protein,20 was conjugated to keyhole limpet hemocyanin and used to immunize New Zealand White rabbits. For immunolabeling, a 1:1000 dilution of rabbit serum was used. Prior to incubation, slides were pretreated for 10 minutes in citrate buffer (microwave). A formalin-fixed paraffin-embedded eye with a healthy human retina was used as a control.

Material was sampled from the formalin-fixed retina and embedded in epoxy resin after dehydration with grading acetone. Semithin sections (1 µm) for light microscopy were made with a glass knife and stained with toluidine blue (1% weight-volume ratio). Ultrathin sections (70-80 nm) were cut with a diamond knife and mounted on unfilmed 300-mesh copper grids. After staining for 30 minutes with uranyl acetate and 2 minutes with lead citrate, the ultrathin sections were examined with a Zeiss EM 902 transmission electron microscope (Carl Zeiss, Oberkochen, Germany) with an acceleration voltage of 80 kV.

Our patient was also enrolled in a large study by the Retinoschisis Consortium21 on screening for mutations of the gene involved in RS (RS1).

The family pedigree revealed an X-linked mode of RS inheritance with several males affected (Figure 1). In our patient, pursuit movements, a convergent strabismus of his right eye, and remnants of persistent pupillary membranes were recorded on early examination. At age 5 years, a cataract developed in his right eye. Visual acuity was light perception OD and 20/200 OS. At age 8 years, his right eye showed a mature cataract with posterior synechiae. Recurrent granulomatous uveitis with large iris nodules occurred in the right eye from age 18 years onward (Figure 1A) and initially responded to topical steroids and cycloplegia. Laboratory testing did not reveal a cause for the uveitis. The patient was treated with 200 mg hydroxychloroquine sulfate per day. Electroretinography and visual evoked potential were almost nonrecordable in the right eye. At age 19 years, iris neovascularization developed in the right eye with secondary glaucoma; it was treated with acetazolamide and local therapy. Eventually, the right eye was enucleated. The visual acuity of the left eye was counting fingers at the most recent examination (Figure 2B).

Place holder to copy figure label and caption
Figure 1.

The family pedigree reveals an X-linked mode of inheritance with several affected males. Open square indicates male; shaded square, male with juvenile retinoschisis; shaded square with slash, male with juvenile retinoschisis who died; open circle, female; circle with dot, carrier female; and asterisk, the index patient.

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Place holder to copy figure label and caption
Figure 2.

Cataract and large iris nodules in the right eye (A). Funduscopy of the left eye (B) of a patient with juvenile retinoschisis shows delicate retinal cysts. In the enucleated eye, a depigmented area is noted macroscopically in the posterior pole (C) with some vascular veils extending anteriorly. Microscopically, the cysts originated from schisis in the nerve fiber layer in the inferotemporal part of the retina (asterisks) (D). The underlying retina and the nasal retina were detached (arrows), and the retina was folded at the base of the schisis cavities (hematoxylin-eosin, original magnification ×1.7). In the nasal-posterior part of the retina (E), there is splitting in the inner and outer plexiform layers (arrows) (hematoxylin-eosin, original magnification ×100). In the central retina (F) multiple PAS (periodic acid–Schiff)–positive globules are present in all retinal layers (original magnification ×400). In the anterior segment (G), occlusion of the pupil is present. The lens shows a hypermature cataract with posterior synechiae and rupture of the anterior lens capsule with a reactive inflammatory infiltrate (hematoxylin-eosin, original magnification ×25). Glial fibrillary acid protein stains strongly positive throughout the retina (H) (original magnification ×400). The nerve fiber layer (I) stains strongly positive with S100 (original magnification ×250). A healthy human retina (J) with strong RS1 antibody immunostaining in the inner segments of the photoreceptors, strong membranous staining in the outer nuclear layer, moderate immunostaining in the inner nuclear layer and the plexiform layers, and negative staining in the ganglion cell layer and the nerve fiber layer (original magnification ×250). The retinoschisis-affected eye with negative RS1 antibody staining in the atrophic central retina (K) and markedly reduced staining in the relatively well-preserved peripheral retina (L) (original magnification ×250).

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The eye was fixed in formalin and transported to the pathology department. Macroscopically, occlusion of the pupil, a mature cataract, and posterior synechiae were noted in the anterior segment. In the posterior pole, a depigmented area was found, with some vascular veils extending anteriorly (Figure 2C). The retina was partly detached, with delicate cysts inferiorly in the eye. On microscopic examination, the cysts were seen to have originated from schisis in the NFL in the inferotemporal part of the retina and were covered by a glial membrane. The underlying retina and the nasal retina were detached (Figure 2D). There was marked splitting in the NFL of the nasal retina along the plane of the ganglion cell layer and detachment of the inner limiting membrane (ILM). Alcian blue/hyaluronidase staining was negative. The retina was folded at the base of the schisis cavities with marked hyalinization of intraretinal vessels and degenerative calcification. In the nasal-posterior part of the retina, there was splitting in the inner and outer plexiform layers (Figure 2E). In the depigmented posterior pole, the retinal pigment epithelium showed proliferative and degenerative changes with atrophy of the photoreceptors and the outer nuclear layer. In the pupil-optic block, the retina was partly detached without obvious schisis cavities. The inner retina showed splitting in the NFL and detachment of the ILM. In the central retina, multiple PAS (periodic acid-Schiff)–positive globules were present in all retinal layers, sometimes with lumens (Figure 2F). In the macular area, degenerative changes were found in the outer plexiform and nuclear layers. In the anterior segment iris, neovascularization, occlusion of the pupil, and iris bombé were present. The lens showed a hypermature cataract with posterior synechiae and rupture of the anterior lens capsule (Figure 2G). A reactive mixed inflammatory infiltrate was present, with histiocytes and giant cells within the lens capsule. Foamy cells surrounded the lens and were present in the anterior chamber. Granulomas were noted along the pigment epithelium of the iris and ciliary body and focally at the retinal pigment epithelium, with associated uveitis.

On immunohistochemical examination, glial fibrillary acid protein (Figure 2H) and vimentin stained strongly positive throughout the retina and the inner and outer layer of the schisis cavities. The NFL (Figure 2I) and the inner and outer layers of the schisis cavities stained strongly positive with S100. The roof of the schisis cavity and the NFL stained focally positive with neurofilaments. The PAS-positive globules stained strongly positive with fibronectin. In the healthy human retina, immunostaining with the RS1 antibody revealed intense staining of the inner segments of the photoreceptors, strong membranous staining in the outer nuclear layer, moderate staining in the inner nuclear layer and the plexiform layers, and negative staining in the ganglion cell layer and the NFL (Figure 2J). The RS-affected eye showed negative staining in the atrophic central retina (Figure 2K) and markedly reduced staining in the relatively well-preserved peripheral retina (Figure 2L).

On electron microscopic examination, splitting had occurred in the NFL in the semithin sections. Intraretinal globules were present in the inner nuclear layer and the inner part of the outer plexiform layer and were composed of basement membrane–like material in the ultrathin sections (Figure 3A). A glial membrane was present at the vitreal side of the ILM. The retinal surface of the ILM was attached to footplates of degenerated Müller cells. The plasma membrane of some Müller cells was focally deficient with intraretinal deposits of intermediate filaments (Figure 3B).

Place holder to copy figure label and caption
Figure 3.

Electron microscopic examination shows intraretinal globules composed of basement membrane–like material (A). The plasma membrane of some Müller cells was focally deficient with intraretinal deposits of intermediate filaments (B) (original magnification ×7000).

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In our patient and his family, the missense mutation Arg102Trp was found in exon 4 containing part of the conserved discoidin domain of the RS1 gene.20

The histological findings in our patient are characteristic of juvenile RS with an unusual complication of phacoantigenic endophthalmitis, which explains the clinical findings of granulomatous anterior uveitis. Immunostaining with the RS1-specific antibody18 was markedly reduced in the RS-affected eye. The healthy human retina stained strongly positive in the inner segments of the photoreceptors and the outer nuclear layer, moderately positive throughout the inner nuclear layer and the plexiform layers, and negative in the inner retina. This is consistent with findings for the same antibody applied in mouse and monkey retinas and a normal human retina.18 Similarly, a retina-specific polyclonal antibody, designated retinoschisin, has been described in mouse and human retinas.19 Although messenger RNA of the causative RS1 gene was detected only in the photoreceptor layer, the protein product of the gene (retinoschisin) was present both in the photoreceptors and within the inner portions of the peripheral human retina, and there was patchy immunoreactivity in the inner and outer nuclear layers at the macula.

By genetic linkage analysis, RS was first mapped to the distal region of Xp, and subsequent refinement eventually localized the RS gene in Xp22.2.22 Sauer et al20 identified a candidate gene for RS, designated RS1 (alias XRLS1). The RS1 gene has 6 exons and encodes a 224 amino acid protein, which contains a highly conserved discoidin domain. The RS1 mRNA encodes a secretable adhesion protein.20,23 Its role is implicated in cell-cell adhesion and phospholipid binding, indicating that RS1 is important in cell adhesion processes during retinal development.20,21 It was postulated that the protein product RS1 is expressed and assembled in photoreceptors of the outer retina and bipolar cells of the inner retina as a disulfide-linked oligomeric protein complex.18,19 Recently, it has been demonstrated in vitro that retinoschisin is selectively taken up and transported by Müller cells into the inner retina in a direction-specific manner.24 Juvenile RS may therefore be caused by abnormalities in the secreted photoreceptor protein at some distance from the site of RS pathologic characteristics.19 Discoidin domains are present in extracellular or transmembrane proteins in cell adhesion or cell-cell interactions.25 The interaction of RS1 protein with a Müller cell surface receptor or the extracellular matrix would be in keeping with its discoidin domain.19

We found no expression of RS1 protein in the central atrophic retina and markedly reduced staining in the relatively well-preserved peripheral retina in the RS-affected eye. This is consistent with a recent study showing reduced antibody staining in chimera mice with a targeted RS1 knockout.26 The reduced staining in the human RS-affected eye may be explained by the missense DNA mutation found in our patient, which may have resulted in a dysfunctional protein with a reduced half-life and defective cellular adhesive function. Many missense and protein-truncated mutations of the causative RS1 gene have now been identified and are thought to be inactivating.19 Such a defective adhesive protein may still be transported by the Müller cells into the inner retina, eventually leading to schisis formation. The basement membrane of the Müller cells forms part of the ILM. The Müller cell is the principal glial cell of the retina and is in intimate contact with the inner segments of the photoreceptors and the cells of the middle retinal layers, surrounding large areas of retinal vessels. The dysfunctional protein or abnormalities in the interaction of the protein with a Müller cell receptor or extracellular matrix may therefore be expected to affect the middle and inner retinal layers and to produce structural defects in the ILM and the NFL. This could account for the schisis, which was present not only in the inner retinal layers but also nasal-posteriorly in the inner and outer plexiform layers. The cone-shaped zone of Müller cells in the central and inner part of the fovea centralis plays an important role in the structural integrity of the macula, and defective cell-cell interaction may explain the characteristic foveo-macular schisis, later replaced by atrophic changes.27 Similarly, Müller cells may also be involved in the extracellular deposits of amorphous PAS-positive dots in the retina and, possibly, walls of small vessels. The PAS-positive deposits were noted in all retinal layers in the atrophic central retina and were not restricted to the schisis cavities.10,11 In our patient, the immunohistochemical (glial fibrillary acid protein, S100, and neurofilament) and electron microscopic findings (presence of degenerative Müller cells and deposits of intermediate filaments) are consistent with earlier findings. However, glial fibrillary acid protein and S100 positivity were not restricted to the retina adjacent to the schisis.10,11 These differences may be explained by the age at the time of enucleation (age, 19 years vs 55, 53, and 83 years10,11); our case probably represents an earlier stage of the disease. We support the hypothesis that the basement membrane–like material and filaments that accumulate extracellularly within the atrophic central retina may be caused by abnormalities in the interaction of the (defective) RS protein and a Müller cell receptor or extracellular matrix.19

In summary, earlier studies18,19 have established through immunohistochemical analysis the cellular distribution localization of RS protein in mammalian and healthy human retinas. The photoreceptors and bipolar cells appeared to be the cell types primarily involved in maintaining the integrity of the central and peripheral retina, secreting a cell adhesion protein taken up and transported by Müller cells into the inner retina.18,19 In our study of an RS-affected human eye, a mutation of the RS1 gene appears to give rise to a dysfunctional adhesive protein, resulting in defective cellular retinal adhesion that eventually leads to schisis formation.

This study was presented in part at the annual meeting of the Verhoeff-Zimmerman Society, Portland, Ore, April 24, 1999.

Corresponding author and reprints: Cornelia M. Mooy, MD, PhD, Pathology Laboratory Dordrecht, Jkvr Van den Santheuvelweg 2A, 3317NL Dordrecht, the Netherlands (e-mail: cmooy@paldordt.com).

Deutman  AF Vitreoretinal dystrophies. Krill  AArcher  DBedsHereditary Retinal and Choroidal Diseases. New York, NY Harper & Row1977;1043- 1108
Forsius  HKrause  UHelve  J  et al.  Visual acuity in 183 cases of X-chromosomal retinoschisis. Can J Ophthalmol. 1973;8385- 393
George  NDYates  JRMoore  AT X-linked retinoschisis. Br J Ophthalmol. 1995;79697- 702
George  NDYates  JRMoore  AT Clinical features in affected males with X-linked retinoschisis. Arch Ophthalmol. 1996;114274- 280
Mann  IMacrae  A Congenital vascular veils in the vitreous. Br J Ophthalmol. 1938;221- 10
Zimmerman  LENaumann  G The pathology of retinoschisis. McPherson  AedNew and Controversial Aspects of Retinal Detachment. New York, NY Harper & Row1968;400- 423
Yanoff  MRahn  EKZimmerman  LE Histopathology of juvenile retinoschisis. Arch Ophthalmol. 1968;7949- 53
Manschot  WA Pathology of hereditary conditions related to retinal detachment. Ophthalmologica. 1971;162223- 234
Manschot  WA Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol. 1972;88131- 138
Condon  GPBrownstein  SWang  NSKearns  AFEwing  CC Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in 3 eyes. Arch Ophthalmol. 1986;104576- 583
Kirsch  LSBrownstein  Sde Wolff-Rouendaal  D A histopathological, ultrastructural, and immunohistochemical study of congenital hereditary retinoschisis. Can J Ophthalmol. 1996;31301- 310
Ewing  CCCullen  AP Fluorescein angiography in X-chromosomal maculopathy with retinoschisis (juvenile hereditary retinoschisis). Can J Ophthalmol. 1972;719- 28
Green  JLJampol  LM Vascular opacification and leakage in X-linked (juvenile) retinoschisis. Br J Ophthalmol. 1979;63368- 373
Ando  ATakahashi  KSho  KMatsushima  MOkamura  AUyama  M Histopathological findings of X-linked retinoschisis with neovascular glaucoma. Graefes Arch Clin Exp Ophthalmol. 2000;2381- 7
Schepens  CL Congenital retinoschisis. Klin Oczna. 1988;90127- 132
Laatikainen  LTarkkanen  ASaksela  T Hereditary X-linked retinoschisis and bilateral congenital retinal detachment. Retina. 1987;724- 27
Kawano  KTanaka  KMurakami  FOhba  N Congenital hereditary retinoschisis: evolution at the initial stages. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1981;217315- 323
Molday  LLHicks  DSauer  CGWeber  BHMolday  RS Expression of X-linked retinoschisis protein RS1 in photoreceptors and bipolar cells. Invest Ophthalmol Vis Sci. 2001;42816- 825
Grayson  CReid  SNEllis  JA  et al.  Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein and is expressed and released by Weri-Rb 1 cells. Hum Mol Gen. 2000;91873- 1879
Sauer  CGGehrig  AWarneke-Wittstock  R  et al.  Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17164- 170
Retinoschisis Consortium, Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XRLS). Hum Mol Genet. 1998;71185- 1192
Arden  GBGorin  MBPolkinghome  PJJay  MBird  AC Detection of the carrier state of X-linked retinoschisis. Am J Ophthalmol. 1988;105590- 595
Reid  SNAkhmedov  NBPiriev  NIKozak  CADanciger  MFarber  DB The mouse X-linked juvenile retinoschisis cDNA: expression in photoreceptors. Gene. 1999;227257- 266
Reid  SNFarber  DB Transport of a photoreceptor-secreted protein, retinoschisin, by Müller cells [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42supplS654
Baumgartner  SHofmann  KChiquet-Ehrismann  RBucher  P The discoidin family revisited: new members from prokaryotes and a homology based fold prediction. Protein Sci. 1998;71626- 1631
Hiriyanna  KTTakada  YKondo  MBingham  ELSieving  PA X-linked retinoschisis: RS1 functional genomics and physiological dysfunction [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42supplS647
Gass  JD Müller cell cone, an overlooked part of the anatomy of the fovea centralis: hypothesis concerning its role in the pathogenesis of macular hole and foveomacular schisis. Arch Ophthalmol. 1999;117821- 823

Figures

Place holder to copy figure label and caption
Figure 1.

The family pedigree reveals an X-linked mode of inheritance with several affected males. Open square indicates male; shaded square, male with juvenile retinoschisis; shaded square with slash, male with juvenile retinoschisis who died; open circle, female; circle with dot, carrier female; and asterisk, the index patient.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cataract and large iris nodules in the right eye (A). Funduscopy of the left eye (B) of a patient with juvenile retinoschisis shows delicate retinal cysts. In the enucleated eye, a depigmented area is noted macroscopically in the posterior pole (C) with some vascular veils extending anteriorly. Microscopically, the cysts originated from schisis in the nerve fiber layer in the inferotemporal part of the retina (asterisks) (D). The underlying retina and the nasal retina were detached (arrows), and the retina was folded at the base of the schisis cavities (hematoxylin-eosin, original magnification ×1.7). In the nasal-posterior part of the retina (E), there is splitting in the inner and outer plexiform layers (arrows) (hematoxylin-eosin, original magnification ×100). In the central retina (F) multiple PAS (periodic acid–Schiff)–positive globules are present in all retinal layers (original magnification ×400). In the anterior segment (G), occlusion of the pupil is present. The lens shows a hypermature cataract with posterior synechiae and rupture of the anterior lens capsule with a reactive inflammatory infiltrate (hematoxylin-eosin, original magnification ×25). Glial fibrillary acid protein stains strongly positive throughout the retina (H) (original magnification ×400). The nerve fiber layer (I) stains strongly positive with S100 (original magnification ×250). A healthy human retina (J) with strong RS1 antibody immunostaining in the inner segments of the photoreceptors, strong membranous staining in the outer nuclear layer, moderate immunostaining in the inner nuclear layer and the plexiform layers, and negative staining in the ganglion cell layer and the nerve fiber layer (original magnification ×250). The retinoschisis-affected eye with negative RS1 antibody staining in the atrophic central retina (K) and markedly reduced staining in the relatively well-preserved peripheral retina (L) (original magnification ×250).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Electron microscopic examination shows intraretinal globules composed of basement membrane–like material (A). The plasma membrane of some Müller cells was focally deficient with intraretinal deposits of intermediate filaments (B) (original magnification ×7000).

Graphic Jump Location

Tables

References

Deutman  AF Vitreoretinal dystrophies. Krill  AArcher  DBedsHereditary Retinal and Choroidal Diseases. New York, NY Harper & Row1977;1043- 1108
Forsius  HKrause  UHelve  J  et al.  Visual acuity in 183 cases of X-chromosomal retinoschisis. Can J Ophthalmol. 1973;8385- 393
George  NDYates  JRMoore  AT X-linked retinoschisis. Br J Ophthalmol. 1995;79697- 702
George  NDYates  JRMoore  AT Clinical features in affected males with X-linked retinoschisis. Arch Ophthalmol. 1996;114274- 280
Mann  IMacrae  A Congenital vascular veils in the vitreous. Br J Ophthalmol. 1938;221- 10
Zimmerman  LENaumann  G The pathology of retinoschisis. McPherson  AedNew and Controversial Aspects of Retinal Detachment. New York, NY Harper & Row1968;400- 423
Yanoff  MRahn  EKZimmerman  LE Histopathology of juvenile retinoschisis. Arch Ophthalmol. 1968;7949- 53
Manschot  WA Pathology of hereditary conditions related to retinal detachment. Ophthalmologica. 1971;162223- 234
Manschot  WA Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol. 1972;88131- 138
Condon  GPBrownstein  SWang  NSKearns  AFEwing  CC Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in 3 eyes. Arch Ophthalmol. 1986;104576- 583
Kirsch  LSBrownstein  Sde Wolff-Rouendaal  D A histopathological, ultrastructural, and immunohistochemical study of congenital hereditary retinoschisis. Can J Ophthalmol. 1996;31301- 310
Ewing  CCCullen  AP Fluorescein angiography in X-chromosomal maculopathy with retinoschisis (juvenile hereditary retinoschisis). Can J Ophthalmol. 1972;719- 28
Green  JLJampol  LM Vascular opacification and leakage in X-linked (juvenile) retinoschisis. Br J Ophthalmol. 1979;63368- 373
Ando  ATakahashi  KSho  KMatsushima  MOkamura  AUyama  M Histopathological findings of X-linked retinoschisis with neovascular glaucoma. Graefes Arch Clin Exp Ophthalmol. 2000;2381- 7
Schepens  CL Congenital retinoschisis. Klin Oczna. 1988;90127- 132
Laatikainen  LTarkkanen  ASaksela  T Hereditary X-linked retinoschisis and bilateral congenital retinal detachment. Retina. 1987;724- 27
Kawano  KTanaka  KMurakami  FOhba  N Congenital hereditary retinoschisis: evolution at the initial stages. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1981;217315- 323
Molday  LLHicks  DSauer  CGWeber  BHMolday  RS Expression of X-linked retinoschisis protein RS1 in photoreceptors and bipolar cells. Invest Ophthalmol Vis Sci. 2001;42816- 825
Grayson  CReid  SNEllis  JA  et al.  Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein and is expressed and released by Weri-Rb 1 cells. Hum Mol Gen. 2000;91873- 1879
Sauer  CGGehrig  AWarneke-Wittstock  R  et al.  Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17164- 170
Retinoschisis Consortium, Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XRLS). Hum Mol Genet. 1998;71185- 1192
Arden  GBGorin  MBPolkinghome  PJJay  MBird  AC Detection of the carrier state of X-linked retinoschisis. Am J Ophthalmol. 1988;105590- 595
Reid  SNAkhmedov  NBPiriev  NIKozak  CADanciger  MFarber  DB The mouse X-linked juvenile retinoschisis cDNA: expression in photoreceptors. Gene. 1999;227257- 266
Reid  SNFarber  DB Transport of a photoreceptor-secreted protein, retinoschisin, by Müller cells [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42supplS654
Baumgartner  SHofmann  KChiquet-Ehrismann  RBucher  P The discoidin family revisited: new members from prokaryotes and a homology based fold prediction. Protein Sci. 1998;71626- 1631
Hiriyanna  KTTakada  YKondo  MBingham  ELSieving  PA X-linked retinoschisis: RS1 functional genomics and physiological dysfunction [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42supplS647
Gass  JD Müller cell cone, an overlooked part of the anatomy of the fovea centralis: hypothesis concerning its role in the pathogenesis of macular hole and foveomacular schisis. Arch Ophthalmol. 1999;117821- 823

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