X-linked Retinoschisis

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Original article contributed by: Brian Lee, MD
All contributors: Brian Lee, MD and Saurabh Deshmukh, MBBS
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Review: Not reviewed



X-linked Retinoschisis
Classification and external resources
ICD-10 [1]14.1
OMIM 312700
DiseasesDB 31283


X-linked Retinoschisis is an inherited retina disorder that causes early vision loss in males.

Disease Entity

X-linked Retinoschisis, or X-Linked Juvenile Retinoschisis is a rare congenital malformation of the retina caused my mutations in the RS1 gene, which encodes retinoschisin, a protein involved in intercellular adhesion.

ICD-10: Q14.1

Disease

X-linked retinoschisis, with a prevalence of about 1 in 15,000 to 30,000, is the main cause of juvenile macular degeneration.[1] It is caused by a large variety of mutations in RS1 on XP22.1, which encodes retinoschisin. This gene is responsible for proteins that are involved in intercellular adhesion. Most affected individuals are males, as heterozygous females are rarely affected. However, retinoschisis has been reported in non-consanguinous females.[2][3] The phenotype can be markedly variable even within the same genotype, and can extend into the erpiheral retina.

Pathophysiology

X-linked retinoschisis is linked to mutations in RS1 on Xp22.1. The gene encodes a 224-amino acid protein called retinoschisin, which is secreted by photoreceptors. [4] This protein is found throughout the retina, and is thought to be involved in cell-cell adhesion and intercellular matrix retinal architecture development through interactions with αβ crystallin and β2-laminin. On histopathological examination, the splitting in X-linked retinoschisis occurs predominantly in the nerve fiber layer. [5]

Diagnosis

History

Patients typically present at school age complaining of poor vision, although they may present in infancy with nystagmus, strabismus, hyperopia, foveal ectopia, hemorrhage, or detachment. However, there is wide variability in disease severity, ranging from normal vision to legal blindness, even among patients carrying the same mutation. X-linked retinoschisis may also present as spontaneous vitreous hemorrhage or retinal detachment. These complications occur commonly and are the main causes of complete vision loss.[6]

Physical examination

Optos photo of a child with foveal retinoschisis

There is large variation in disease severity among patients, even among patients with the same genetic mutation. Patients typically present complaining of difficulty in school, although younger patients may present earlier with strabismus or nystagmus. Visual acuity may range from 20/20 to blindness, and depends on the amount and area of schisis. The vision is often stable until middle-age.

Peripheral vision may be normal in the unaffected areas. Absolute scotoma may be present in areas of peripheral retinoschisis. Color vision is often normal as well.

On fundoscopic examination, 98-100% of patients have foveal schisis, noted as a spokewheel pattern radiating from the fovea and a domelike elevation of thin layer or retina. Schisis is most often in the macular, but extension into the periphery occurs in more than half of patients.[7] The bullous retinoschisis may improve over time.

Subretinal linear fibrosis, pigmentation, white retinal flecks, vascular attenuation, and vascular sheathing may also be present.

Visual function may be severely limited with progression to retinal detachment, most often rhegmatogenous, in 5-20%. Vitreous hemorrhage is another common complication, and hemorrhage may also occur within the schisis cavity.

Other complications include intraretinal splitting, neovascular glaucoma, macular dragging, and optic atrophy.

Clinical diagnosis

Diagnostic procedures

  • Digital fundus photography may help with examination of a child
  • Red-free illumination may help to highlight the area of foveal schisis
  • Fundus autofluorescence may also help to highlight areas of foveal schisis
Fundus autofluorescence photo of a child with foveal retinoschisis
  • Optical coherence tomography (OCT) reveals schisis in the superficial neural retina. There are often large cystic-like spaces, especially large below the fovea. These cystic spaces may be present in any layer of the retina and reveal areas of schisis not visible on fundus examination.
OCT of a child with foveal retinoschisis
  • Fluorescein angiography is not required for diagnosis. Unlike cystic macula edema, there may be pooling but no leakage of the cystic spaces.
  • Full-field electroretinogram (ffERG) is electronegative (Reduced b-wave with preserved a-wave). This is not diagnostic as the differential for electronegative ERG includes several other retinal disorders, and the a-wave may be reduced as the disease progresses.
  • Genetic testing can confirm the diagnosis.

Laboratory test

Genetic testing is available for the RS1 gene that encodes retinoschisin.

Differential diagnosis

Autosomal dominant and recessive schisis will have a different inheritance pattern and may normal ffERG [8]

Goldmann-Favre (Enhanced S cone syndrome) has associated nyctalopia and pigment clumping

Degenerative retinoschisis typically occurs in older individuals

Dominantly inherited CME and other causes of CME

Eales disease

Wagner syndrome

Alport’s syndrome

Management

Genetic counseling: Males will pass the x-linked recessive mutation to all daughters, but not sons. Female carriers have a 50% chance of passing the mutation, all sons with the mutation will be affected, daughters will most likely be asymptomatic carriers.

Medical therapy

Carbonic anhydrase inhibitors may help to improve the schisis cavities seen on OCT. Topical dorzolamide or systemic acetazolamide have both been reported to be beneficial in improving the cystic-appearing spaces on OCT.[9][10][11] Clinical improvement can be monitored with visual acuity improvements and reduction in the cystic fluid on OCT.

Gene therapy with intra-ocular RS1 in knockout mice has restored b-wave function and there are several human clinical trials that are recruiting subjects including NCT02317887 and NCT02416622.

Surgery

  • Complications such as retinal detachment and vitreous hemorrhage may require surgical intervention.
  • Laser photocoagulation may prevent detachment. However, it may also induce detachment.
  • External drainage has also been attempted.[12]

Prognosis

Vision is typically stable until the 5th or 6th decade.

Additional Resources

References

  1. Sikkink SK, Biswas S, Parry NRA, Stanga PE, Trump D. X-linked retinoschisis: an update. Journal of Medical Genetics. 2007 Apr 1;44(4):225–32.
  2. Saleheen D, Ali A, Khanum S, Ozair MZ, Zaidi M, Sethi MJ, et al. Molecular analysis of the XLRS1 gene in 4 females affected with X-linked juvenile retinoschisis. Can J Ophthalmol. 2008 Oct;43(5):596–9.
  3. Rodríguez FJ, Rodríguez A, Mendoza-Londoño R, Tamayo ML. X-linked retinoschisis in three females from the same family: a phenotype-genotype correlation. Retina (Philadelphia, Pa). 2005 Jan;25(1):69–74.
  4. Grayson C, Reid SNM, Ellis JA, Rutherford A, Sowden JC, Yates JRW, et al. Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri–Rb1 cells. Hum Mol Genet. 2000 Jul 22;9(12):1873–9.
  5. Yassur Y, Nissenkorn I, Ben-Sira I, Kaffe S, Goodman RM. Autosomal Dominant Inheritance of Retinoschisis. American Journal of Ophthalmology. 1982 Sep 1;94(3):338–43.
  6. George NDL, Yates JRW, Moore AT. Clinical Features in Affected Males With X-Linked Retinoschisis. Arch Ophthalmol. 1996 Mar 1;114(3):274–80.
  7. George NDL, Yates JRW, Moore AT. Clinical Features in Affected Males With X-Linked Retinoschisis. Arch Ophthalmol. 1996 Mar 1;114(3):274–80.
  8. Yassur Y, Nissenkorn I, Ben-Sira I, Kaffe S, Goodman RM. Autosomal Dominant Inheritance of Retinoschisis. American Journal of Ophthalmology. 1982 Sep 1;94(3):338–43.
  9. Zhang L, Reyes R, Lee W, Chen C-L, Chan L, Sujirakul T, et al. Rapid resolution of retinoschisis with acetazolamide. Doc Ophthalmol. 2015 Aug;131(1):63–70.
  10. Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina (Philadelphia, Pa). 2006 Sep;26(7):741–5.
  11. Gupta K, Das D, Bhattacharjee H, Deka H, Magdalene D, Deshmukh S. Juvenile X-Linked retinoschisis: Response to topical dorzolamide therapy. TNOA J Ophthalmic Sci Res [serial online] 2018 [cited 2018 Sep 2];56:35-7. Available from: http://www.tnoajosr.com/text.asp?2018/56/1/35/233726
  12. Rishi E, Gopal L, Rishi P, Deshmukh H. Congenital x-linked retinoschisis: a novel approach for management of a large schitic cavity overhanging the macula. Retin Cases Brief Rep. 2009;3(1):105–7.