The protein encoded by the gene mutated in X-linked retinoschisis is involved in which function?

Intercellular adhesion and retinal organization X-linked retinoschisis results from mutations in the RS1 gene on Xp22.1-p22.3, whose protein is involved in intercellular adhesion and likely retinal cellular organization.

Retinoid transport in the visual cycle

The rod phototransduction cascade

RPE phagocytosis of outer segments

What prevalence does the article give for X-linked retinoschisis?

About 1 in 15,000 to 30,000 With a prevalence of about 1 in 15,000 to 30,000, X-linked retinoschisis is one of the main causes of juvenile macular degeneration in males.

What pattern of macular involvement characterizes X-linked retinoschisis?

Symmetric, bilateral, beginning in the first decade X-linked retinoschisis is characterized by symmetric bilateral macular involvement that begins in the first decade of life.

Asymmetric, unilateral, beginning in adolescence

Symmetric, bilateral, beginning after age 50

Unilateral, beginning in the first decade

In the article's X-linked retinoschisis case, in which retinal layers did OCT show cystic lesions?

Inner nuclear and outer plexiform layers OCT showed cystic lesions in the inner nuclear and outer plexiform layers, which together with the other findings led to the diagnosis of bilateral retinoschisis.

Beneath the retinal pigment epithelium

Ganglion cell and nerve fibre layers

Between the photoreceptors and the RPE

What electroretinogram pattern was recorded in the article's X-linked retinoschisis case?

Reduced b-wave with a normal a-wave The ERG showed reduced b-wave amplitude in the combined response with a normal a-wave, together with a reduced photopic response.

Reduced a-wave with a normal b-wave

Extinguished rod and cone responses

Normal b-wave, supernormal photopic response

What did fundoscopy show in the 12-year-old boy with X-linked retinoschisis described in the article?

Silver-grey reflex with cartwheel-like maculae Smartphone fundoscopy showed a silver-grey retinal reflex and bilateral cartwheel-like macular changes, while fluorescein angiography was normal.

Bilateral bull's-eye maculopathy

A cherry-red spot at each fovea

Yellow vitelliform macular lesions

How should an affected male with X-linked retinoschisis be counseled about passing on the mutation?

All daughters inherit it; no sons do Affected males pass the mutation to all their daughters, who will most likely be asymptomatic carriers, but do not pass it to their sons.

All sons inherit it; no daughters do

Only sons inherit it, half affected

Why are patients with X-linked retinoschisis advised to avoid head trauma and high-impact sports?

Increased risk of retinal detachment Patient education includes avoiding head trauma and high-contact or high-impact sports because of the increased risk of retinal detachment.

Risk of traumatic lens subluxation

Risk of angle-recession glaucoma

Risk of traumatic optic neuropathy

Which medical therapy may improve the schisis cavities seen on OCT in X-linked retinoschisis?

Topical dorzolamide or oral acetazolamide Carbonic anhydrase inhibitors, topical dorzolamide or systemic acetazolamide, have been reported to improve the cystic spaces; response is followed by visual acuity and reduced cystic fluid on OCT.

Intravitreal anti-VEGF injections

Why is prophylactic laser photocoagulation controversial in X-linked retinoschisis?

It may create iatrogenic breaks and detachment Laser photocoagulation may prevent retinal detachment, but it can also induce one by creating iatrogenic retinal breaks, which makes prophylactic laser controversial.

It enlarges the foveal schisis cavities

It triggers choroidal neovascularization

It causes severe secondary glaucoma

X-Linked Retinoschisis: Genetics and management

CASE REPORT

A 12-year-old male child came to an ophthalmology department with reduced vision in both eyes since childhood, which was gradual in onset and progressive in nature.

On examination, his Visual acuity was 6/24 and 6/12 in right and left eye respectively. There was no improvement with the pinhole or glasses. Intraocular pressure recorded by non-contact tonometer was 17 mmHg in both eyes.

Smartphone fundoscopy showed silver grey retinal reﬂex and bilateral cartwheel-like macular degeneration. Fundus ﬂuorescein angiography was normal. Electroretinogram showed a reduction in b-wave amplitude for combined response and normal a wave and reduced photopic response.

Optical coherence tomography showed cystic lesions in the inner nuclear and outer plexiform layer of the retina. With all the above ﬁndings, the diagnosis of retinoschisis in both eyes was made out.

DISEASE

X-linked Retinoschisis or X-Linked Juvenile Retinoschisis is a rare congenital disease of the retina caused by mutations in the RS1 gene, which encodes retinoschisin, a protein involved in intercellular adhesion and likely retinal cellular organization.

X-linked retinoschisis has also been referred to as: juvenile retinoschisis, congenital retinoschisis, juvenile macular degeneration/dystrophy, and vitreous veils of the retina.

X-linked retinoschisis, with a prevalence of about 1 in 15,000 to 30,000, is one of the main causes of juvenile macular degeneration in males. It is characterized by symmetric bilateral macular involvement beginning in the first decade of life.

It is caused by a large variety of mutations in the RS1 gene on Xp22.1-p22.3, which encodes the protein retinoschisin. This protein is involved in intercellular adhesion and likely retinal cellular organization. X-linked retinoschisis is inherited in an X-linked manner with complete penetrance and variable expressivity.

Most affected individuals are males, as heterozygous females are rarely affected. However, retinoschisis has been reported in non-consanguinous females. The phenotype can be markedly variable even within the same genotype and can involve the peripheral retina.

Test your knowledge 10 questions from this article

MANAGEMENT

For those below 10 years old: Annual evaluation by a pediatric ophthalmologist or retina specialist.

Patient education: Avoid head trauma and high-contact/impact sports due to the increased risk of retinal detachment.

Amblyopia: Treat amblyopia, especially in cases of severe retinoschisis, hypermetropia, or following surgery for vitreous hemorrhage or retinal detachment.

Genetic counseling: male patients should be counseled that they will pass the mutation to all daughters (who will most likely be asymptomatic heterozygote carriers), but will not pass the mutation to sons.

Female carriers have a 50% chance of passing the mutation – all sons who inherit the mutation will be affected, and daughters who inherit the mutation will most likely be asymptomatic carriers.

For those with low vision: Low vision aids (large-print textbooks), preferential seating in the front of the classroom, and handouts with high contrast.

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.

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. In 2015, two human XLRS gene therapy trials were initiated:

The NEI trial is evaluating the safety of a gene transfer vector (AAV-RS1) in humans. It found closure of schisis cavities in one individual at higher dosing, which also caused ocular inflammation.
The AGTC trial is evaluating the safety and efficacy of a recombinant adeno-associated virus vector expressing retinoschisin (rAAV2tYF-CB-hRS1) in patients with X-linked retinoschisis.

Surgery

Complications such as retinal detachment and vitreous hemorrhage may require surgical intervention such as vitrectomy or scleral buckling.
Laser photocoagulation may prevent retinal detachment. However, it may also induce detachment by creating iatrogenic retinal breaks. Thus, the prophylactic laser is controversial.
External drainage has also been attempted.

REFERENCES

American Academy of Ophthalmology. X-linked juvenile retinoschisis.
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.
Sieving PA, MacDonald IM, Hoang S. X-Linked Congenital Retinoschisis. 2003 Oct 24 [Updated 2020 Nov 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1222/
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.
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.
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.
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.

Test yourself

A few questions straight from this article.

1 / 10 0 correct

The protein encoded by the gene mutated in X-linked retinoschisis is involved in which function?
X-linked retinoschisis results from mutations in the RS1 gene on Xp22.1-p22.3, whose protein is involved in intercellular adhesion and likely retinal cellular organization.
What prevalence does the article give for X-linked retinoschisis?
With a prevalence of about 1 in 15,000 to 30,000, X-linked retinoschisis is one of the main causes of juvenile macular degeneration in males.
What pattern of macular involvement characterizes X-linked retinoschisis?
X-linked retinoschisis is characterized by symmetric bilateral macular involvement that begins in the first decade of life.
In the article's X-linked retinoschisis case, in which retinal layers did OCT show cystic lesions?
OCT showed cystic lesions in the inner nuclear and outer plexiform layers, which together with the other findings led to the diagnosis of bilateral retinoschisis.
What electroretinogram pattern was recorded in the article's X-linked retinoschisis case?
The ERG showed reduced b-wave amplitude in the combined response with a normal a-wave, together with a reduced photopic response.
What did fundoscopy show in the 12-year-old boy with X-linked retinoschisis described in the article?
Smartphone fundoscopy showed a silver-grey retinal reflex and bilateral cartwheel-like macular changes, while fluorescein angiography was normal.
How should an affected male with X-linked retinoschisis be counseled about passing on the mutation?
Affected males pass the mutation to all their daughters, who will most likely be asymptomatic carriers, but do not pass it to their sons.
Why are patients with X-linked retinoschisis advised to avoid head trauma and high-impact sports?
Patient education includes avoiding head trauma and high-contact or high-impact sports because of the increased risk of retinal detachment.
Which medical therapy may improve the schisis cavities seen on OCT in X-linked retinoschisis?
Carbonic anhydrase inhibitors, topical dorzolamide or systemic acetazolamide, have been reported to improve the cystic spaces; response is followed by visual acuity and reduced cystic fluid on OCT.
Why is prophylactic laser photocoagulation controversial in X-linked retinoschisis?
Laser photocoagulation may prevent retinal detachment, but it can also induce one by creating iatrogenic retinal breaks, which makes prophylactic laser controversial.