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X-linked retinoschisis: for patients


Overview

X-linked retinoschisis (schisis—abnormal splitting of the retinal layers), also known as juvenile retinoschisis, is an inherited retinal condition caused by mutations in the RS1 gene, affecting one in 5,000 to one in 20,000 people.[1] 

As the macula is predominantly affected, patients tend to notice blurring of their vision and difficulties in recognising fine visual details, usually around childhood or adolescence. However, the severity of symptoms are highly variable, even among family members and some may only experience symptoms later in life. Visual sharpness (visual acuity) typically deteriorates very slowly over time, although a proportion of patients may experience a sudden decline in visual function due to a retinal detachment (retina being pulled away from the underlying supportive tissue) or vitreous haemorrhage (bleeding into the the clear jelly substance in front of the retina), which are known complications of this condition.

All males carrying a faulty RS1 gene copy will be affected (albeit with variable severity), while females are unaffected.[2] This is because changes in the RS1 gene are inherited in an X-linked recessive manner. There is currently no treatment for this condition but eye surgery may rarely be recommended, usually if there is a retinal detachment or the vitreous haemorrhage does not clear on its own. The purpose of the surgery is to preserve the level of vision a patient had previously instead of improving vision.  

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The condition

Symptoms

Patients typically present during childhood or adolescence with blurry vision and reduced visual  acuity. In younger pre-verbal children, parents may notice abnormal visual behaviour/poor visual development, a squint (misalignment of the eyes) or rarely, involuntary movement of the eyes (nystagmus) instead, which will prompt them to seek urgent medical attention.

The visual acuity tends to deteriorate very slowly over time, though some complications may precipitate further visual loss, such as bleeding into the vitreous and retinal detachment. This can happen at any time, but it occurs more frequently during childhood and adolescence.[3,4] Up to 50% of patients are at risk of developing these complications as the outside areas (periphery) of their retina are affected by schisis as well.[4]  

Cause

X-linked retinoschisis is caused by mutations in the RS1 gene. The geneprovides instructions for the production retinoschisin, a protein that is involved in the development and maintenance of the retinal structure. It binds different types of sepcialised retinal cells together (cell adhesion), enabling the retina to function normally.[5,6] When this protein does not work properly, the adhesion of cells is disrupted, hence splitting of the retinal layers (schisis) can occur. 

How is it diagnosed?

X-linked retinoschisis can be diagnosed by an ophthalmologist based on a suggestive family history (X-linked recessive) and characteristic features on clinical examination. 

During the eye clinic appointment, the ophthalmologist will perform a few tests to help with the diagnosis. An eye drop will be used to dilate the pupils so that the macula and the rest of the retina can be examined. Often, specialised cameras are used to assess the retina and macula in more detail, and to help identify the characteristic splitting of retinal layers. In a small number of cases, the macula may not have this typical appearance and can even appear normal instead.[7] 

Comparison between the macula of a patient with X-linked retinoschisis and an unaffected individual. The macula of the patient with X-linked retinoschisis has a cystic-like appearance while this is not apparent in the unaffected individual.
The splitting of the retinal layers at the macula of a patient with X-linked retinoschisis is clearly seen (A) using a specialised scan called optical coherence tomography (OCT). (B) is an OCT scan of the macula of an unaffected individual.

You/your child may also see other healthcare professionals such as an optometrist during the appointment to assess if glasses are need to improve vision. In addition, a specialised electrodiagnostic test called an electroretinogram (ERG) will also be arranged. ERG is used to evaluate the overall function of the retina and macula. 

Given the variable severity of symptoms among patients, even within families, genetic testing is advised to confirm the diagnosis by identifying changes in the RS1 gene. 

How is it inherited?

1) X-linked recessive inheritance

The genetic changes causing X-linked retinoschisis is inherited in this manner. The RS1 gene is located on the X chromosome. The X chromosome determines our gender together with the Y chromosome. Females have two X chromosomes whereas males have one X and one Y chromosome. Only one functioning copy of the RS1 gene is required for the retina to operate normally.

As a result, males are affected in X-linked retinoschisis while females do not display any features as they have another functioning copy of the RS1 gene. They are hence termed carriers.  

If the mother is a “carrier” and the father is healthy: 

  • Each son has a 50% chance of being affected
  • Each daughter has a 50% chance of being a carrier like the mother
If a mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
X-linked recessive inheritance

If the father is affected and the mother is healthy: 

  • None of his sons will be affected
  • All of his daughters will be carriers

If you or your child are affected by X-linked retinoschisis, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

1) Supportive visual measures

There is currently no treatment available but researchers are exploring various approaches. In the meantime, treatment is mainly focused on optimising remaining sight, preventing the development of a “lazy” eye and retinal detachment surveillance. These include:

  • Regular monitoring of visual function and prescribing glasses (if required)
  • Patching treatment may be required if a “lazy” eye is detected in children (usually involves patching of the better seeing eye)
  • Utilising visual aids and assistive technology to improve quality of life
  • Regular assessment by a retinal specialist
  • Having a healthy diet consisting of fresh fruits and green leafy vegetables
  • Using blue light screen protectors on mobile devices or computer screens*

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

2) Medications

A specific class of eye drops and oral medication called carbonic anhydrase inhibitors (CAIs) have been shown to improve vision, but the treatment response among patients is highly variable.[8-13] Most patients usually experience little or no change in visual acuity with CAIs.

3) Surgery

Surgery is rarely recommended unless there is a retinal detachment that threatens the central vision (i.e the macula) or if the vitreous haemorrhage does not clear on its own. The decision to pursue surgery is made on a case-by-case basis as the procedure is likely to be complicated and the results are poor. Therefore, a discussion with your treating ophthalmologist is recommended before you decide to go for an operation. Patients with schisis in the peripheral retina that are stable (no change over a period of time) are usually observed in clinic as the risk of progression into a retinal detachment is low.[14]    

4) Optimisation of development

As vision is important in normal childhood development and education, children with visual impairment due to X-linked retinoschisis should be referred to developmental paediatricians and advisory teaching services for children/adolescents with visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

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Current research in X-linked retinoschisis

1) Gene therapy

Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins. A healthy copy of the RS1 gene is accommodated into a harmless virus, which is then injected into the eye (intravitreal injection).

Injection of a drug into the clear jelly (vitreous) of the eye.
Intravitreal injection

For X-linked retinoschisis, the safety and effectiveness of intravitreal RS1 gene therapy are investigated in two clinical trials (NCT 02416622 and NCT 02317887). The former trial has ceased as some of the injected eyes had marked inflammation (resolved with drops and medications).[15,16] In the latter trial, initial analysis has shown that the procedure is generally well-tolerated, but has little clinical effect on visual function.[17] However, the main purpose of these trials is to evaluate safety and tolerability of the therapy, while clinical effect is usually assessed in larger trials (with more number of participants) once the therapy is considered safe for human usage.    

Related links

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Practical advice

Living with X-linked retinoschisis

Patients are still able to lead independent lives through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Utilising visual aids and assistive technology that may improve quality of life
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.  

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Further information and support

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References

  1.  Rao P, Dedania VS, Drenser KA. Congenital X-Linked Retinoschisis: An Updated Clinical Review. Asia Pac J Ophthalmol (Phila). May-Jun 2018;7(3):169-175. doi:10.22608/apo.201803
  2.  Retinoschisis Consortium. Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium. Hum Mol Genet. Jul 1998;7(7):1185-92. doi:10.1093/hmg/7.7.1185
  3.  Kellner U, Brümmer S, Foerster MH, Wessing A. X-linked congenital retinoschisis. Graefes Arch Clin Exp Ophthalmol. 1990;228(5):432-7. doi:10.1007/bf00927256
  4.  Fahim AT, Ali N, Blachley T, Michaelides M. Peripheral fundus findings in X-linked retinoschisis. Br J Ophthalmol. Nov 2017;101(11):1555-1559. doi:10.1136/bjophthalmol-2016-310110
  5.  Wu WW, Wong JP, Kast J, Molday RS. RS1, a discoidin domain-containing retinal cell adhesion protein associated with X-linked retinoschisis, exists as a novel disulfide-linked octamer. J Biol Chem. Mar 18 2005;280(11):10721-30. doi:10.1074/jbc.M413117200
  6.  Shi L, Ko ML, Ko GY. Retinoschisin Facilitates the Function of L-Type Voltage-Gated Calcium Channels. Front Cell Neurosci. 2017;11:232. doi:10.3389/fncel.2017.00232
  7.  Vincent A, Robson AG, Neveu MM, et al. A phenotype-genotype correlation study of X-linked retinoschisis. Ophthalmology. Jul 2013;120(7):1454-64. doi:10.1016/j.ophtha.2012.12.008
  8.  Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. Sep 2006;26(7):741-5. doi:10.1097/01.iae.0000237081.80600.51
  9.  Walia S, Fishman GA, Molday RS, et al. Relation of response to treatment with dorzolamide in X-linked retinoschisis to the mechanism of functional loss in retinoschisin. Am J Ophthalmol. Jan 2009;147(1):111-115.e1. doi:10.1016/j.ajo.2008.07.041
  10.  Khandhadia S, Trump D, Menon G, Lotery AJ. X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype. Eye (Lond). Jul 2011;25(7):922-8. doi:10.1038/eye.2011.91
  11.  Gurbaxani A, Wei M, Succar T, McCluskey PJ, Jamieson RV, Grigg JR. Acetazolamide in retinoschisis: a prospective study. Ophthalmology. Mar 2014;121(3):802-3.e3. doi:10.1016/j.ophtha.2013.10.025
  12.  Verbakel SK, van de Ven JPH, Le Blanc LMP, et al. Carbonic Anhydrase Inhibitors for the Treatment of Cystic Macular Lesions in Children With X-Linked Juvenile Retinoschisis. Investigative Ophthalmology & Visual Science. 2016;57(13):5143-5147. doi:10.1167/iovs.16-20078
  13.  Pennesi ME, Birch DG, Jayasundera KT, et al. Prospective Evaluation of Patients With X-Linked Retinoschisis During 18 Months. Invest Ophthalmol Vis Sci. Dec 3 2018;59(15):5941-5956. doi:10.1167/iovs.18-24565
  14.  Ferrone PJ, Trese MT, Lewis H. Vitreoretinal surgery for complications of congenital retinoschisis. Am J Ophthalmol. Jun 1997;123(6):742-7. doi:10.1016/s0002-9394(14)71120-1
  15.  Sieving PA, MacDonald IM, Hoang S. X-Linked Congenital Retinoschisis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews(®). University of Washington, Seattle Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.
  16.  Rahman N, Georgiou M, Khan KN, Michaelides M. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options. Br J Ophthalmol. Nov 8 2019;doi:10.1136/bjophthalmol-2019-315086
  17.  Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther. Sep 5 2018;26(9):2282-2294. doi:10.1016/j.ymthe.2018.05.025

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Updated on December 28, 2020
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