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X-linked retinoschisis: for professionals


Overview

Prevalence
  • 1:5,000 to 20,000[1]
Inheritance
  • X-linked recessive
Genes involved (OMIM No.)
Clinical phenotype (OMIM phenotype no.)
Symptoms
  • Central vision disturbance/loss
  • Central visual function tends to remain relatively stable over time
  • Acute visual loss in cases with retinal detachments and vitreous haemorrhage
Signs
  • Early onset nystagmus may rarely occur
  • Foveal schisis that appears in a characteristic spoke-wheel pattern; most apparent on fundus autofluorescence (FAF) imaging
  • Macular atrophy tends to appear in older individuals due to progressive outer retinal degeneration
  • Peripheral schisis (about 50% of cases) and other peripheral features may be present
  • Retinal detachment and vitreous haemorrhage are known complications; higher risk of development with peripheral schisis
  • Hypermetropia is common
Systemic features
  • No specific associated extraocular features
Key investigations
  • Orthoptic assessment and refraction
  • FAF
  • OCT: Intraretinal cysts +/- outer retinal atrophy
  • Full-field ERG: reduced b-to-a wave amplitude ratio of variable severity on dark-adapted flash ERG; many display an electronegative ERG; Variable degree of delay and reduction in cone response
  • Pattern ERG: Reduced P50 amplitude
Molecular diagnosis
  • Targeted gene testing via Sanger sequencing
  • Targeted gene panels (retinal)
Management
  • Supportive management
  • Intraretinal cysts may resolve with topical or systemic carbonic anhydrase inhibitor but treatment response is variable
  • Surgery may rarely be required with progression of peripheral schisis detachment into the macula, or recurrent dense non clearing vitreous haemorrhage
  • Optimisation of early childhood development
Therapies under research
  • Gene therapy (phase 1/2)

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Clinical phenotype

Presenting features

X-linked retinoschisis is one of the most common form of juvenile-onset retinal dystrophy among male adolescents.[2] Over 190 variants in the causative RS1 gene have been identified thus far with complete penetrance but variable expressivity.[3] This leads to significant intra- and interfamilial variability in terms of age of onset, clinical presentation and rate of progression.

Patients typically present within the first two decades of life in various ways, including the development of strabismus shortly after birth, central vision loss, nystagmus and anisometropia (hypermetropia is common). Males are affected while female carriers are asymptomatic and do not display any fundal nor electrophysical abnormalities.

Visual acuity (VA) is highly variable among patients, ranging from 6/7.5 (0.1 LogMAR) to worse than 6/60 (1.0 LogMAR).[4-8] VA tends to deteriorate at a very slow rate over time, and does not seem to correlate with the presence and/or extent of macular atrophy, which are more common in older patients.[7-10] Patients may experience acute visual decline secondary to retinal detachments (rhegmatogenous, tractional or exudative) and vitreous haemorrhage, which tend to occur during childhood or adolescence.[11,12] 

Electrophysiology is the key investigation in confirming diagnosis in a suspected case as it is one of the few causes of an electronegative electroretinogram (ERG) on dark-adapted bright flash ERG. One group has reported a genotype-phenotype relationship, with patients harbouring nonsense, splice-site and frameshift mutations having worse VA and higher frequency of electronegative ERG compared to those with missense mutations.[4] This is however not observed in other studies.[5,9,10] On the other hand, there are variable degree of delay and reduction in cone responses.[10]

Fundal appearance

One of the most consistent fundal features among patients is the presence of foveal schisis (splitting of inner retinal layers), which may appear in a characteristic spoke-wheel pattern that is best appreciated on fundus autofluorescence (FAF) imaging. The schisis appear as intraretinal cystic changes on optical coherence tomography (OCT). Over time, the schitic cavities may resolve with progressive degeneration of the outer retinal structures, eventually leading to macular atrophy in older individuals.[5,9,13,14] Other macular features reported include mottling of the retinal pigment epithelium (RPE) and white dots in the macula.[4,6] In a small number of cases, the macula can appear normal fundoscopically and on multimodal imaging.[4, 5,12]

In addition to macular alterations, a proportion of patients also display peripheral findings, which include[7, 11,12]:

  • Peripheral retinoschisis (most common peripheral finding; present in around 50% of patients)
  • Metallic sheen 
  • Vitreous veils (large inner leaf breaks with membranous remnant of the posterior hyaloid face with peripheral vessels often appearing to hang in the vitreous)
  • RPE pigment disturbances (may present as a sequalae of spontaneous peripheral bullous retinoschisis resolution[15])
  • Neovascularisation
  • Vascular sheathing
  • White spiculations 

Clinicians should be aware that presence of these features, particularly peripheral retinoschisis, confer higher risk of retinal detachment and vitreous haemorrhage development.[12]

Peripheral schisis in the temporal retina in a patient with molecularly confirmed X-linked retinoschisis
FAF imaging shows macular schisis on OCT (B) which appears in a characteristic spoke-wheel pattern on FAF imaging (A)

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Genetics

The gene associated with X-linked retinoschisis was first identified in 1997 by Sauer et al. The gene encodes the retinoschisin protein, which is involved in maintaining cell-to-cell adhesion within the inner photoreceptor segments and the photoreceptor-bipolar cell synapse.[16,17] Over 190 variants have been identified thus far with complete penetrance but variable expressivity.[3] The majority of variants are missense changes. (Human Gene Mutation Database

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Key investigations

1) Orthoptic assessment and refraction

To assess current level of vision and determine if amblyopia therapy and/or refractive correction are required to optimise vision.

2) Fundus autofluorescence imaging (FAF)

A number of FAF features can be observed among patients, but the most common and characteristic feature is a spoke-wheel pattern of hyper- and hypo-AF centrally that correlates to the foveal schisis. Other less common features include[4]:

  • Normal FAF pattern
  • Atrophic macula surrounded by a hyper-AF ring
  • A broad hyper-AF ring surrounding normal or increased foveal AF

3) Optical coherence tomography (OCT)

Foveal schisis appear as intraretinal cysts on OCT. Over time, the cysts tend to flatten and outer retinal changes can be observed which can eventually lead to macular atrophy. Some patients may display a normal macular OCT. 

4) Electrophysiology

On full-field ERG, a reduced b-to-a wave amplitude ratio on dark-adapted bright flash is usually observed but the extent of reduction is highly variable, but most patients display an electronegative ERG. There is variable delay and reduction in cone responses. Furthermore, reduction in the P50 amplitude on pattern ERG has also been reported, providing psychophysical evidence of central vision dysfunction.[4]

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Diagnosis

X-linked retinoschisis can be diagnosed clinically in males presenting with suggestive fundal features, and the specific electrophysiological signs described above. Given the variability in clinical phenotype even within families, and the implications to relatives of X-linked inheritance, the diagnosis is best confirmed through genetic testing. The gene is tractable to targeted sequencing as it is composed of six small coding exons. Moreover, exonic deletions are not easily missed with PCR in male heterozygotes, which it consistently fails to detect heterozygous deletions in autosomal genes or X-linked carrier females. RS1 is also consistently included in panels used to diagnose inherited retinal disorders. 

Related links

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Management

Ocular

1) Supportive ocular management

Due to the relatively stable natural history of X-linked retinoschisis, management are mainly supportive with the main goals of vision optimisation, preventing amblyopia development and retinal detachment surveillance. Supportive measures include:  

  • Correcting any refractive errors
  • Urgent commencement of amblyopia treatment if detected
  • Regular assessment by a vitreoretinal surgeon
  • Referral to low vision services
  • Directing patients to supporting organisations 
  • Encourage the use of assistive technology that may improve quality of life
  • Encourage a healthy diet consisting of fresh fruit and vegetables 
  • 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) Medical management

Topical and systemic carbonic anhydrase inhibitors (CAIs) such as topical dorzolamide, topical brinzolamide and oral acetazolamide have been shown to reduce macular thickness and improve VA, but the treatment response among patients is highly variable.[10] [18-22] Most patients usually experience little or no change in VA or macular thickness, and the reduction in cystic cavity volume measured on OCT does not correlate with VA improvement.[10]  

3) Surgical management

Referral to a vitreoretinal surgeon is recommended if e any associated complications such as retinal detachments or vitreous haemorrhage. 

Patients with stable peripheral schisis tend to be managed conservatively due to the low rates of progression to retinal detachment.[23] Prophylactic laser barricade is usually avoided due to the high risk of iatrogenic breaks and subsequent progression to rhegmatogenous retinal detachments.[11] 

In cases where there is schisis progression or retinal detachment, management becomes more complex and surgery may be required. The decision to pursue surgery and the type of surgery (scleral buckling or vitrectomy) are based on a multitude of factors, including the configuration of the schisis/detachment, visual potential, chronicity of the detachment and the presence/absence of proliferative vitreoretinopathy. In general, vitrectomy surgery is likely to be complicated and the results are poor.

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.

Family management and counselling

ABCA4-retinopathies are inherited in an X-linked recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in X-linked retinoschisis

1) Gene therapy

Gene therapy works by introducing a normal gene into the appropriate cells (transgene) to compensate for the mutated gene that is not producing enough functional protein. The transgene is carried by a viral vector, usually adeno-associated virus (AAV) and delivered to the target cells through sub-retinal/intravitreal injections. 

The safety and efficacy of intravitreal RS1 gene therapy are being investigated in two trials (NCT 02416622 and NCT 02317887). The former trial has ceased due to marked ocular inflammation associated with the procedure and lack of positive clinical response.[24,25] In the latter trial, initial analysis from an 18-month follow-up period of 9 participants has shown that the procedure is generally well tolerated and the reported adverse events was mainly transient ocular inflammation (dose-dependent), which settled with topical +/- systemic steroids. One participant experienced posterior uveitis, a subsequent small retinal tear which was treated with laser retinopexy and vitreous haemorrhage which cleared with vitrectomy. The BCVA of the participant returned to baseline at the 18-month period.[26]

Related links

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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.  Pontikos N, Arno G, Jurkute N, et al. Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom. Ophthalmology. Oct 2020;127(10):1384-1394. doi:10.1016/j.ophtha.2020.04.008
  3.  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
  4.  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
  5.  Orès R, Mohand-Said S, Dhaenens CM, et al. Phenotypic Characteristics of a French Cohort of Patients with X-Linked Retinoschisis. Ophthalmology. Oct 2018;125(10):1587-1596. doi:10.1016/j.ophtha.2018.03.057
  6.  Apushkin MA, Fishman GA, Rajagopalan AS. Fundus findings and longitudinal study of visual acuity loss in patients with X-linked retinoschisis. Retina. Jul-Aug 2005;25(5):612-8. doi:10.1097/00006982-200507000-00012
  7.  Roesch MT, Ewing CC, Gibson AE, Weber BH. The natural history of X-linked retinoschisis. Can J Ophthalmol. Apr 1998;33(3):149-58
  8.  Kjellström S, Vijayasarathy C, Ponjavic V, Sieving PA, Andréasson S. Long-term 12 year follow-up of X-linked congenital retinoschisis. Ophthalmic Genet. Sep 2010;31(3):114-25. doi:10.3109/13816810.2010.482555
  9.  Cukras CA, Huryn LA, Jeffrey BG, Turriff A, Sieving PA. Analysis of Anatomic and Functional Measures in X-Linked Retinoschisis. Investigative ophthalmology & visual science. 2018;59(7):2841-2847. doi:10.1167/iovs.17-23297
  10.  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
  11.  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
  12.  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
  13.  Apushkin MA, Fishman GA, Janowicz MJ. Correlation of optical coherence tomography findings with visual acuity and macular lesions in patients with X-linked retinoschisis. Ophthalmology. Mar 2005;112(3):495-501. doi:10.1016/j.ophtha.2004.08.027
  14.  Menke MN, Feke GT, Hirose T. Effect of aging on macular features of X-linked retinoschisis assessed with optical coherence tomography. Retina. Jun 2011;31(6):1186-92. doi:10.1097/IAE.0b013e3181ff0d2d
  15.  Hinds AM, Fahim A, Moore AT, Wong SC, Michaelides M. Bullous X linked retinoschisis: clinical features and prognosis. Br J Ophthalmol. May 2018;102(5):622-624. doi:10.1136/bjophthalmol-2017-310593
  16.  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.M41311720
  17.  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
  18.  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
  19.  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
  20.  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
  21.  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
  22.  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.
  23.  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
  24.  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
  25.  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
  26.  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 1, 2020

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