Case report of an atypical early onset X-linked retinoschisis in monozygotic twins

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Abstract

Background

X-linked Retinoschisis (XLRS) is one of the most common macular degenerations in young males, with a worldwide prevalence ranging from 1:5000 to 1:20000. Clinical diagnosis of XLRS can be challenging due to the highly variable phenotypic presentation and limited correlation has been identified between mutation type and disease severity or progression.

Case presentation

We report the atypical early onset of XLRS in 3-month-old monozygotic twins. Fundus examination was characterized by severe bullous retinal schisis with pre-retinal and intraretinal haemorrhages. Molecular genetic analysis of the RS1 was performed and the c.288G > A (p. Trp96Ter) mutation was detected in both patients.

Conclusions

Early onset XLRS is associated with a more progressive form of the disease, characterized by large bullous peripheral schisis involving the posterior pole, vascular abnormalities and haemorrhages. The availability of specific technology permitted detailed imaging of the clinical picture of unusual cases of XLRS. The possible relevance of modifying genes should be taken into consideration for the future development of XLRS gene therapy.

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Most cited references 9

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X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms.

Robert Molday, Ulrich Kellner, Bernhard Weber (2012)

X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long-term retinoschisin expression and rescue of retinal structure and function providing a 'proof of concept' that gene therapy may be an effective treatment for XLRS. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.

Adrian M. Timmers, Naoyuki Tanimoto, Bernhard Weber … (2005)

X-linked juvenile retinoschisis (RS) is a common cause of juvenile macular degeneration in males. RS is characterized by cystic spoke-wheel-like maculopathy, peripheral schisis, and a negative (b-wave more reduced than a-wave) electroretinogram (ERG). These symptoms are due to mutations in the RS1 gene in Xp22.2 leading to loss of functional protein. No medical treatment is currently available. We show here that in an Rs1h-deficient mouse model of human RS, delivery of the human RS1 cDNA with an AAV vector restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice. More importantly, unlike an earlier study with a different AAV vector and promoter, this work shows for the first time that therapeutic gene delivery using a highly specific AAV5-opsin promoter vector leads to progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.

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X-linked retinoschisis: clinical phenotype and RS1 genotype in 86 UK patients.

D Trump, Bill J. Yates, James N. George … (2005)

Inactivating mutations of the gene RS1 lead to X-linked retinoschisis, a progressive retinal dystrophy characterised by schisis within the inner layers of the neuroretina. The mutation spectrum is large and the phenotype variable. To determine whether there is a correlation between mutation type and disease severity. We identified the causative mutation in 86 affected patients and examined each of these patients in detail. Different categories of mutation were compared for each phenotypic characteristic. We found a reduction in visual acuity with increasing age and worsening macular pathology in patients over 30 years old (p < or = 0.001), but there was no correlation between mutation type and severity of disease. Furthermore, we found a wide variation in phenotype even within families. Identifying the causative mutation in patients with X-linked retinoschisis is helpful in confirming diagnosis and in counselling of family members but cannot be used to predict prognosis for an individual patient.

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Author and article information

Contributors

Vittoria Murro: vittomurro@yahoo.it

Roberto Caputo: roberto.caputo@unifi.it

Giacomo Maria Bacci: giacomo.bacci@meyer.it

Andrea Sodi: asodi@tin.it

Dario Pasquale Mucciolo: +39 055 2751730 , dario.mucciolo@gmail.com

Sara Bargiacchi: sara.bargiacchi@meyer.it

Sabrina Rita Giglio: sabrinarita.giglio@unifi.it

Gianni Virgili: gianni.virgili@unifi.it

Stanislao Rizzo: stanislao.rizzo@unifi.it

Journal

Journal ID (nlm-ta): BMC Ophthalmol

Journal ID (iso-abbrev): BMC Ophthalmol

Title: BMC Ophthalmology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2415

Publication date (Electronic): 24 February 2017

Publication date PMC-release: 24 February 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 19

Affiliations

[1 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department of Translational Surgery and Medicine, Eye Clinic, , University of Florence, ; Largo Brambilla, Florence, 3-50134 Italy

[2 ]Ophthalmology Unit, Department of Pediatrics, Anna Meyer Children’s University Hospital, Florence, Italy

[3 ]Genetics and Molecular Medicine Unit, Department of Pediatrics, Anna Meyer Children’s University Hospital, Florence, Italy

Article

Publisher ID: 406

DOI: 10.1186/s12886-017-0406-6

PMC ID: 5324242

PubMed ID: 28235399

SO-VID: 2927b75d-2699-4c73-853f-dbfa45918b65

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 October 2016

Date accepted : 25 January 2017

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ScienceOpen disciplines: Ophthalmology & Optometry

Keywords: x-linked retinoschisis,juvenile retinoschisis,rs1,bullous peripheral schisis,case report

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ScienceOpen disciplines: Ophthalmology & Optometry

Keywords: x-linked retinoschisis, juvenile retinoschisis, rs1, bullous peripheral schisis, case report

Case report of an atypical early onset X-linked retinoschisis in monozygotic twins

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Abstract

Background

Case presentation

Conclusions

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Most cited references 9

X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms.

Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.

X-linked retinoschisis: clinical phenotype and RS1 genotype in 86 UK patients.

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