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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. X-linked juvenile retinoschisis is characterized by symmetrical bilateral macular involvement with onset in the first decade of life, in some cases as early as three months of age. Fundus examination shows areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern. Schisis of the peripheral retina, predominantly inferotemporally, occurs in about 50% of individuals. Affected males typically have vision of 20/60 to 20/120. Visual acuity often deteriorates during the first and second decades of life but then remains relatively stable until the fifth or sixth decade.
Diagnosis/testing. The clinical diagnosis of X-linked juvenile retinoschisis is based on fundus findings and electrophysiologic examination. Molecular genetic testing is also available for confirmation of the diagnosis. RS1 is the only gene known to be associated with X-linked juvenile retinoschisis. Approximately 95% of individuals of Finnish heritage have one of three founder mutations. Mutation analysis for these three mutations is available on a clinical basis. Sequence analysis of the RS1 gene is available on a clinical basis.
Management. Individuals with X-linked juvenile retinoschisis benefit from low vision aids such as large-print textbooks, preferential seating in the front of the classroom, and use of handouts with high contrast. Surgery may be required to address infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. Surveillance includes annual evaluation of children under the age of 10 years by a pediatric ophthalmologist or retina specialist. Affected individuals should avoid head trauma and high-contact sports.
Genetic counseling. X-linked juvenile retinoschisis is inherited in an X-linked recessive manner. If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will nearly always have normal visual function and electrophysiology. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing of at-risk female relatives is available on a clinical basis if the disease-causing mutation has been identified in the proband. Prenatal testing is possible for pregnancies of women who are carriers of the RS1 mutation.
Affected males. The diagnosis of X-linked juvenile retinoschisis is made in a young male with the following findings:
Reduced visual acuity, typically between 20/60 and 20/120
The following findings on fundus examination:
Areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern
Schisis of the peripheral retina, predominantly inferotemporally, in about 50% of individuals [Eksandh et al 2000]. The associated elevation of the surface layer of the retina into the vitreous has been described as "vitreous veils."
On occasion, the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light [de Jong et al 1991]
Electroretinogram (ERG) showing selective reduction of the amplitude of the dark-adapted b-wave amplitude but preservation of the a-wave amplitude [Peachey et al 1987, Nakamura et al 2001]
Note: Because an individual with X-linked juvenile retinoschisis with an identified RS1 mutation has had a technically normal ERG in which the b-wave was still present [Sieving, Bingham et al 1999], the diagnosis of X-linked juvenile retinoschisis cannot be excluded based on a normal ERG, although this occurrence is extremely rare.
A family history consistent with X-linked inheritance
Carrier females. In most cases, carrier females cannot be identified by clinical examination. Carrier females nearly always have normal visual function and a normal ERG. Rarely, examination of the peripheral retina may show white flecks or areas of schisis [Kaplan et al 1991].
Intravenous fluorescein angiogram appears normal in younger individuals, whereas older individuals may have atrophic changes in the retinal pigment epithelium (RPE).
Optical coherence tomography (OCT) shows small cystic-appearing spaces in the perifoveal region and larger cystic-like spaces within the fovea in most younger individuals [Apushkin et al 2005]. OCT scans of older individuals may appear normal because of flattening of cysts with age.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. RS1 is the only gene known to be associated with X-linked juvenile retinoschisis.
Clinical uses
Confirmatory diagnostic testing
Clinical testing
Targeted mutation analysis. Approximately 95% of affected individuals of Finnish heritage have one of three founder mutations [p.Glu72Lys (214G>A), p.Gly74Val (221G>T), and p.Gly109Arg (325G>C)] [Huopaniemi et al 1999].
Sequence analysis. RS1 mutations are identified by sequence analysis in nearly 90% of males with a clinical diagnosis of X-linked juvenile retinoschisis [Sieving, Yashar et al 1999].
Deletion analysis is available clinically to detect the less common gross deletions in RS1 in affected individuals. Carrier testing. Multiplex ligation-dependent probe amplification (MLPA) and real time PCR copy number are also available clinically to detect the less common gross deletions in the RS1 gene in at-risk relatives of affected individuals.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | RS1 mutations p.Glu72Lys, p.Gly74Val, p.Gly109Arg | ~95% 2 | Clinical
 |
| Sequence/deletion analysis | Various RS1 mutations | 90% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
In general, the diagnosis can be made by ophthalmologic examination and confirmed by electroretinogram.
To identify the mutation in an affected individual:
In individuals of Finnish heritage, perform targeted mutation analysis of the four common mutations.
If the mutation is not identified, and for individuals of non-Finnish heritage, perform sequence analysis.
In individuals in whom a mutation is not identified by sequence analysis, consider deletion analysis.
X-linked juvenile retinoschisis is the only phenotype associated with mutations in RS1.
X-linked juvenile retinoschisis is a symmetrical bilateral macular disorder with onset in the first decade of life, in some cases as early as three months of age. Affected males generally present with reduction in vision by early grade school. Affected males typically have vision of 20/60 to 20/120 on first presentation. Visual acuity may deteriorate during the first and second decades of life but then remain relatively stable, with only very slowly progressive reduction from macular atrophy, until the fifth or sixth decade [Eksandh et al 2000, Apushkin et al 2005]. Visual loss may progress to legal blindness (acuity <20/200) by the sixth or seventh decade. In individuals over 50 years of age, macular pigmentary changes and some degree of atrophy of the RPE are common [George et al 1996]. Variation in disease presentation and disease progression is observed even among members of the same family.
Apperance of foveal lesions varies from largely radial striations (3%), microcystic lesions (34%), honeycomblike cysts (8%), or their combinations (31%) to non-cystic-appearing foveal changes such as pigment mottling (8%), loss of the foveal reflex (8%), or an atrophic-appearing lesion (8%) [Apushkin et al 2005].
X-linked juvenile retinoschisis progresses to retinal detachment in fewer than 10% of individuals. Retinal detachment can occur in infants with severe retinoschisis. Even fewer individuals with X-linked juvenile retinoschisis develop vitreous hemorrhage.
No genotype-phenotype correlations have been identified [Sieving, Yashar et al 1999; Eksandh et al 2000; Inoue et al 2000].
Missense, splice site, frameshift, insertion, and deletion mutations all result in the same phenotype. Some studies suggest that mutations that putatively cause protein truncation result in greater clinical severity [Sieving, Yashar et al 1999].
Mutations are most commonly found in the coding regions of exons 4-6, corresponding to the discoidin domain [Hewitt et al 2005].
X-linked juvenile retinoschisis exhibits complete penetrance with variable expressivity.
Other terms correctly used in the past to refer to X-linked juvenile retinoschisis:
Juvenile retinoschisis
Congenital retinoschisis
Juvenile macular degeneration/dystrophy
Other terms incorrectly used in the past to refer to X-linked juvenile retinoschisis:
Cone dystrophy
Macular hole
Estimates of the prevalence of X-linked juvenile retinoschisis vary from one in 5,000 to one in 25,000.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
While the presence of retinoschisis in an individual with a positive family history of X-linked juvenile retinoschisis establishes the diagnosis in that person, making the diagnosis in a male with no known family history may be more difficult.
Cystoid macular edema may mimic foveal retinoschisis. Macular edema may be caused by diabetes mellitus, inflammatory conditions of the eye (uveitis), or intraocular surgery.
Amblyopia can be a referring diagnosis when foveal schisis changes are subtle. Suspicion of X-linked juvenile retinoschisis is raised if family history indicates other affected males in an X-linked inheritance pattern.
Goldmann-Favre vitreoretinal degeneration may mimic X-linked juvenile retinoschisis [Fishman et al 1976]. In this autosomal recessive condition, coarse intraretinal cysts may be seen with peripheral retinoschisis. No vitreous veils are observed in Goldmann-Favre syndrome. The onset of Goldmann-Favre syndrome occurs in infancy. Generally, individuals have severely impaired vision, severe night blindness, and a markedly reduced electroretinogram a-wave and b-wave with altered timing rather than simply the reduction in the b-wave amplitude found in X-linked juvenile retinoschisis.
Retinitis pigmentosa (RP) is the referring diagnosis in many persons with X-linked juvenile retinoschisis [George et al 1996]. Characteristics of RP that distinguish it from X-linked juvenile retinoschisis include some or all of the following: optic nerve gliotic pallor, narrowing of retinal vessels, and intraretinal pigment dispersion or clumping. The X-linked form of RP may cause confusion with X-linked juvenile retinoschisis, and other family members should be examined; the ERG in RP (particularly X-linked RP) is markedly diminished rather than having the selective reduction in b-wave amplitude seen in X-linked juvenile retinoschisis. Noble and colleagues (1978) reported a family with rod-cone dystrophy and associated foveal schisis. For this reason, foveal retinoschisis alone does not make the diagnosis of X-linked juvenile retinoschisis.
Wagner disease is an autosomal dominant disorder with myopia and a high risk of retinal detachment [Brown et al 1995]. In Wagner disease, the macula is normal and the ERG is reduced in all components, whereas in X-linked juvenile retinoschisis, the macula is always abnormal and the ERG abnormality is usually limited to reduction in b-wave amplitude.
Degenerative retinoschisis is an idiopathic, degenerative disease of the peripheral retina. No evidence suggests genetic etiology [Lewis 2003]. In degenerative or age-related peripheral retinoschisis, splitting occurs in the outer retina through the outer nuclear layer and plexiform layer, whereas in X-linked juvenile retinoschisis, splitting is found in the nerve fiber layer and the ganglion cell layer [Sieving 1998].
Retinal detachment, in which the full-thickness retina elevates and lifts off from the underlying ocular support, differs from retinoschisis, in which the retina splits through the nerve fiber layer. Retinal detachment in an otherwise normal eye can be surgically repaired, whereas retinal detachment associated with retinoschisis usually cannot.
To establish the extent of disease in an individual diagnosed with X-linked juvenile retinoschisis, the following evaluations are recommended:
Visual acuity
Goldmann visual field
Electroretinogram
Funduscopic examination
Optical coherence tomography
Low vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs.
Public school systems are mandated by federal law to provide appropriate education for children who have vision impairment. Assistance may include larger print textbooks, preferential seating in the front of the classroom, and use of handouts with higher contrast.
Many individuals with X-linked juvenile retinoschisis are able to obtain a restricted driver's license. Some individuals have found specially designed telescopic lenses useful when driving; however, legal use of telescopic lenses may vary by locale.
Retinoschisis affects primarily the inner retinal layers; hence, retinoschisis alone (without retinal detachment) is, at best, difficult to treat surgically.
Treatment of retinoschisis may require the care of a retinal surgeon to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. The clinical presentation of a large area of peripheral retinoschisis may mask a true retinal detachment. Advice from an ophthalmologist or retinal surgeon should be sought when in doubt.
Children under age ten years should be evaluated by a qualified pediatric ophthalmologist or retina specialist on a yearly basis.
Older children and adults need less frequent monitoring.
Although retinal detachment and vitreous hemorrhage occur in a minority of affected individuals (only 5%-22% and 4%-40%, respectively), general avoidance of head trauma and high contact sports is recommended.
At-risk male relatives of a proband should be examined by an ophthalmologist to confirm affected or non-affected status.
A mouse model of human X-linked juvenile retinoschisis is being studied to determine whether supplementation with functional normal retinoschisin protein can produce improvement in ERG function and retina morphology [Zeng et al 2004, Min et al 2005]. Current evaluation of the mouse model confirms that it appropriately mimics structural features of human X-linked juvenile retinoschisis. Replacements of the deficient protein through use of a neomycin resistance cassette or through use of an AAV vector have both been successful, suggesting that, with additional study, gene therapy may become a viable strategy for therapeutic intervention.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
X-linked juvenile retinoschisis is inherited in an X-linked recessive manner.
Parents of a proband
The father of an affected male will not have the disease or be a carrier of the mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
Obligate carriers do not exhibit any signs in the macula, and only rarely are peripheral retinal changes associated with the carrier state [Kaplan et al 1991].
If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation and, thus, the mother is not a carrier. De novo mutations have been reported but are rare.
If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.
When an affected male represents a simplex case (i.e., the only affected individual in the family), several possibilities regarding his mother's carrier status need to be considered:
He has a de novo disease-causing mutation in the RS1 gene and his mother is not a carrier.
His mother has a de novo disease-causing mutation in the RS1 gene, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore present in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
His mother has a disease-causing mutation that she inherited from a maternal female ancestor.
Sibs of a proband
The risk to sibs depends upon the carrier status of the mother.
If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers. Carriers nearly always have normal visual function and normal electrophysiology (i.e., ERG).
If the mother is not a carrier, the risk to sibs is low but may be higher than that of the general population because the risk of germline mosaicism in mothers is not known.
Offspring of a proband. Males will pass the disease-causing mutation to all of their daughters and none of their sons.
Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending upon their gender, may be at risk of being carriers or of being affected.
Carrier testing of at-risk female relatives is available on a clinical basis if the disease-causing mutation has been identified in the proband.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal testing is possible for pregnancies of women who are carriers if the RS1 mutation has been identified in a family member. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions such as X-linked juvenile retinoschisis are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| RS1 | Xp22.2-p22.1 | Retinoschisin |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 312700 | RETINOSCHISIS 1, X-LINKED, JUVENILE; RS1 |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| RS1 | RS1 | 6247 (MIM No. 312700) | RS1 |
For a description of the genomic databases listed, click here.
For many years, X-linked juvenile retinoschisis has been thought of as a possible defect in the Muller cell, acting as a cellular scaffold within the retinal architecture. Recent studies on gene expression and immunolocalization of the normal protein, retinoschisin, indicate that it is expressed within the photoreceptors and has a complex interaction within cells of the retina. Retinoschisin is most highly expressed in the inner segments of the photoreceptors in human eye sections [Mooy et al 2002] and other mammals including mice [Molday et al 2001]. The protein was secreted by differentiated retinoblastoma cells (Weri-Rb1) [Grayson et al 2000]. From expression studies, it remains unclear whether the protein product of mutant disease-causing alleles is secreted properly [Wang et al 2002, Wu & Molday 2003].
In studying the mouse model of retinoschisis created by gene knockout, Weber and colleagues (2002) noted disruption of the normal retinal cellular organization and the appearance of schisis-like cavities in the inner retina. The electroretinogram was affected with selective reduction of the ERG b-wave and a severe effect on the cone ERG. Atypical photoreceptor synapses were also observed, implicating a role for retinoschisin in the normal maintenance of the photoreceptor-bipolar synapse.
Normal allelic variants: A comprehensive list of allelic variants (sequence polymorphisms) is maintained through the RetinoschisisDB© of the Retinoschisis Consortium.
Pathologic allelic variants: Over 125 mutations in the RS1 gene have been associated with X-linked juvenile retinoschisis. Most disease-causing mutations occur in the discoidin domain of the RS1 gene, exons 4-6. An up-to-date listing of these mutations may be found by consulting the RetinoschisisDB© of the Retinoschisis Consortium.
Normal gene product: Retinoschisin is a 224-amino acid protein. Retinoschisin is an extracellular protein that exists as a novel disulfide-linked octamer. While it is expected to play a crucial role in cellular organization of the retina, the function of retinoschisin is as yet unknown [Wu et al 2005].
Abnormal gene product: The abnormal gene product may be sequestered in the cell and degraded or secreted [Wang et al 2002, Wu & Molday 2003].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Foundation Fighting Blindness
11435 Cronhill Drive
Owings Mill MD 21117-2220
Phone: 888-394-3937 (toll-free); 800-683-5555 (toll-free TDD); 410-568-0150 (local)
Email: info@blindness.org
www.blindness.org
The Low Vision Gateway
www.lowvision.org
Retina International
Ausstellungsstrasse 36
Zurich CH-8005
Switzerland
Phone: 044 444 10 77
Email: info@rpinternational.org
www.retina-international.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
18 June 2007 (cd) Revision: MLPA used for carrier testing for female relatives, as current PCR methodologies detect deletions in affected males only
18 January 2006 (me) Comprehensive update posted to live Web site
28 June 2004 (cd) Revision: change in test availability
24 October 2003 (me) Review posted to live Web site
1 July 2003 (ps) Original submission
