X-linked retinoschisis (XLRS) is a retinal dystrophy that leads to schisis (splitting) of the neural retina leading to reduced visual acuity in affected men. The condition accounts for almost all congenital retinoschisis, with occasional reports of autosomal dominant ... X-linked retinoschisis (XLRS) is a retinal dystrophy that leads to schisis (splitting) of the neural retina leading to reduced visual acuity in affected men. The condition accounts for almost all congenital retinoschisis, with occasional reports of autosomal dominant retinoschisis (see 180270) making up the remainder. The split in the retina occurs predominantly within the inner retinal layers and is very different from retinal detachment, which is a split between the neural retina and the retinal pigment epithelium. In general, carrier females remain asymptomatic (summary by Sikkink et al., 2007).
Gieser and Falls (1961) observed a macular cyst in 1 eye of a possible female carrier in a kindred with 9 affected males and suggested that it might represent an expression of the carrier state. In contrast to ... Gieser and Falls (1961) observed a macular cyst in 1 eye of a possible female carrier in a kindred with 9 affected males and suggested that it might represent an expression of the carrier state. In contrast to previous reports, Kaplan et al. (1991) concluded that heterozygous carriers frequently express the disease and display peripheral retinal alterations similar to those found in affected males. Retinoschisis is, in the opinion of Gieser and Falls (1961), the same condition as that described by Mann and MacRae (1938) as congenital vascular veil in the vitreous and also the same as the X-linked retinal detachment described by Sorsby et al. (1951). So-called congenital falciform fold of the retina (ablatio falciformis retinae congenita) is probably an expression of the same gene as that for retinoschisis. See 312550. Weve (1938) observed falciform fold and pseudoglioma in the same family. Forsius et al. (1963) described a family with a homozygous affected female who was the daughter of an affected male and his second cousin. All 3 of the homozygote's sons, by 2 different husbands, were affected. Yanoff et al. (1968) reported the histologic appearance in the eye of a 50-month-old boy whose brother was also affected. The splitting occurred in the sensory retina, predominantly in the nerve fiber layer. Forsius (1977) described a homozygous female, the offspring of an affected male and his second cousin. Newton et al. (1991) described a family in which there was typical X-linked retinoschisis in 3 generations except that a male born in 1963 had apparently inherited his retinal disease from his unaffected father, born in 1941, who had 2 affected brothers and an affected maternal uncle. Genealogic search revealed, however, that the mother of the man born in 1963 was related as a third cousin once removed to his father and was connected to the original affected individuals in a pattern consistent with X-linked inheritance. Kato et al. (2001) examined the relationship between ocular axial length and refractive error in patients with X-linked retinoschisis. They found that the refractive error was significantly more hypermetropic and the axial length was significantly shorter in the adult patient group than in the normal adult group (P less than 0.001). The authors concluded that the hypermetropia in patients with X-linked retinoschisis may be axial hypermetropia. The Mizuo phenomenon, also called the Mizuo-Nakamura phenomenon, is a change in the color of the fundus from red in the dark-adapted state to golden immediately or shortly after exposure to light. The color of the fundus reflex can be either homogeneous or streaky. It has been observed mainly in Oguchi disease (258100) and in X-linked recessive cone dystrophy (304020). De Jong et al. (1991) observed the phenomenon in 4 unrelated males with retinoschisis. They suggested that altered potassium ion flux may be responsible for the phenomenon. George et al. (1995) provided a review of X-linked retinoschisis. They suggested that the first description was that of Haas (1898), who illustrated the disease in 2 males with a beautiful drawing of the typical radiating cystic maculopathy. Sauer et al. (1997) stated that the disorder has been reported in patients as young as 3 months but may already be present at or before birth. Although foveal retinoschisis occurs in essentially all affected individuals, there is a wide phenotypic variability; approximately 50% of patients have bilateral schisis cavities in the peripheral retina. Typically, in the early stages of the disease, perifoveal radial microcysts form in the deep nerve fiber layer in a cartwheel-like pattern. Although Haas (1898) believed that the changes were inflammatory in origin, Pagenstecher (1913) published a pedigree that showed an X-linked pattern of inheritance. George et al. (1995) stated that young patients show moderate visual impairment, although some patients have been reported with normal acuity. Most patients retained reasonable vision until their fifth or sixth decades, when some deterioration may occur due to macular atrophy. Total blindness is an exception, although Forsius et al. (1973) reported that all patients over 70 years of age had a visual acuity of less than 6/60. George et al. (1995) suggested that when the molecular defect is identified, the role of the Mueller cell may be defined. A primary defect with the Mueller cell would concur with observations of histopathology and electrophysiology. The Mueller cell, the principal glial cell of the retina, spans the full depth of the retina and is in intimate contact with photoreceptors and cells of the middle retinal layers. Its basement membrane forms part of the inner limiting membrane (ILM). George et al. (1995) presented the cases of 5 male infants with nystagmus and/or strabismus who were found to have bilateral highly elevated bullous retinoschisis involving the macula. There was hemorrhage within the schisis cavity or the vitreous in 4 patients. The bullous retinoschisis eventually reattached spontaneously, leaving pigment demarcation lines. A family history of X-linked retinoschisis was known in 2 of the patients and in the other 3 subsequent investigation showed other male family members to be affected. This uncommon presentation of XLRS is important to recognize so that appropriate genetic counseling can be given. Surgical treatment is not usually indicated and the visual prognosis is better than the initial appearance might suggest. Eksandh et al. (2000) described the clinical phenotype of juvenile X-linked retinoschisis in 30 patients with 7 different mutations in the XLRS1 gene. The authors concluded that juvenile retinoschisis shows a wide variability in phenotype between, as well as within, families with different genotypes. Electroretinogram (ERG) findings showed reduced b-wave to a-wave ratios of dark-adapted recordings and prolonged implicit times of 30-Hz flicker response. Eksandh et al. (2000) concluded that ERG findings provide a useful marker for confirming the clinical diagnosis. They stressed the importance of complementing the ophthalmologic exam with full-field ERG and molecular genetics in boys with visual failure of unknown etiology to determine the diagnosis early in the course of the disease. Ozdemir et al. (2004) reported the optical coherence tomographic findings in a child with X-linked familial foveal retinoschisis. The cleavage planes were between the outer plexiform layer and the adjacent nuclear layers of the retina. Hayashi et al. (2004) described the clinical phenotypes of 4 unrelated Japanese male patients with juvenile retinoschisis. All 4 affected patients showed cystoid- or wheel-like foveal changes with little or no fluorescein leakage and negative ERG b-wave patterns in both eyes. Optical coherence tomography (OCT) showed foveal retinoschisis occurred in the putative fibers of Henle. In 3 patients, the authors identified 3 different missense mutations, 1 of them novel, in the functionally important discoidin domain of the RS1 gene. No nucleotide substitutions were detected in the fourth patient, whose parents were unrelated and asymptomatic. No other member of the fourth family for 3 generations had had juvenile retinoschisis. Although the inheritance pattern was uncertain in the patient without the RS1 mutation, the clinical and ERG findings were indistinguishable from those of patients with RS1 mutations, pointing to possible genetic heterogeneity of juvenile retinoschisis. Sikkink et al. (2007) reviewed the clinical, pathologic, and electrophysiologic features of X-linked retinoschisis and its molecular basis.
In a study of 86 patients with X-linked retinoschisis in whom the causative RS1 mutation had been identified, Pimenides et al. (2005) reported no correlation between mutation type and severity of disease, even in patients of similar ages. ... In a study of 86 patients with X-linked retinoschisis in whom the causative RS1 mutation had been identified, Pimenides et al. (2005) reported no correlation between mutation type and severity of disease, even in patients of similar ages. Visual acuity, foveal changes, peripheral schisis, and disease complications were compared. Mutations were classified into groups including protein truncating, missense, mutations in different exons, discoidin domain mutations and those affecting other residues, and mutations affecting cysteine residues and those affecting other residues.
Sauer et al. (1997) performed mutation analyses of XLRS1 in affected individuals from 9 unrelated RS families and identified 1 nonsense, 1 frameshift, 1 splice acceptor, and 6 missense mutations (e.g., 300839.0001) segregating with the disease phenotype in ... Sauer et al. (1997) performed mutation analyses of XLRS1 in affected individuals from 9 unrelated RS families and identified 1 nonsense, 1 frameshift, 1 splice acceptor, and 6 missense mutations (e.g., 300839.0001) segregating with the disease phenotype in the respective families. The gene mutant in retinoschisis was the fourth to be implicated in macular dystrophy and the first one isolated by positional cloning. Mutation in peripherin/RDS (PRPH2; 179605) is associated with a variety of forms of macular dystrophy. The tissue inhibitor of metalloproteinase-3 (TIMP3; 188826) is implicated in autosomal dominant Sorsby fundus dystrophy (136900). A member of the ABC transporter gene family (ABCR; 601691) is involved in autosomal recessive Stargardt disease (248200). The Retinoschisis Consortium (1998), consisting of a large number of individuals in 6 separate collaborating groups in the Netherlands, Italy, U.S., Finland, Germany, and U.K., screened the RS gene for mutations in 234 familial and sporadic retinoschisis cases and identified 82 different mutations in 214 (91%). Thirty-one mutations were found more than once, i.e., 2 to 10 times, with the exception of the 214G-A mutation (300839.0003) which was found in 34 apparently unrelated cases. The origin of the patients, the linkage data, and the site of the mutations (mainly CG dinucleotides) indicated that most recurrent mutations had independent origins, suggesting the existence of a 'significant' new mutation rate in the gene, which they symbolized XLRS1. The mutations identified covered the entire spectrum, from small intragenic deletions (7%) to nonsense (6%), missense (75%), small frameshifting insertions/deletions (6%), and splice site mutations (6%). Since, regardless of the mutation type, no females with a typical RS phenotype were identified, RS seems to be caused by loss-of-function mutations only. Mutations occurred nonrandomly, with hotspots at several CG dinucleotides and a C6 stretch. Exons 1 to 3 contained few, mainly translation-truncating mutations, arguing against an important functional role for this segment of the protein. Exons 4 to 6, encoding the discoidin domain, contained most, mainly missense mutations. An alignment of 32 discoidin domain proteins was constructed to reveal the consensus sequence and to deduce the functional importance of the missense mutations identified. The mutation analysis revealed a high preponderance of mutations involving or creating cysteine residues, pointing to sites important for the tertiary folding and/or protein function, and highlighted several amino acids that may be involved in XLRS1-specific protein-protein interactions. Despite the enormous mutation heterogeneity, patients have relatively uniform clinical manifestations, although with great intrafamilial variation in age at onset and progression. The 20 retinoschisis cases in which mutations were not identified may have had mutations affecting transcription initiation and mRNA processing, e.g., promoter or intronic mutations. Mutations occurred in 12 of the 26 CpG dinucleotides in the XLRS1 coding region. Hiriyanna et al. (1999) screened 31 unrelated patients and families for XLRS1 mutations in addition to previously reported mutations for 60 of their families reported by the Retinoschisis Consortium (1998). They found 23 different mutations, including 12 novel ones in 28 patients. Two novel mutations, 38T-C (L13P; 300839.0007) and 667T-C (C223R; 300839.0008), respectively, presented the first genetic evidence for the functional significance of the putative leader peptide sequence and for the functional significance at the carboxy terminal of the XLRS1 protein beyond the discoidin domain. Mutations in 25 of the 28 families were localized to exons 4-6, emphasizing the critical functional significance of the discoidin domain of the XLRS1 protein. Gehrig et al. (1999) reported a missense mutation (300839.0010) in a Greek family. Two affected boys and their mother were found to carry the mutation, while it was not present in either maternal grandparent. Haplotype analysis suggested that the mutation had arisen on the grandpaternal X chromosome. Gehrig et al. (1999) considered this to be the first molecular evidence of a de novo mutation in RS1. Inoue et al. (2000) analyzed the XLRS1 gene in 10 Japanese men diagnosed with juvenile retinoschisis. Point mutations in the XLRS1 gene were identified in all 10 patients. Identical mutations were found in 2 pairs of brothers. Six of the point mutations represented missense mutations, 1 was a nonsense mutation, and 1 was a frameshift mutation. Five of the mutations were newly reported. Inoue et al. (2000) stated that these limited data failed to reveal a correlation between mutation and disease phenotype. Wang et al. (2002) expressed 7 pathologic RS1 mutations in COS-7 cells and investigated their intracellular processing and transport by immunoblotting and confocal fluorescent immunocytochemistry. Transfected cells showed normal secretion of wildtype RS1, but either reduced or absent secretion of mutant RS1 and intracellular retention. RS1 bearing the only mutation of the 7 to occur within the signal peptide was degraded by proteasomes, and in vitro transcription/translation revealed defects in both cleavage of its signal peptide and translocation into the endoplasmic reticulum. Wang et al. (2002) concluded that the pathologic basis of RS1 may be intracellular retention of the majority of mutant proteins, which may explain why disease severity is not mutation-specific. Saldana et al. (2007) reported a 5-year-old girl with classic findings of X-linked retinoschisis who was heterozygous for a mutation in the RS1 gene (300839.0011). Her affected father and his brother also carried the mutation. Although the authors postulated skewed X-inactivation, such studies were uninformative. Tsang et al. (2007) described 7 patients with a mutation in the RS1 gene, including 1 with the 214G-A mutation (300839.0003), who had an atypical retinoschisis phenotype. Several of the patients had previously been diagnosed with macular degeneration (see 603075), Stargardt disease, or Goldmann-Favre syndrome (268100). All 7 had fine white dots resembling drusen-like deposits, which were sometimes associated with retinal pigment epithelial abnormalities, in the maculas. An electronegative bright-flash electroretinogram (ERG) configuration was present in all patients tested, and abnormal pattern ERG findings confirmed macular dysfunction. A parafoveal ring of high-density autofluorescence, which had not previously been described in retinoschisis, was present in 3 eyes, and 1 patient showed high-density foci concordant with the white dots. Optical coherence tomography did not show foveal schisis in 3 of 4 eyes. Tsang et al. (2007) concluded that fine white dots in the macula might be the initial fundus feature with RS1 mutations. In 60 XLRS patients who shared 27 missense mutations in RS1, Sergeev et al. (2010) evaluated possible correlations of the molecular modeling with retinal function as determined by the ERG a- and b-waves. The b/a-wave ratio reflects visual-signal transfer in retina. The majority of RS1 mutations caused minimal structural perturbations and targeted the protein surface. Maximum structural perturbations from either the removal or insertion of cysteine residues or changes in the hydrophobic core were associated with greater difference in the b/a-wave ratio with age, with a significantly smaller ratio at younger ages. The molecular modeling suggested an association between the predicted structural alteration and/or damage to retinoschisin and the severity of XLRS as measured by the ERG analogous to the RS1-knockout mouse. Duncan et al. (2011) evaluated the macular cone structure in 2 patients with X-linked retinoschisis caused by mutations in exon 6 of the RS1 gene. Two unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic electroretinogram b-wave was reduced more than the a-wave. Spectral domain optical coherence tomography showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. Adaptive optics scanning laser ophthalmoscopy images of the 2 patients revealed increased cone spacing and abnormal cone packing in the macula of each patient, but cone coverage and function were near normal outside of the central foveal schisis cavities. The mutation in each patient occurred within the discoidin domain of the retinoschisin protein.
Forsius and Eriksson (1980) stated that more than 200 cases had been found in Finland, whereas up to 1970 only about 100 cases had been reported elsewhere. However, reports since 1970 suggest that it may be more common ... Forsius and Eriksson (1980) stated that more than 200 cases had been found in Finland, whereas up to 1970 only about 100 cases had been reported elsewhere. However, reports since 1970 suggest that it may be more common in the United States and Canada than previously thought. De la Chapelle et al. (1994) stated that the prevalence of RS in Finland is greater than 1 in 17,000. Alitalo et al. (1991) found that the haplotype association in patients from southwest Finland differed from that in patients from north central Finland, favoring the possibility that the mutations in the 2 groups arose independently. Huopaniemi et al. (1999) studied the haplotypes and mutations in the XLRS1 gene in 55 RS families with about one-third of all RS patients in Finland, including 117 affected males and 1 affected female. Most of the RS families were clustered in the western region of Finland and about one-fifth in the northern region. Haplotype analysis, using 9 microsatellite markers spanning 1 cM in Xp22.2, showed 8 different haplotypes. Representatives from these 8 haplotypes were studied for mutations, and 7 missense mutations were identified. No genotype-phenotype correlation could be found. The western and northern groups possessed different haplotypes; the former carried the glu72-to-lys (accounting for 70% of all RS patients) and the gly74-to-val (6%) founder mutations, whereas the latter carried the gly109-to-arg (19%) founder mutation. Based on genealogic data, the glu72-to-lys founder mutation was estimated to be the oldest, at least 1,000 years old.
Affected males. The diagnosis of X-linked juvenile retinoschisis is made in a young male with the following findings: ...
DiagnosisClinical DiagnosisAffected 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 (Figure 1). Schisis of the peripheral retina, predominantly inferotemporally, in approximately 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" (Figure 2). On occasion, more severe involvement of the macula (Figure 3)On occasion, the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light Electroretinogram (ERG) showing selective reduction of the amplitude of the dark-adapted b-wave amplitude but relative preservation of the a-wave amplitude [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 et al 1999a], 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 FigureFigure 1. Fundus photo of a male with juvenile retinoschisis. Arrow points to typical spoke-wheel pattern of foveal cysts. FigureFigure 2. Fundus photo of the peripheral retina of a male with juvenile retinoschisis. Area marked with arrows shows a partial-thickness retinal hole. FigureFigure 3. Fundus photo of a male with juvenile retinoschisis showing atypical, more severe findings with arrows pointing to atrophic macular changes 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. TestingIntravenous 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 school-age individuals [Apushkin et al 2005]. Cystic spaces are not as evident after adolescence. OCT scans of older individuals may appear normal because of flattening of cysts with age.Molecular Genetic TestingGene. RS1 is the only gene in which mutation is known to cause X-linked juvenile retinoschisis.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 et al 1999b]. Deletion/duplication testing detects gross deletions in RS1, which occur in approximately 6% of affected males and female carriers [The Retinoschisis Consortium 1998].Table 1. Summary of Molecular Genetic Testing Used in X-Linked Juvenile RetinoschisisView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier Females 2RS1Targeted mutation analysisp.Glu72Lys, p.Gly74Val, p.Gly109Arg~95% 3ClinicalSequence analysisSequence variants~90%90%Partial- and whole-gene deletion6% 40% 5Deletion / duplication testing 6Partial- and whole-gene deletions~6%~6%2. When no affected males in the family are available for testing3. In persons of Finnish heritage4. Gel sizing analysis can detect putative exonic, multiexonic, and whole-gene deletions in RS1 in affected males because of lack of amplification by PCR.5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons in RS1 in females.6. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, or array GH may be used.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming the diagnosis in a proband. In general, the diagnosis in a proband can be made by ophthalmologic examination and confirmed by electroretinogram.To identify the mutation in an affected male: 1.In males of Finnish heritage, perform targeted mutation analysis of the four common mutations. 2.If the mutation is not identified, and for males of non-Finnish heritage, perform sequence analysis. 3.In males in whom a mutation is not identified by sequence analysis, consider deletion testing. Carrier testing for at-risk female relatives. (1) Carriers are heterozygotes for this X-linked disorder and rarely develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication test methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersX-linked juvenile retinoschisis is the only phenotype associated with mutations in RS1.
X-linked juvenile retinoschisis is a symmetric bilateral macular disorder with onset in the first decade of life, in some cases as early as age three months. 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. ...
Natural HistoryX-linked juvenile retinoschisis is a symmetric bilateral macular disorder with onset in the first decade of life, in some cases as early as age three months. 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 age 50 years, macular pigmentary changes and some degree of atrophy of the RPE are common. Variation in disease presentation and disease progression is observed even among members of the same family.Appearance of foveal lesions varies from largely radial striations (3%), microcystic lesions (34%), honeycomb-like cysts (8%), or their combinations (31%) to non-cystic-appearing foveal changes including 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 an estimated 5% to 22% of affected individuals. Retinal detachment can occur in infants with severe retinoschisis. About 4% to 40% of individuals with X-linked juvenile retinoschisis develop vitreous hemorrhage.
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....
Differential DiagnosisWhile 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 and enhanced S-cone syndrome, caused by mutations in NR2E3, may mimic X-linked juvenile retinoschisis. Onset occurs in infancy. Generally, affected individuals have severely impaired vision including marked visual field loss and severe night blindness. Coarse intraretinal cysts may be seen with peripheral retinoschisis; no vitreous veils are observed. The electroretinogram shows markedly reduced a-waves and b-waves with altered timing rather than simply the reduction in the b-wave amplitude found in X-linked juvenile retinoschisis. Inheritance is autosomal recessive.Retinitis pigmentosa (RP) is the referring diagnosis in many persons with X-linked juvenile retinoschisis. 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 et al [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. VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), is characterized by reduced visual acuity and night blindness of variable degree, mild or occasionally moderate-to-severe myopia, presenile cataract, “optically-empty vitreous” on slit-lamp examination and avascular vitreous strands and veils, progressive chorioretinal atrophy, and retinal detachment at advanced stages of the disease. The first signs usually become apparent during early adolescence but onset can be as early as age two years. Mutations in VCAN (previously CSPG2) are causative. Inheritance is autosomal dominant.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:...
ManagementEvaluations Following Initial Diagnosis 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 Family history Electroretinogram Funduscopic examination Optical coherence tomography Treatment of ManifestationsLow 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; 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.SurveillanceAnnual evaluation of children under age ten years by a pediatric ophthalmologist or retina specialist is recommended.Older children and adults need less frequent monitoring.Agents/Circumstances to AvoidAlthough retinal detachment and vitreous hemorrhage occur in a minority of affected individuals (5%-22% and 4%-40%, respectively), general avoidance of head trauma and high-contact sports is recommended.Evaluation of Relatives at RiskAt-risk male relatives of a proband should be examined by an ophthalmologist to confirm affected or non-affected status for early treatment of retinal detachment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA 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 [Kjellstrom et al 2007]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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