X-linked Juvenile Retinoschisis (XLRS)
X-linked juvenile retinoschisis is a condition characterized by impaired vision that begins in childhood and occurs almost exclusively in males. This disorder affects the retina, which is a specialized light-sensitive tissue that lines the back of the eye. Damage to the retina impairs the sharpness of vision (visual acuity) in both eyes. Typically, X-linked juvenile retinoschisis affects cells in the central area of the retina called the macula.
The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. X-linked juvenile retinoschisis is one type of a broader disorder called macular degeneration, which disrupts the normal functioning of the macula. Occasionally, side (peripheral) vision is affected in people with X-linked juvenile retinoschisis.
X-linked retinoschisis (XLRS) is an inherited early onset retinal degenerative disease caused by mutations in the RS1 gene. It is the leading cause of juvenile macular degeneration in males. XLRS is characterized by abnormal splitting of the layers of the retina, resulting in poor visual acuity in young boys, which can progress to legal blindness in adult men.
The disease begins early in childhood and affected boys typically have best-corrected visual acuity of 20/60 to 20/120 at initial diagnosis. Severe complications such as retinal hemorrhage or retinal detachment occur in up to 40% of patients, especially in older individuals. There are currently no approved treatments for XLRS.
AGTC is developing a gene therapy product to treat XLRS. In animal models of XLRS, treatment with this product leads to long-term improvement in retinal function and prevention of retinal cell degeneration. Based on the strong preclinical proof-of-concept data, AGTC is currently conducting a clinical study to evaluate the safety and efficacy of an investigational gene therapy in patients with XLRS.
X-linked juvenile retinoschisis is usually diagnosed when affected boys start school and poor vision and difficulty with reading become apparent. In more severe cases, eye squinting and involuntary movement of the eyes (nystagmus) begin in infancy. Other early features of X-linked juvenile retinoschisis include eyes that do not look in the same direction (strabismus) and farsightedness (hyperopia).
Visual acuity often declines in childhood and adolescence but then stabilizes throughout adulthood until a significant decline in visual acuity typically occurs in a man’s fifties or sixties. Sometimes, severe complications develop, such as separation of the retinal layers (retinaldetachment) or leakage of blood vessels in the retina (vitreous hemorrhage). These eye abnormalities can further impair vision or cause blindness.
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 RS1gene (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 RS1gene 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 RS1gene 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.
X-linked retinoschisis (XLRS) is a genetic condition affecting boys and men. It is typically diagnosed in childhood, in some cases as early as three months of age. The main symptom is reduced vision that cannot be improved with glasses. While some people with XLRS may experience progressive vision loss throughout their life, other people may have relatively stable vision throughout their lifetime.
XLRS is caused by mutations in a gene on the X chromosome called RS1 which encodes a protein called retinoschisin. This protein is important for the development and maintenance of the retina (the tissue lining the back of the eye). Without normal retinoschisin protein, the layers of the retina split (“schisis”), inter-cell communication is disrupted and vision is lost.
The main symptom of XLRS is reduced visual acuity. While variable, vision is typically in the 20/60 to 20/120 range. Some people with XLRS experience retinal detachment or bleeding within the eye.
The natural history of XLRS is still not entirely understood. Classically, it has been described as progressive in childhood, plateauing, then progressive in later adulthood. However, this has not been observed in the reviewer’s experience. In uncomplicated cases, visual prognosis is good and there can be very little progression in a person’s lifetime. Most patients with XLRS never reach the point of legal blindness.
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.
XLRS is caused by a change (mutation) in a gene. Genes provide information and instruction to make proteins, much like a blueprint. Proteins are the building blocks of cells and allow cells to have their unique functions.
XLRS is caused by mutations in a gene on the X chromosome called RS1.
XLRS is inherited as an X-linked trait. Men only have one X chromosome, whereas women have two. Women who have an abnormal RS1 gene “carry” the condition, but do not have any vision problems associated with XLRS since they almost always have a second normal RS1 gene. Men who have an abnormal RS1 gene have symptoms of XLRS.
Women who are carriers have a 50% chance of passing on their abnormal RS1 gene to each of their children. When passed to a daughter, the daughter will also be a carrier for XLRS. When passed to a son, the son will have XLRS. When men with XLRS have children, all of their daughters will be carriers and none of their sons will have XLRS.
Mutations in the RS1 gene cause most cases of juvenile retinoschisis. The RS1 gene provides instructions for producing a protein called retinoschisin, which is found in the retina. Studies suggest that retinoschisin plays a role in the development and maintenance of the retina, perhaps playing a role in cell adhesion (the attachment of cells together).
RS1 gene mutations lead to a reduced amount or complete absence of retinoschisin, which can cause tiny splits (schisis) or tears to form in the retina. This damage often forms a “spoke-wheel” pattern in the macula, which can be seen during an eye examination. In about half of individuals, these abnormalities are seen in the area of the macula, affecting visual acuity. In the other half, the sides of the retina are affected, resulting in impaired peripheral vision.
Some individuals with juvenile retinoschisis do not have a mutation in the RS1 gene. In these individuals, the cause of the disorder is unknown.
Diagnosis of XLRS is made by eye examination using various testing modalities. Individuals have reduced vision, schisis that can be seen on examination and imaging, and abnormal electroretinograms (a test that assesses the function of the retina) in most cases. Some individuals also have a family history consistent with X-linked inheritance. Molecular genetic testing for mutations in the RS1 gene is available to confirm the diagnosis.
There is large variation in disease severity among patients, even among patients with the same genetic mutation. Patients typically present complaining of difficulty in school, although younger patients may present earlier with strabismus or nystagmus. Visual acuity may range from 20/20 to blindness, and depends on the amount and area of schisis. The vision is often stable until middle-age.
Peripheral vision may be normal in the unaffected areas. Absolute scotoma may be present in areas of peripheral retinoschisis. Color vision is often normal as well.
On fundoscopic examination, 98-100% of patients have foveal schisis, noted as a spokewheel pattern radiating from the fovea and a domelike elevation of thin layer or retina. Schisis is most often in the macular, but extension into the periphery occurs in more than half of patients. The bullous retinoschisis may improve over time.
Subretinal linear fibrosis, pigmentation, white retinal flecks, vascular attenuation, and vascular sheathing may also be present.
Visual function may be severely limited with progression to retinal detachment, most often rhegmatogenous, in 5-20%. Vitreous hemorrhage is another common complication, and hemorrhage may also occur within the schisis cavity.
Other complications include intraretinal splitting, neovascular glaucoma, macular dragging, and optic atrophy.
- Digital fundus photography may help with examination of a child
- Red-free illumination may help to highlight the area of foveal schisis
- Fundus autofluorescence may also help to highlight areas of foveal schisis
- Optical coherence tomography (OCT) reveals schisis in the superficial neural retina. There are often large cystic-like spaces, especially large below the fovea. These cystic spaces may be present in any layer of the retina and reveal areas of schisis not visible on fundus examination.
- Fluorescein angiography is not required for diagnosis. Unlike cystic macula edema, there may be pooling but no leakage of the cystic spaces.
- Full-field electroretinogram is electronegative (Reduced b-wave with preserved a-wave). This is not diagnostic as the differential for electronegative ERG includes several other retinal disorders, and the a-wave may be reduced as the disease progresses.
- Genetic testing can confirm the diagnosis.
Genetic testing is available for the RS1 gene that encodes retinoschisin.
- Autosomal dominant and recessive schisis will have a different inheritance pattern and may normal ffERG
- Goldmann-Favre (Enhanced S cone syndrome) has associated nyctalopia and pigment clumping
- Degenerative retinoschisis typically occurs in older individuals
- Dominantly inherited CME and other causes of CME
- Eales disease
- Wagner syndrome
- Alport’s syndrome
Juvenile retinoschisis is inherited in an x-linked recessive pattern. The gene associated with this condition is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition.
In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition.
In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In X-linked recessive inheritance, a female with one mutated copy of the gene (mutation) in each cell is called a carrier. She can pass on the mutation, but usually does not experience signs and symptoms of the condition. Carrier women have a 50% chance of passing the mutation to their children, males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will nearly always have normal vision. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.
Treatment is generally symptomatic and supportive. Low-vision aids such as large-print textbooks; preferential seating in the front of the classroom; and use of handouts with high contrast can be useful. Treatment of retinoschisis may require the care of a retinal surgeon to address the infrequent complications of vitreous hemorrhage (bleeding in the eye) and retinal detachment.
Affected boys and men are recommended to avoid activities such as contact sports, which may pose an increased risk for retinal detachment. Genetic counseling is recommended for boys and men with XLRS and their families.
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