X-Linked Juvenile Retinoschisis Latest Facts: Etiology, Diagnosis and Treatment

What is X-linked Juvenile Retinoschisis?

X linked Juvenile Retinoschisis or Juvenile Retinoschisis is a rare genetic disorder affecting the eye and causing early vision loss in affected patients. It arises from the mutations in the RS1 gene, predominantly affecting males due to the X-linked inheritance pattern. Retinoschisis affects the cells in the central part of the retina called the macula, which is responsible for sharp, clear vision. This leads to impaired visual acuity, in both eyes and macular degeneration in the affected males. This decline in visual acuity is seen in the first decade of life, reaching a stable point after adolescence. In the fourth and fifth decades, there is a significant decrease again.

X-Linked Juvenile Retinoschisis.

X-Linked Juvenile Retinoschisis. Courtesy of Domaina, Kashmiri and SUM1

Epidemiology and Other names of X-Linked Juvenile Retinoschisis

X linked Juvenile Retinoschisis affects males, and rarely the heterozygous females. It is one of the main causes of juvenile macular degeneration in males, with 1 in 15,000 to 30,000 cases worldwide. It has no geographical preference and follows an X-linked recessive pattern of inheritance. Affected males can only pass it to their daughters, not sons. And the daughters become carriers, with a 50% chance of passing it on to their sons.

X-Linked Juvenile Retinoschisis is called by many names, such as juvenile retinoschisis, congenital retinoschisis, juvenile macular degeneration/dystrophy, and degenerative retinoschisis, although this affects older individuals mostly.

Cause of X-Linked Juvenile Retinoschisis

Juvenile Retinoschisis occurs as a result of a mutation in the gene RS1, which encodes for the retinoschisin protein. This protein, after being secreted by photoreceptors, plays a vital role in the development of retina by facilitating cell-cell adhesion and intercellular matrix retinal architecture development. As a result of this mutation, retinoschisin is either decreased or completely absent, negatively affecting retinal development. Since it plays an active role in cell to cell adhesion, the decrease/absence of it causes tiny splits, mostly in the nerve fiber layer of the retina. This tearing and splitting forms a ‘spoke-wheel’ pattern in the macula, leading to macular degeneration.

It is important to note that some cases of Juvenile Retinoschisis have been identified that do not have RS1 gene mutation. The etiology of the disease in these patients is yet unclear.

Clinical Manifestations of XLRS

Juvenile Retinoschisis is a disease of the eye that can impair vision. Most of the patients present in infancy, with general eye-related symptoms as follows:

  1. Nystagmus
  2. Strabismus
  3. Hyperopia
  4. Foveal ectopia
  5. Hemorrhage

Retinal detachment (this is a complication rather than a symptom; however some patients may present with this as the only symptom)

However, most patients present with impaired vision once in school and are diagnosed then. The disease has complete penetrance and variable expressivity, explaining the wide variety of symptoms and complications seen in all cases. Furthermore, some patients may go on to lose vision completely whereas some might only develop mild visual disturbances. This blindness compared to the mildly impaired visual acuity may also be due to the specific location of the defect, or tear in the retinal.

It is important to note that peripheral vision in XLRS is rarely affected.

Diagnosis of X-Linked Juvenile Retinoschisis

As discussed above, the onset and symptoms of Retinoschisis vary greatly. It is important to ask for the history of the patient to see if the patient ever suffered from nystagmus and strabismus as an infant. It is also important to ask for family history, especially for the presence of X-linked genetic disorders in the family.

Diagnosis of Juvenile Retinoschisis is based on physical exam, clinical manifestations, and genetic testing. Physical examination is performed using fundus examination using Digital Fundus Photography, and fundus autofluorescence imaging. These, along with Red-free illumination show the location of foveal schisis, which can help make the diagnosis. Some other methods of diagnosis include:

  1. Ocular Coherence Tomography (shows schisis cavities in the superficial nerve fiber layer, normally not visible with fundoscopy)
  2. Fluorescein Angiography (to help differentiate between CME and five always schisin seen in Juvenile Retinoschisis)
  3. Full-Field retinogram (not diagnostic due to variability of results)
  4. To confirm the diagnosis, genetic testing to check for the RS1 gene mutation needs to be performed.

Differential Diagnosis

  • Eales disease
  • Wagner syndrome
  • Alport’s syndrome
  • Enhanced S cone Syndrome
  • Cystoid Macular Edema (CME)

Treatment of XLRS

Genetic counseling should be provided to all patients with Juvenile Retinoschosis, just like with any other genetic disorder. Medical treatment for Juvenile Retinoschosis aims to treat the schisis spaces visible in the OCT. The use of carbonic anhydrase inhibitors results in decreased fluid in cystic spaces and improvement of visual acuity. External drainage of cystic fluid in schisis spaces can also be performed, however, its benefits are yet unclear.

For complications associated with Retinoschisis, surgical treatment might be required. However, surgical therapy may cause some of the complications. Due to this, surgical therapy isn’t the recommended treatment in patients with XLRS.

Management of XLRS

The best choice of treatment is managing XLRS to prevent complications by,

  1. Routine ophthalmological exams, evaluating the progression of the disease.
  2. Educating the patient on behaviors or actions that might cause complications like head trauma. It may be recommended for the patients to not participate in contact sports.

It is important to help these patients with vision disturbances by using visual aids in classrooms and homes.

Prognosis of XLRS

X-linked Juvenile Retinoschisis causes severe symptoms in the ocular system, however, it is not a deadly disease. Due to its variable expressivity, not every case may lead to blindness. However, the general pattern of the disease is a decrease in visual acuity early on in life, stabilizing visual acuity after adolescence till the fourth or fifth decade of life, where it may start decreasing again. By the age of 60, patients might become legally blind.

Complications of X-Linked Juvenile Retinoschisis

XLRS can cause blindness, which decreases the quality of life significantly. It can also cause a spontaneous hemorrhaging and retinal detachment, which is treated by laser surgery. Some of the other complications of it include intraretinal splitting, subretinal exudate, neovascular glaucoma, macular dragging, and optic atrophy.

References

1. American Academy of Ophthalmology. X-linked juvenile retinoschisis. https://www.aao.org/image/x-linked-juvenile-retinoschisis Accessed May 20, 2020.

2. Sikkink SK, Biswas S, Parry NRA, Stanga PE, Trump D. X-linked retinoschisis: an update. Journal of Medical Genetics. 2007 Apr 1;44(4):225–32.

3. Sieving PA, MacDonald IM, Chan S. X-linked Juvenile Retinoschisis. 2003 Oct 24 [Updated 2014 Aug 28] In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

4. Saleheen D, Ali A, Khanum S, Ozair MZ, Zaidi M, Sethi MJ, et al. Molecular analysis of the XLRS1 gene in 4 females affected with X-linked juvenile retinoschisis. Can J Ophthalmol. 2008 Oct;43(5):596–9.

5. Rodríguez FJ, Rodríguez A, Mendoza-Londoño R, Tamayo ML. X-linked retinoschisis in three females from the same family: a phenotype-genotype correlation. Retina (Philadelphia, Pa). 2005 Jan;25(1):69–74.

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