X-linked retinoschisis (ORPHA:792)
A rare disorder involving multiple structure of the eye characterized by reduced visual acuity in males due to juvenile macular degeneration. Clinical features such as vitreous hemorrhage, retinal detachment, and neovascular glaucoma can be observed in advanced stages.
Epidemiology
X-linked retinoschisis prevalence is estimated to range between 1/5,000-1/25,000 males worldwide.
Clinical description
XLRS is a symmetrical bilateral macular disorder with onset in the first decade of life. It manifests with poor vision and reading difficulties. In severe cases, nystagmus may also be observed. Severe cases involve full-thickness retinal detachment that leads to impaired vision or blindness. In more advanced stages of the disease, vitreous hemorrhage, retinal detachment, and neovascular glaucoma, which may induce severe loss of vision, can be seen. Correlation exists between visual acuity, patient age, and OCT features. There is clinical variability. Female carriers rarely have any vision impairment.
Etiology
The disease is caused by mutations on the RS1 gene (Xp22.2-p22.1), including missense, nonsense, frameshift, and splice site mutations, deletions, and insertions. RS1 codes for retinoschisin, an adhesive protein, localized in photoreceptors and bipolar cells, and secreted in the extracellular matrix. In the adult retina, retinoschisin is essential for maintaining the structural and functional integrity of the retina and participates in molecular pathways at the photoreceptor bipolar synapse.
Diagnostic methods
The diagnosis of XLRS can be made clinically, based on fundus appearance. Fundus examination shows microcystic changes of the macular region of the retina and areas of splitting within the nerve fiber layer, or schisis (spoked-wheel pattern), and vitreous veils. Electroretinogram (ERG) usually shows generalized cone system dysfunction with a reduction in the amplitude of the beta-wave and a relative preservation of the negative alpha-wave in scotopic ERG (electronegative rods and mixed ERG) and a normal photopic ERG. Optical coherence tomography (OCT) shows schisis areas in the macular region. There is also a family history consistent with X-linked inheritance. Molecular genetic analysis by direct sequencing of the RS1 gene detects mutations in approximately 90% of patients. NGS panels for Inherited Retinal dystrophies, including the RS1 gene represent also an appropriate approach.
Differential diagnosis
Differential diagnosis includes retinitis pigmentosa and Goldmann-Favre syndrome. The presence of an autosomal recessive inheritance, severe nyctalopia, pigmentary retinopathy, and reduced alpha- and beta-waves on the electroretinogram (ERG) help to differentiate Goldmann-Favre syndrome from XLRS.
Genetic counseling
There are more than 290 mutations described in RS1, most missense (~51%). Nonsense, splicing, small indels and CNVs variants have also been reported. XLRS is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if a RS1 mutation is identified in an affected family member.
Management and treatment
Management includes periodic ophthalmologic examination to monitor progression of XLRS. Additionally, patients are informed about possible ophthalmic complications that can be surgically treated (i.e., retinal detachment, vitreous haemorrhage, cataracts or strabismus). Therefore, patient education and close follow-up are the only clinical alternatives to early identification and treatment of vision-threatening complications.
Prognosis
In XLRS, vision slowly decreases until adolescence, and then in most patients remains relatively stable during young adulthood. The disease does not progress again until the fourth or fifth decade of life, when a significant decline in visual acuity typically occurs.

                            Last update: 
                            August 2020


                            - Expert reviewer(s): 
                            Dr Carmen AYUSO  - Dr Marta CORTON PÉREZ  -  Marta DEL POZO VALERO  - Dr José María MILLÁN SALVADOR