Overview
X-linked retinoschisis (XLRS) is an X-linked recessive retinal dystrophy affecting males, caused by mutations in the RS1 gene encoding retinoschisin. It is characterized by splitting (schisis) of the retinal layers, particularly in the fovea, leading to reduced central vision from early childhood. It is one of the most common causes of juvenile macular degeneration in males, with an estimated prevalence of 1 in 5,000–25,000.
Genetics
XLRS is caused by mutations in RS1 (Xp22.13), encoding retinoschisin, a secreted protein essential for retinal cell adhesion and synaptic function. Over 200 pathogenic variants have been identified.
| Gene | Locus | Inheritance | Notes |
|---|---|---|---|
| RS1 | Xp22.13 | X-linked recessive | Retinoschisin; secreted adhesion protein; >200 pathogenic variants |
Clinical Presentation
Early childhood
- Reduced visual acuity (often first noticed at school age)
- Strabismus or nystagmus in some cases
- Foveal schisis on OCT
Adolescence–adulthood
- Stable or slowly progressive central vision loss
- Peripheral schisis in ~50%
- Risk of vitreous hemorrhage and retinal detachment
Complications
- Vitreous hemorrhage
- Retinal detachment (rare but serious)
- Gradual atrophy in some patients
Diagnosis
- OCT: Foveal schisis (spoke-wheel pattern) — hallmark finding
- ERG: Characteristic electronegative ERG (reduced b-wave with preserved a-wave)
- Fundus: Foveal cysts; peripheral schisis in ~50%
- Visual acuity: Typically 20/60–20/120 in affected males
- Genetic testing: RS1 sequencing
- Female carriers: Usually asymptomatic; may show subtle OCT changes
Current Research & Treatment
AAV-mediated gene therapy for XLRS using RS1 delivered intravitreally is in Phase 1/2 clinical trials (AGTC and Applied Genetic Technologies). Carbonic anhydrase inhibitors (dorzolamide, acetazolamide) can reduce foveal schisis in some patients and are used as medical management. Gene therapy results have shown variable outcomes, with ongoing optimization of vector and dosing.
Active Clinical Trials
The following active clinical trials are investigating treatments for X-linked Retinoschisis. Trial status and enrollment may change; always verify directly on ClinicalTrials.gov.
Supporting Organizations
The following nonprofit organizations fund research, support patients, and advocate for advances in the treatment and cure of X-linked Retinoschisis.