Novel Phenotypic and Genotypic Findings in X-Linked Retinoschisis

X-linked retinoschisis (XLRS) is a common cause of macular dysfunction in young men,1,2 with an incidence of 1 in 5000 to 1 in 25 000.3 Individuals with XLRS are typically first identified as school-aged boys who fail vision screening examinations (60%), have strabismus (30%), or have vitreous hemorrhage.1,2,4 Initially, the characteristic “spoke-wheel” appearance may be seen at the fovea, caused by cystic changes,3 but this is commonly replaced with nonspecific macular atrophy in middle age.5 There is allelic heterogeneity at the retinoschisis (X-linked, juvenile) 1 locus (RS1), with different mutations causing a wide spectrum of phenotypes. The gene mutated in XLRS, RS1, has 6 exons that encode the 224–amino acid protein retinoschisin, which is processed by means of N-terminal cleavage of a 23–amino acid hydrophobic leader sequence into a mature protein of 201 amino acid residues (23 kDa) and is assembled into a disulfide-linked octamer.6 In many cases, this mutant protein cannot fold properly and is retained intracellularly.4 The predicted protein sequence contains a highly conserved discoidin domain, which is implicated in cell-cell adhesion and phospholipid binding. This function is consistent with the observed splitting of the fiber layer of Henle in the retina of patients with XLRS,7,8 suggesting that retinoschisin is essential during retinal development.9 The electronegative electroretinographic (ERG) configuration that is typically seen in patients with XLRS describes a waveform with a b-wave smaller than the a-wave and suggests that the primary functional defect occurs after phototransduction or is inner retinal. This study describes 7 patients with genetically confirmed mutations in RS1 that manifest atypical signs in the form of multiple white spots at the macula. The genotype and functional (ERG) phenotype are described.