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X-Linked Juvenile Retinoschisis
I. CASE HISTORY:
 11-year-old Hispanic male
 Chief complaint: long-standing blurred vision at distance and near
 Ocular/medical history: unremarkable.
 Medications: none
 Family ocular history: X-linked Juvenile Retinoschisis (brother)
II.
PERTINENT FINDINGS:
 BCVA: 20/100, OD/OS (NIPH)
 Fundus evaluation: wrinkling of the macular tissue noted in a radiating pattern; peripheral
retinal elevation noted temporally, OD/OS
 Macular OCT evaluation: cystic areas of convexity noted in the foveal area within the retinal
nerve fiber layer extending to the nuclear layer, OD/OS
 HVF 10-2 SITA Fast Fovea On testing: moderate paracentral defects, OD/OS
III.
DIFFERENTIAL DIAGNOSIS:
 Age-related degenerative retinoschisis
 Rhegmatogenous retinal detachment
IV.
DIAGNOSIS & DISCUSSION:
 XLRS is a hereditary retinal disease that affects predominantly males early in life with a
prevalence of 1:5,000 to 1:25,000 worldwide.1 Characteristic features of the condition
include mild to severe central vision loss, radial streaks arising from foveal schisis, splitting
of inner retinal layers in the inferior-temporal peripheral retina, and a negative ERG arising
from marked reduction in b-wave amplitude.2 Severity of the condition is highly variable but
often symmetric. The patient’s visual acuity is reduced to an average of 20/100 with gradual
onset early in life with little to no progression.3 Secondary complications are rare and include
vitreous hemorrhage and retinal detachment.2

Retinoschisin is the protein identified to be deficient or absent in the XLRS. It is normally
secreted from the retina and it binds to the surface of photoreceptors and bipolar cells to help
maintain integrity of the retina and structure of the photoreceptor-bipolar synapse.2
Retinoschisin is a protein that the mRNA of the RS1 gene translates into.2

RS1 mRNA protein expression is specifically carried out in the retina and pineal gland with
both areas having a common neuroectodermal origin.4 Retinoschisin has consistently been
observed at the extracellular surfaces of the inner and outer segments of rod and cone
photoreceptors, bipolar cells, and the inner and outer plexiform layers.4 Adult pattern
labelling in the knockout mouse model has shown that sustained expression of retinoschisin
is necessary throughout adulthood in order to maintain retinal integrity.

A total of 191 unique variants of the RS1 gene have been reported and associated with the
XLRS phenotype.5 Of these, the most common variants include missense mutations affecting
all regions of the protein.2 Any residual translation of the gene into the resulting protein
likely results in an unstable, truncated polypeptide that would be rapidly degraded within the
cell. Hence, the disease phenotype for such mutations is expected to arise from a complete
deficiency of retinoschisin.2
V.
TREATMENT AND MANGAGEMENT:
 Treatment of XLRS has commonly been observational with patients being followed via
fundus photography to detect structural changes and Humphrey visual field testing to monitor
for functional loss to the patient’s central visual field. In addition, the ERG was historically
the major diagnostic technique for XLRS with the characteristic negative b-wave.

OCT has changed the diagnostic approach for XLRS and is now the major diagnostic
technique for the disease.2 OCT has revealed that the spoke-wheel pattern of retinoschisis
actually extends beyond that of which is ophthalmoscopically visible, extending up to the
vascular arcades.2,5 The convenience and accessibility of the OCT compared to ERG has
diminished the diagnostic role for ERG in XLRS.2 Additionally, a negative ERG b-wave is
present in only about 50% of patients and therefore a normal ERG does not exclude the
diagnosis of XLRS.2

The concurrent use of oral and topical carbonic-anhydrase inhibitors (CAI’s) has been shown
to be effective for the improvement of foveal cystic-appearing lesions in patients with
XLRS.6 Although structural improvement via reduction in lesion size does not necessarily
correlate to improvement in vision, several literature articles cite improvement, ranging
between 4-7 letters of acuity.6 Although progression of the condition is limited, patients
should be treated with topical and oral therapy and monitored via OCT imaging for rebound
phenomena.2,5

More recent studies have focused on the viability of gene therapy as an approach to prevent
or slow vision loss in recessive inherited retinal degenerative diseases such as XLRS. Many
studies have employed recombinant adeno-associated viral (rAAV) vector in mouse models
to deliver the gene of interest to photoreceptor or RPE cells.7 As previously discussed, XLRS
results in partial or complete loss in protein function. In these cases, the delivery of the
normal gene to cells harboring the defective gene is often sufficient to restore protein
function and thereby halt or at least slow retinal degeneration.7

Bibliography:
1. Junhui, Y, et. Al. “Novel RS1 mutations associated with X-linked juvenile
retinoschisis.” Int J Mol Med (2012): 1-7. Pub Med. Web. 08 Aug. 2015.
2. Molday, R, Ulrich Kellner, and Bernhard Weber. “X-linked juvenile retinoschisis:
Clinical diagnosis, genetic analysis, and molecular mechanisms.” Prog Retin Eye Res
(2012): 195-212. Pub Med. Web. 08 Aug. 2015.
3. Wu WW, Wong JP, Kast J and Molday. “RS:RS1, a discoidin domain-containing
retinal cell adhesion protein associated with X-linked retinoschisis, exists as a novel
disulfide-linked octamer.” J Biol Chem 280 (2005): 10721-10730. Pub Med. Web. 08
Aug. 2015.
4. Y. Takada, R.N. Fariss, A. Tanikawa, Y. Zeng, D. Carper, R. Bush, P.A. Sieving. “A
retinal neuronal developmental wave of retinoschisin expression begins in ganglion
cells during layer formation.” Invest. Ophthalmol. Vis. Sci. 45 (2004): 3302–3312.
Pub Med. Web. 08 Aug. 2015.
5. C. Gerth, R.J. Zawadzki, J.S. Werner, E. Heon. “Retinal morphological changes of
patients with X-linked retinoschisis evaluated by Fourier-domain optical coherence
tomography.” Arch. Ophthalmol. 126 (2008): 807–811. Pub Med. Web. 08 Aug.
2015.
6. Khandhadia, S, D. Trump, G. Menon, and A.J. Lotery. “X-linked retinoschisis
maculopathy treated with topical dorzolamide, and relationship to genotype.” Eye 25
(2011): 922-928. Pub Med. Web. 08 Aug. 2015.
7. M.M. Liu, J. Tuo, C.C. Chan. “Gene therapy for ocular diseases.” Br. J. Ophthalmol.
95 (2010): 604–612. Pub Med. Web. 08 Aug. 2015.
VI.
CONCLUSION:
 Always practice good bedside manner. A diagnosis of this degree can be a hardship for
families.
 Be ready to incorporate family ocular history into the eventual diagnosis. This recessive
condition was present in the patient’s older brother before the patient’s eventual
diagnosis.