Dr. Matteo Scaramuzzi M.D., is affiliated with the San Giuseppe Hospital, University Eye Clinic, Milan, Italy. Dr. Scaramuzzi acquired his Medical training from the School of Medicine at the San Raffaele University, Milan, during the preiod of 2008 – 2014 & also pursued a few fellwoships simultaneously. In 2011 he pursued an Internship in Anesthesia with Prof. Luigi Beretta, from the Dept of Anesthesia San Raffaele University, Milan, followed by an Internship in General Medicine and Immunology in 2012, with Prof. Maria Grazia Sabbadini, from the Dept of Immonology, San Raffaele University, Milan. He then went on to do an Internship in Ophthalmology with Prof. Francesco Bandello, of the Dept of Ophthalmology, San Raffaele University, Milan from 2012 – 2014 & also pursued an Internship in Ophthalmology, with Maurizio Battaglia Parodi MD from 2013 – 2015, of the Dept of Medical Retina and Retinal Dystrophy, San Raffaele University, Milan simultaneously. Matteo is currenlty pursuing a Clinical Research Fellowship in Pediatric Ophthalmology and Ophthalmic Genetics (2015 – 2018) from the Cole Eye Institute, Cleveland Clinic, under Dr. Elias I Traboulsi, in addition to an Ophthalmology Residency Program (2017 – 2018), from the San Giuseppe Hospital, University of Milan, Milan under Prof. Paolo Nucci and Prof. Giovanni Staurenghi. Dr. Scaramuzzi has publications in reputed peer-reviewed journals in addition to Chapters in textbooks of repute.

1) Which is the gene expected to be mutated in a patient with JXLR?

RS1. This gene is found on chromosome Xp22.2 and encodes Retinoschisin, a retina-specific protein implicated in cell-cell interactions and cell adhesion. To date, more than 190 mutations in RS1 have been identified, most of them being missense mutations leading to misfolding, misrouting, or functional loss of the protein.

2) Is this patient at risk for retinal detachment?

Yes, but low risk. JXLR presents a variety of phenotypical manifestations. Retinal detachment is one of them, but fortunately, it is not a common one. However, it is one of the most serious sight-threatening complications of the disease. Retinal detachments have been reported in 5–22% of affected individuals, while in a more recent study, this complication has been described in only 3% of patients. Detachments could be classified as rhegmatogenous, secondary to outer retinal breaks in areas of peripheral schisis with concurrent inner retinal breaks or from full-thickness retinal breaks occurring during vitreous detachment, or tractional – from the retinoschisis cavity and / or posterior hyaloidal contraction. Considering this patient, infero-temporal far periphery schisis is described, without any breaks or any demarcation line. Peripheral retinoschisis does not usually progress or extend, but a low rate of serious complications has to be taken in consideration.

3) Which treatment would you consider starting for this patient?

Carbonic anhydrase inhibitors. Bilateral foveal schisis is the most common clinical finding in patients with JXLR, with an overall frequency of about 90%.  Recently, carbonic anhydrase inhibitor efficacy has been shown in patients with cystic-appearing macular lesions, with an average improvement in visual acuity and an improvement in the extent of cystic macular lesions in a high percentage of cases.

4) What would be your work-up for intraretinal cystoid spaces?

Considering that oral and topical carbonic anhydrase inhibitors (CAI) are effective in reducing foveal schisis in patients with JXLR, I suggest to introduce a therapy with topical Dorzolomide TID. This would, on one hand, reduce the cystoid spaces, and on the other hand, avoid the side effects associated with oral assumption. After the introduction of CAI therapy, patients should be monitored on a monthly basis, checking visual acuity evolution and changes in foveal thickness and cystoid lesions on OCT. Even in case of no visual acuity improvement, treatment should be continued in order to maintain macular architecture and decrease the occurrence of later-onset atrophic lesions and associated visual loss.

5) What is the role of carbonic anhydrase inhibitors in JXLR?

Carbonic anhydrase is an enzyme that is very diffused over our body. In the retina, the retinal pigment epithelium (RPE) contains primarily the membrane-bound form of this enzyme. Carbonic anhydrase inhibitors mainly modulate the membrane-bound carbonic anhydrase receptors present in RPE layer, enhancing fluid transportation and retinal adhesiveness.

6) What would you tell the family about the long-term prognosis?

The natural history varies considerably between patients, but visual acuity usually deteriorates between second and fifth decades, in consequence of foveal schisis and defects in outer photoreceptor layer abnormalities. On long-term photoreceptor defects evolve in macular atrophy, with severe central visual function impairment.

7) Is there any ongoing research that could potentially help patients with JXLR?

Yes. Since retinoschisin is expressed in the retina during early development and maintained throughout life, gene replacement has become a target for therapeutic intervention. Adeno-associated viral vector delivery of the RS1 gene has shown efficacy in mouse models, as retinoschisin was successfully expressed in all retinal layers, the b-wave amplitude was restored on electroretinography and reorganization of the photoreceptor-depolarizing bipolar cell synapse was induced. The vectors were injected into the vitreous, differently from recently approved Luxturna, a gene replacement subretinal injection for patients with inherited retinal dystrophy due to mutation on RPE65 gene. Nowadays there are two clinical trials in recruitment phase (NCT02317887 and NCT02416622), conducting a phase 1 / 2 dose-escalation clinical trial on human patients.