X-linked retinoschisis

Synonyms

X-linked retinoschisis (XLRS); Juvenile retinoschisis; Congenital retinoschisis; Juvenile macular degeneration/dystrophy; OMIM #312700.

Former terms: Neuroretinal disease in men; Congenital vascular veils in the retina; Vitreous veils.

Definition

X-linked retinoschisis (XLRS) is an inherited retinal disorder caused by mutations in the RS1 gene and characterized by a splitting of the neural retina which will eventually lead to decrease vision. The condition accounts for almost all congenital retinoschisis.

XLRS was first described in 1898 by J. Haas and documented as X-linked in 1913 by H. Pagenstecher.

Epidemiology, onset & clinical features

Epidemiology

Based on data from Finland (where the highest prevalence has been reported, due to 3 founder mutations) and The Netherlands, the prevalence is estimated to be 1 in 15,000 to 1 in 30,000. XLRS has also been reported in Indonesian, Chinese, Japanese, Indian, and Portuguese families. The disease is primarily seen in males and is a leading cause of macular degeneration in male children. Rarely, women with pathogenic mutations on both alleles of the gene have been reported.

Onset

XLRS is diagnosed in the first decade of life, most frequently in school-age children but in some cases as early as age of 3 months.

Clinical features

Majority of patients presents at school age with decreased vision and reading difficulties. Some patients present early in infancy with squint and nystagmus. Variation in disease presentation, severity and progression is typical, and is observed even within the same family or among individuals who carry the same mutation in the causative gene.
Visual impairment is variable with best-corrected visual acuity from 20/20 to 20/600. Affected males typically have vision of 20/60 to 20/120. Visual acuity often deteriorates during the first and second decades of life. Then it remains relatively stable and very slowly progressing. Atrophic changes in the macula, usually symmetric and bilateral, are common in individuals over age 50 years. Visual loss may progress to legal blindness by the sixth or seventh decade.

The hallmark feature of the disease is foveal schisis (retinal splitting) though over time this may become less distinct. More than 50% of patients have some peripheral retinoschisis (mostly in the inferotemporal region) that can vary from shallow schisis to marked elevation in the inner leaflet over a large retinal area. Breaks occur within the inner layer varying from small holes to large tears. Vessels crossing between the walls of the schisis may be unsupported and at risk of hemorrhage. Additional peripheral changes may include pigmentation, which can resemble retinitis pigmentosa, sublinear retinal fibrosis, white retinal flecks and vascular attenuation or sheathing. Some patients present an inner retinal reflex resembling a tapetal reflex. XLRS may progress to retinal detachment in 5-22% of affected individuals, including infants with severe retinoschisis. Four to 40% of individuals with XLRS may develop vitreous hemorrhage.

Carrier females almost always have normal visual function and normal electroretinogram (ERG). Rarely, white flecks or areas of schisis in the peripheral retina can be present. So far, affected females have been reported only twice in the literature, one of these report describing females with XLRS from a highly consanguineous Columbian family.

Etiology and pathogenesis

The gene responsible for XLRS, RS1 (also known as XLRS1), was identified in 1997. So far, more than 160 inactivating mutations have been found. The mutations are predominantly missense and are clustered in exons 4-6, which encode the discoidin domain. Deletions, insertions and splice site mutations have also been described.

The RS1 gene is located on band Xp22 (Xp22.2-p22.1) and encodes a 224 amino acid protein retinoschisin that is expressed in photoreceptor and bipolar cells and is involved in cellular adhesion and cell-cell interactions within the inner nuclear layer as well as synaptic connection between photoreceptors and bipolar cells.
There is no genotype/phenotype correlation, suggesting that there may be other factors influencing disease severity, such as genetic modifiers or environmental factors.

Mode of inheritance

XLRS is inherited in an X-linked recessive manner and the risk to sibs depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected. Female sibs who inherit the mutation will be carriers. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons.

An unusual autosomal dominant retinoschisis with both macular and peripheral involvement has been reported in which male-to-male transmission was documented.
Genetic counseling should be offered to families to explain the X-linked inheritance pattern and recurrence risks in future offsprings. It is particularly important to explain the extreme variation in severity of the disease even within families.

Diagnosis

The diagnosis of XLRS is based on the findings of fundus examination, electrophysiologic testing and molecular genetic testing. The identification of foveal schisis in a male, associated with a reduced b-wave on ERG and a family history consistent with X-linked inheritance, makes the diagnosis very likely. Cases with subtle foveal schisis can make the diagnosis by ophthalmoscopy difficult. In these cases, Optical Coherence Tomography (OCT) can be helpful for the diagnosis.

Electrodiagnostic testing shows a characteristic electronegative ERG with a severely reduced b-wave and variation of b:a ratio in dark-adapted condition. However, a similar ERG pattern can be seen in other hereditary and acquired retinal disorders, notably, congenital stationary night blindness. It also shows a wide variability between and within families, thus it cannot be the sole investigation for XLRS.

Molecular genetic testing is available on a clinical basis and can be performed to confirm a diagnosis. RS1 is the only gene known to be associated with XRLS. Mutations can be detected in 90-95% of patients who have a clinical diagnosis when all six exons and splice junctions are sequenced. Carrier testing for at-risk female relatives, and prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies are possible if the disease-causing mutation in the family is known.

Differential diagnosis

The differential diagnoses include cytoid macular edema, retinoblastoma, Norrie disease, familial exudative vitreoretinopathy (FEVR), incontinentia pigmenti, Goldman-Favre disease, enhanced S-cone syndrome, congenital stationary night blindness, autosomal-dominant retinoschisis, acquired degenerative retinoschisis, amblyopia, retinitis pigmentosa, VCAN-related vitreoretinopathy (Wagner syndrome and erosive vitreoretinopathy).

Management

At present, no treatment to halt the natural progression of schisis formation is available. Because of the slowly progressive nature of the disease, a conservative approach is advocated for majority of XLRS cases. Supportive measures include refractive correction, educational support and low vision aids such as large-print textbooks, preferential seating in the front of the classroom, use of handouts with high contrast.

Amblyopia prevention therapy is indicated in cases of hypermetropia or severe retinoschisis. General avoidance of head trauma and high-contact sports is recommended to reduce the risk of retinal detachment and vitreous hemorrhage.

Retinal holes or tears can be treated with laser therapy or cryotherapy to prevent their progression to a full-scale detachment. Vitreous hemorrhage when not associated with retinal detachment may resolve spontaneously. Surgery (scleral buckling, pneumatic retinopexy, vitrectomy) may be required for the management of the vision-threatening complications, such as severe vitreous hemorrhage and retinal detachment.

Some success of treatment on schisis cavities and visual acuity with topical carbonic anhydrase inhibitor dorzolamide has recently been reported but need further studies to confirm the effect and its duration. Gene therapy research on a mouse model of human retinoschisis has shown a restoration of the expression of retinoschisin protein in photoreceptors and normal ERG configuration, making gene therapy a viable therapeutic option in the future.

Follow-up and prognosis

Follow-up

Careful funduscopic examinations by a pediatric ophthalmologist or retina specialist should be performed at 6-12-month intervals in the first decade of life. Thereafter, patients can be monitored on an annual basis.

Prognosis

Visual prognosis is highly variable, depending on the XLRS phenotypic variability. With prompt identification and management of the disease, the vision could be preserved adequately.

References

Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D. X-linked retinoschisis: an update. J Med Genet 2007;44:225-232.

Kjellstrom S, Bush RA, Zeng Y, Takada Y, Sieving PA. Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration. Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3837-45.

Paul A Sieving, Ian M MacDonald, Meira Rina Meltzer, Nizar Smaoui. X-Linked Juvenile Retinoschisis. GeneReviews. Assessed May 12, 2009. [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=retinoschisis]

Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. Sep 2006;26(7):741-5.

Tantri A, Vrabec TR, Cu-Unjieng A, Frost A, Annesley WH Jr, Donoso LA. X-linked retinoschisis: a clinical and molecular genetic review. Surv Ophthalmol. Mar-Apr 2004;49(2):214-30.

Yassur Y, Nissenkorn I, Ben-Sira I, Kaffe S, Goodman RM. Autosomal dominant inheritance of retinoschisis. m J Ophthalmol. 1982 Sep;94(3):338-43.

Contributors

Katia Marazova, PhD (June 2010),  Prof. José Alain Sahel, MD, PhD and Dr Isabelle Audo, MD, PhD

Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment