X-Linked Juvenile Retinoschisis

Laura S. Gilmore, MD, MS

Grand Rounds

October 7, 2005

Texas Tech University HSC

Lubbock, TX

Discussants: Jorge Corona, MD Wade Graham, MD

History• CC: “I want some glasses to help me read.”

• Ocular History: 51yo black male with poor vision since childhood, told he had a ‘lazy eye’ but later diagnosed with XLJR at age 24 in Air Force

• Feels vision slowly worsening since then.

History Continued

• PMH: HTN, hypothyroidism

• SH: polysubstance abuse, currently in rehab program

• Meds: clonidine, folic acid, HCTZ, sertraline, trazodone, clindamycin, synthroid, felodopine, hydroxyzine

Family History

? ? No known disease

Presumed carrier

carrier Our patient

Ocular Exam

• BCVA: 20/200 –2.25 +1.75 X 10

20/100 –1.25 + .75 X 178

• Pupils: normal OU

• Motility: Full OU

• IOP: 19, 17

• Ant segment: pterygium OD, NVS cataract OU

Fundus Exam

• No picture available

• Stellate ERM in macula surrounding a central pseudohole (Watzke negative)

• No obvious peripheral pathology

parafoveal spoked-wheel pattern of radially oriented cavities.

peripheral schisis

peripheral schisis with holes

Typical Findings

• VA range 20/20 to 20/200--usually 20/70

• Typically hyperopic with astigmatism

• Often see fine membrane from iris root to Schwalbe line on gonio

• negative ERG.

Typical Fundus Findings

• Stellate spoke-like maculopathy with microcysts

• RPE changes can mimic AMD• Optic disc dragging• peripheral schisis with inner holes and

traction• Vitreous veils• Female carrier with subtle ILM changes

cystoid changes and schisis cavities within the retina

The ERG has a specific abnormality showing a normal a-wave but no b-wave. It is a negative ERG. The picture is similar to that recorded in central retinal artery occlusion and Congenital Stationary Night Blindness Type 2.

Acquired Retinoschisis

• Most common form of retinoschisis

• Usually occurs after age 50

• 70% patients are hyperopic

• Over 50% have bilateral disease

• Often asymptomatic and found on routine exam

• May need laser if macula-threatening

Juvenile Retinoschisis• X-linked recessive

• Prevalence from 1 in 5,000 to 1 in 25,000 live births

• Highest prevalence in Finland

• Usually presents with decreased vision around age 10, though present at birth

• Almost always bilateral

Differential Diagnosis

• Stargardt disease

• Cone dystrophy

• Nicotinic acid maculopathy

• CME

• Norrie disease

• Familial exudative vitreoretinopathy

Differential Diagnosis, Cont

• Retinitis pigmentosa

• Goldman-Favre vitreoretinal dystrophy

• Wagner’s vitreoretinal dystrophy

• Sticklers syndrome

Clinical Description• Spoke-like streaks in the fovea• Retina splits in inner retina, in NFL, ILM or

ganglion cell layer. (Senile splits in OPL or ONL)• Separated layers are often filled with blisters and

ruptured vessels that can leak into vitreous• Peripheral visual loss in about half of cases• Expressed in males, female carriers asymptomatic.• Incomplete penetrance, and disease severity

variable even within families; ie, expression is not mutation-specific.

Clinical Course and Prognosis

• Macula almost always impacted, with central visual loss

• Often slow progression until age 20• Most retain ~20/70 vision after second decade• Schisis cavities may lead to ruptured vessels and

vitreous bleeds• May rarely get RRD• Follow to deal with complications, but no current

treatment for disease itself.

Or is There?• RS1 gene identified in 1997.• Mutation in this gene produces defective retinoschisin

protein; more than 100 mutations identified.• Retinoschisin holds layers of the retina together• Mutant protein is unable to fold properly and is retained

intracellularly.• This intracellular retention is

pathological mechanism underlying XLR

Current Studies

• Researchers at the University of Florida have injected a functional RS1 gene via an adeno-asssociated virus vector into sub-retinal space of 15-day old mice (equivalent to 10 yo boys). – Normal retinal function persisted 6 months

after injection.

Current Studies• Subsequent studies at UF, published this month,

demonstrate in an Rs1h-deficient mouse model of human RS using a highly specific AAV5-opsin promoter vector:– delivery of the human RS1 cDNA with an AAV vector

restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice.

– Therapeutic gene delivery using this highly specific vector resulted in progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.

Current Studies

Researchers at the NEI in Bethesda, Maryland presented their Rs1h knockout mouse model at the 2004 ARVO convention. Delivery of RS1 restored retinal function, as assessed by ERG findings, and retinal expression of RS protein by immunohistochemistry.

Implications

• Identification and isolation of the responsible gene in a disease process makes gene therapy an attractive possibility

• This knockout mouse model demonstrates reversal of functional loss and regaining of physiological function after restoration of functional protein

• Still a long way to go, but• This leads us to the question of gene therapy in

humans with XLJR, if it could restore visual function and reduce structural sequelae, such as RD

• Human trials expected within two to five years

Bibliography• Min SH, et al. Prolonged Recovery of Retinal

Structure/Function after Gene Therapy in an RS1h-Deficient Mouse Model of X-Linked Juvenile Retinoschisis. Mol Ther. 2005 Oct;12(4):644-51.

• Shaberman, Ben A., et al. Researchers Use Human Gene to Restore Vision in Mice with Retinoschisis. University of Florida. August 2, 2005 E-Medicine discussion board.

• Song, Mi-Kyoung. Retinoschisis, Juvenile. E-Medicine. June 29, 2005.

• Yong Zeng, et al. RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with Reversal of the Electronegative Waveform of X-Linked Retinoschisis. Investigative Ophthalmology and Visual Science. 2004. 45:3279-3285.).