X-Linked Juvenile Retinoschisis

1
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

2
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.

3
History Continued

• PMH HTN, hypothyroidism
• SH polysubstance abuse, currently in rehab
  program
• Meds clonidine, folic acid, HCTZ, sertraline,
  trazodone, clindamycin, synthroid, felodopine,
  hydroxyzine

4
Family History

• Presumed
• carrier

No known disease
?
?
carrier
Our patient
5
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

6
Fundus Exam

• No picture available
• Stellate ERM in macula surrounding a central
  pseudohole (Watzke negative)
• No obvious peripheral pathology

7
peripheral schisis with holes
peripheral schisis
parafoveal spoked-wheel pattern of radially
oriented cavities.
8
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.

9
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

10
cystoid changes and schisis cavities within the
retina
11

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.
12
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

13
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

14
Differential Diagnosis

• Stargardt disease
• Cone dystrophy
• Nicotinic acid maculopathy
• CME
• Norrie disease
• Familial exudative vitreoretinopathy

15
Differential Diagnosis, Cont

• Retinitis pigmentosa
• Goldman-Favre vitreoretinal dystrophy
• Wagners vitreoretinal dystrophy
• Sticklers syndrome

16
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.

17
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.

18
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

19
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.

20
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.

21
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.

22
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

23
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 Oct12(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.
  453279-3285.).