Transcript Epiretinal Membranes in Macular Dysfunction

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
Presumed
carrier
?
carrier
?
No known disease
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
peripheral schisis with holes
peripheral schisis
parafoveal spoked-wheel pattern of
radially oriented cavities.
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 awave 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
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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
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Stargardt disease
Cone dystrophy
Nicotinic acid maculopathy
CME
Norrie disease
Familial exudative vitreoretinopathy
Differential Diagnosis, Cont
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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 subretinal 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 RS1hDeficient 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.).