INHERITED EYE DISEASES IN CHILDRENMatthew Weed, MDOphthalmic Genetics FellowUniversity of Iowa

Disclosures• I have no financial interest to disclose

Outline• Comparison of inherited eye disease then and now• Eight sample cases• Brief summary of recent exciting developments

Key Points• Most of these conditions progress very, very slowly• Clinical skill + genetic testing allows accurate diagnoses• Hope is here and incredible things are happening• Don’t tell these patients there is nothing that can be done

In the Past…• Relatively little was known about these diseases• No cures• Patients were often told “There’s nothing we can do”

…Now• A tremendous amount is

known about these conditions• And more is being learned

every day• Effective treatments are being

dreamed up and developed• The future is extremely

bright• Patients with an inherited

eye disease should neverbe told there is nothing that can be done.

Case # 1• Healthy 10-year-old boy referred after failing school vision• No affected family members• VA: 20/80 OD, 20/63 OS• Small central scotoma OU on visual field testing

Dominant Optic Atrophy• Presenting Symptoms

• Gradual central vision loss in a school-age child

• Abnormal color vision• Clinical Signs

• Subnormal acuity (20/30-20/200)

• Subtle visual field abnormalities

• Pallor of optic nerve head (classically temporal half)

• Healthy retina

Dominant Optic Atrophy• Genetics/Inheritance

• OPA1 mutations• Autosomal dominant with variable expressivity

• Systemic Features• None

• Prognosis/Treatment• Slowly progressive in up to 50% of cases• Genetic counseling• Supportive therapy

Case #2• Healthy 6-year-old boy referred for decreasing vision• Had normal vision until age 5, started to have trouble• VA 20/60 OD and OS at age 5• 3 months later 20/100 OD, 20/125 OS• Now (3 more months later), 20/200 OD, 20/200 OS

Batten Disease• Presenting Symptoms

• Progressive loss of previously normal visual acuity OU over the course of months beginning at age 5-7

• Followed by cognitive decline – but not till after age 10

• Clinical Signs• Progressive acuity loss• Arteriolar narrowing• Bull’s eye maculopathy• Flattening of ERG

Age Visual Acuity<5 Normal5 20/60

5.5 20/1006 20/200

Batten Disease• Genetics/Inheritance

• CLN3 mutations• Autosomal recessive

• Systemic Features• Initially…none!• Cognitive decline, speech problems, behavior problems, seizures

follow

• Prognosis/Treatment• Visual acuity drops to counts fingers steadily and rapidly• Fatal by age 20-30• CellCept has shown some promise in slowing progression• Genetic counseling – preimplantation genetic testing• Near future: gene therapy

Case #3• 5-month-old girl referred for abnormal eye appearance

and abnormal visual behavior• Parents aren’t sure what she can see• Unable to fixate and follow• Nystagmus• Iris transillumination defects OU

Aniridia• Presenting Symptoms

• Poor visual acuity (often <20/200)

• Light sensitivity• Abnormal iris appearance

• Clinical Signs• Partial or complete lack of iris• Foveal hypoplasia• Glaucoma• Corneal pannus

Aniridia• Genetics/Inheritance

• PAX6 mutations• May be autosomal dominant• May be spontaneous

• Systemic Features• WAGR: Wilm’s tumor, aniridia, genitourinary abnormalities, mental

retardation

• Prognosis/Treatment• If there is no family history, referral for renal evaluation• Variable prognosis depending on severity• Supportive care (sunglasses), management of glaucoma

Case #4• 14-year-old female referred for several years of declining

vision• Multiple affected family members including brother• She was seen 2 years prior, found to have 20/25 vision,

normal-appearing retina• 20/160 OD, 20/160 OS

Stargardt Disease• Presenting Symptoms

• Subnormal vision at age 7-20 (or later)

• Often labeled as functional vision loss

• Clinical Signs• Subnormal acuity (range from

20/25-20/200)• Yellow pisciform flecks• Peripapillary sparing• Vermillion fundus

Stargardt Disease• Genetics/Inheritance

• ABCA4 mutations• Autosomal recessive

• Systemic Features• None

• Key Differential Diagnosis• Batten disease (especially if age 4-8 with vision loss and visible macular lesion)

• Prognosis/Treatment• Variable prognosis• If vision drops to 20/50, typically it will progress to 20/200 within 5 years, then hold• Vitamin A supplements are harmful, not helpful• Safety glasses/avoidance of contact sports, as retina is extra sensitive to trauma• Genetic counseling – preimplantation genetic testing• Gene therapy

Case #5• 4-month-old healthy female with inability to “follow faces

well”• Able to fixate and follow light OD and OS• Nystagmus OU• Non-recordable electroretinogram (ERG)

Leber Congenital Amaurosis• Presenting Symptoms

• Very poor vision from birth

• Clinical Signs• Very poor visual acuity• Nonrecordable ERG• Nystagmus• Relatively healthy-appearing

retina

Leber Congenital Amaurosis• Genetics/Inheritance

• 17 known causative genes (RPE65, CRB1, CRX, NPHP6…)• Autosomal recessive

• Systemic Features• Sometimes present, sometimes not• Can be associated with kidney disease (nephronophthisis)• Joubert syndrome (ataxia, breathing problems, poor muscle tone)

• Prognosis/Treatment• A stable condition• Genetic counseling – preimplantation genetic testing• Gene therapy

Leber Congenital Amaurosis• Gene therapy

• For LCA caused by mutations in the RPE65 gene, gene therapy clinical trials have been performed in humans

• A “correct version” of the RPE65 gene is placed into a virus, and this virus is injected underneath the patient’s retina

• The virus carries the gene into the patient’s retina cells, which incorporate the corrected gene and start using it to make the correct protein

Gene Therapy

Gene Therapy

Treatment for Leber Congenital Amaurosis

Treatment for Leber Congenital Amaurosis

Case # 6 • 11-year-old male referred for decreased vision OU• Unable to see 20/20 since 3rd grade• 4 siblings (2 boys, 2 girls), all with normal vision• 20/60 OD and OS

X-Linked Retinoschisis• Presenting Symptoms

• Poor central vision

• Clinical Signs• Decreased acuity• “Spoke-wheel” fovea• Characteristic OCT• “Electronegative ERG”

X-Linked Retinoschisis• Genetics/Inheritance

• RS1 gene• X-linked

• Systemic Features• None

• Prognosis/Treatment• Slowly progressive• Good outcomes with topical carbonic anhydrase inhibitors

• E.g. dorzolamide or brinzolamide

X-Linked Retinoschisis

VA 20/60

VA 20/40

Brinzolamide 3 times daily

Case #7• 19-year-old male referred for one year of decreased

peripheral vision only present in dim lighting conditions• Both older siblings, and their father, have been having

similar problems• 20/15 OD, 20/25 OS

Retinitis Pigmentosa• Presenting Symptoms

• Night blindness• Glare• Peripheral vision loss

• Clinical Signs• Waxy pallor of optic nerve• Attenuated arterioles• Bone-spicule-like

pigmentation in retina• Ring scotoma on visual

field testing

Retinitis Pigmentosa

Normal Visual Field (right eye)

Sample Visual Field in Retinitis Pigmentosa

Retinitis Pigmentosa• Genetics/Inheritance

• 70% autosomal recessive (USH2A)• 15% autosomal dominant (rhodopsin)• 15% X-linked recessive (RPGR)

• Systemic Features• Occasionally present• Usher syndrome: RP, deafness, balance problems• Bardet-Biedl syndrome: RP, obesity, extra digits, developmental delay,

cardiac/renal/genital disorders

• Prognosis/Treatment• Stable or very slowly progressive• Genetic counseling• Future: gene therapy if disease is still early• Future: stem cell treatment if disease is more advanced

Case #8• 14-year-old boy with a known inherited eye disease, and

multiple affected family members• Referred for evaluation of sudden visual decline OD 1

week ago• Vision had previously been 20/15 OD and OS

Best Disease• Presenting Symptoms

• Mildly decreased vision• Often asymptomatic

• Clinical Signs• Acuity as good as 20/20• Single, symmetric, yellow,

ovoid lesion in central macula OU

• “Vitelliform” lesion• May develop retinal

hemorrhage from trauma or choroidal neovascularization

Best Disease• Genetics/Inheritance

• Best1 mutations• Almost always autosomal dominant

• Systemic Features• None

• Prognosis/Treatment• Very slowly progressive• Excellent acuity often preserved for many decades• Surveillance for retinal bleeding from choroidal neovascularization• Genetic counseling• Supportive therapy• Future: gene therapy

Best Disease – Back to our Patient20/160ObservationReturn in 1 week, then 2 weeks, then 3 weeks

20/125Avastin intravitreal injectionRepeated 1 month later

20/20Observation

3 months later

6 weeks later

Genes which have been replaced in animal models showing some efficacy• LCA--RPE65 (mice, dogs, humans)• LCA—GUCY2D (mice)• LHON--ND4 (mice)• Achromatopsia—CNGA3 (mice)• BBS4 (mice)• BBS1 (mice)• RP—Rho—mice• RP—PDE6Beta—mice• Stargardt—ABCA4 (humans, mice)• Usher 1b—Myo7a (mice, humans)• RP--CNGB1 (mice)• CNV—AAV-anti-VEGF shRNA

(mice)

• AMD—EIAV-endostatin/angiostatin(monkey, rabbit)

• LCA—MERTK (rats, humans)

• XLRP—RPGR (dogs)• Choroideremia—

CHM/REP1 lentivirus(mice)

• Neovascular diseases—Flt-1 receptor (non-human primates)

• ADRP—GCAP1 siRNA(mice)

• Achromatopsia—CNGB3 (mice)

• Usher 2D (mice)

Stem Cells• Cells that haven’t decided what they’re going to do• Found in every embryo• Growth factor molecules make them turn into different

types of tissue in the human body

• After many years, patients with severe retinal diseases essentially have no functioning retina cells left

• Wouldn’t it be nice if we could give them a new retina?• We could use stem cells – turn them into retina – and

transplant them into the patient• Where do we get the stem cells?

• No longer has to be from embryos!

Induced Pluripotent Stem Cells: Turning a Patient’s Own Skin Cells into Retina

Keratinocytes Stem cells

Yamanaka factors

The stem cells are then incubated with a succession of different media to drive the cells towards becoming retina tissues

45 days 70 days 150 days

200 µm 200 µm 1 cm

90

Neurosensory Retina

RPE

400 µm

Thank You