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I.
II.
Orphan Diseases
Definitions
Retinitis Pigmentosa
a. Prevalence
i. 1 in 3500 people worldwide; 100,000 in the US
b. Clinical characteristics
i. Attenuated arterioles
ii. Pigment degeneration
iii. Pale waxy disc
iv. PSC cataract
v. CME
c. Symptoms
i. Night blindness
ii. Field loss
d. Types
i. Diffuse RP
ii. Sector RP
iii. RP Sine Pigmento
iv. RP Albescens
v. Usher’s syndrome (RP with deafness)
1. 16,000 cases in US
e. Diagnostic testing
i. ERG
ii. VF
f. Hereditary patterns
i. AD, AR, Sex-linked
g. Differential from cone-rod dystrophies
h. Genetics
i. Dominant RP Genes
1. RHO (Rhodopsin)-30%
a. 12-15%: Pro23His mutations
b. 5%: Pr0347Leu mutations
2. Peripherin/human Retinal degeneration Slow (RDS-10%
ii. Recessive
1. As many as 60 genes
iii. X-linked RP
1. RPGR gene (75%)
2. RP2 (25%)
iv. Usher’s Syndrome
i. Treatment for a Future of Care
i. Genetic testing
ii. Gene specific treatments
1. Gene replacement
2. Knockdown by RNAi
iii. Other treatments
1. Neurotophic factors-photoreceptor cell rescue
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III.
IV.
V.
2. Vaccination against neurodegeneration
3. Drug therapy
4. Nutrient therapy
Leber Congenital Amaurosis
a. Prevalence
i. 5000 cases in the US
b. Clinical characteristics
i. Normal fundus early on
ii. Eventual mottling and degeneration
c. Symptoms
i. Severely reduced VA from birth
ii. Nystagmus
iii. Night blindness
d. Diagnostic tests
i. ERG
e. Types
i. Simple LCA
ii. Complicated LCA
f. Hereditary patterns
i. AR
ii. AD (extremely rare)
g. Genetics
i. Eight genes account for 10% of cases
1. RPE65, RDH12,CRX, RP-GRIP, AIPL1, CRB1,
GUCY2D, TULP1 genes
h. Treatment for a Future of Care
i. Genetic testing
ii. Bypassing biochemical steps
iii. Prevention of cone loss using injections of 11-cis chromophores
iv. Gene replacement
1. Success in Briard dogs
Achromatopsia
a. Clinical characteristics
i. Macular granularity
b. Symptoms
i. Nystagmus
ii. Reduced VA from birth
iii. Abnormal color vision
c. Hereditary pattern
i. AR
d. Genetics
i. ACHM2, ACHM3
ABCA-4 Dystrophies
a. Stargardt Disease/ Fundus Flavimaculatus
i. Prevalence
1. 1 in 10,000 children; 30,000 in the US
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VI.
ii. Clinical characteristics (may include one or more)
1. Early macular granularity
2. Eventual “beaten-bronze” macula
3. Fish-tail shaped lipofuscin flecks
iii. Symptoms
1. Loss of acuity in teenage years
2. Central scotomas (paracentral)
3. Various rates of progression
iv. Diagnostic testing
v. Hereditary patterns
1. AR, AD Stargardt-Like Dystrophy
vi. Differential Diagnosis from other White Dot Diseases
vii. Genetics
1. ABCA-4 mutations on short arm of chromosome 1
a. Results in formation of toxic A2E
i. Contributes to lipofuscin formation
viii. Treatment for a Future of Care
1. Genetic testing
2. Drugs to reduce A2E accumulation
b. Other ABCA-4 Dystrophies
i. Cone and Cone-rod dystrophy
1. Clinical characteristics
a. Bull’s eye macular lesion
b. Macular granularity
2. Symptoms
a. Color vision loss
b. Acuity loss
c. Variable progression
3. Diagnostic tests
a. ERG
b. FA
4. Hereditary patterns
a. AR, AD
ii. AMD (1-2%)
Other Macular Disorders
a. Pattern Dystrophy of the RPE
i. Clinical characteristics
1. Lipofuscin deposits in the macula
a. Butterfly-shaped
b. Reticular pattern
ii. Symptoms
1. Mild loss of VA
iii. Hereditary pattern
1. AD
iv. Genetics
1. RDS gene
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VII.
b. X-Linked Juvenile Retinoschisis
i. Clinical Characteristics
1. Foveal schisis
2. Reduced VA at birth
3. Inferotemporal schisis
ii. Hereditary pattern
1. Sex-linked
2. Males affected
iii. Genetics
1. XLRS1 gene
c. Best’s Vitelliform Dystrophy
i. Clinical characteristics
1. Lipofuscin disorder of the RPE
2. Egg-yolk macular lesion early on with good VA
3. Scrambled-egg lesion with reduced VA
a. CNV development
ii. Diagnostic testing
1. EOG
iii. Hereditary pattern
iv. Differential from other maculopathies
1. Adult-onset vitelliform dystrophy
v. Genetics
1. Bestrophin gene mutations
vi. Treatment for a Future of Care
1. No good animal models available at present
2. Monitor for CNV
A Future of Care
a. Importance of Diagnosing Orphan Disease
i. Pedigree construction
1. Determine pattern of inheritance in single gene diseases
2. Ask about consanguinity or close geographic relation
ii. Genetic testing
1. Available sites:
a. www.carverlab.org
b. www.genetests.org