Clinical characteristics: RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy (RPE65-LCA/EOSRD) is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and age five years. While central vision varies, the hallmark of this disorder is the presence of severe visual impairment with a deceptively preserved retinal structure. Vision is relatively stable in the first decade of life, but begins to decline in adolescence. Most affected individuals are legally blind (visual acuity 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, visual acuity declines further and by the fourth decade all affected individuals are legally blind and many have complete loss of vision (i.e., no light perception). Milder disease phenotypes have been described in individuals with hypomorphic alleles.
Diagnosis/testing: The diagnosis of RPE65-LCA/EOSRD is established in a proband with suggestive findings and biallelic pathogenic variants in RPE65 identified by molecular genetic testing.
Management: Treatment of manifestations: Individuals with any type of inherited retinal dystrophy are advised to eat a healthy balanced diet to reach the minimum Reference Daily Intake (RDI) for nutrients, as recommended by the USDA. Due to poor night vision, patients are advised to use a flashlight for illumination. Children with RPE65-LCA/EOSRD are usually of normal intellect but may experience learning difficulties and/or psychiatric/behavioral issues as a result of their visual impairment. Those with learning disabilities will benefit from referral to a developmental pediatrician for consideration of enrollment in a continuing program of care and support.
Subretinal gene augmentation, an FDA-approved therapy, compensates for loss-of-function RPE65 variants (and hence improves vision) by providing the cells that use the protein product of RPE65 with a functional copy of the gene using recombinant adeno-associated virus (AAV) vectors. Individuals age 12 months to 65 years with molecularly confirmed RPE65-LCA/EOSRD may be eligible for this therapy.
Surveillance: Follow up at regular intervals of ophthalmologic manifestations, developmental/educational needs, psychiatric/behavioral issues, and family support/resource needs.
Agents/circumstances to avoid: Although not typically seen in RPE65-IRDs, repeatedly poking and pressing on the eyes should be discouraged as it may cause damage to the cornea and/or retina.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of sibs of an individual with RPE65-LCA/EOSRD in order to identify those who may benefit from gene replacement therapy or other treatments.
Therapies under investigation: Clinical investigations of variations of the FDA-approved gene replacement therapy are underway. Oral retinoid supplementation is also being investigated as a possible therapy.
Genetic counseling: RPE65-LCA/EOSRD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RPE65 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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