Clinical characteristics.

The three phenotypes of autosomal recessive RPE65-related retinal degeneration, from most severe to mildest, are Leber congenital amaurosis (LCA), early-onset severe retinal dystrophy (EOSRD), and juvenile retinitis pigmentosa (RP).

In RPE65-related LCA, onset of visual manifestations frequently occurs in infancy during the first year of life. Central vision can be variable, but children ages four to ten years in the largest case series had severe visual impairment (mean visual acuity: 20/126). While vision is relatively stable in the first decade of life, it begins to decline again starting in the teens, with 50% of individuals being legally blind (visual acuity of 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, vision loss is more rapidly progressive: all affected individuals are legally blind by the fourth decade and many have complete loss of vision (i.e., no light perception).

In RPE65-related EOSRD, onset of visual manifestations typically occurs in early childhood often presenting with nyctalopia (i.e., inability or reduced ability to see in dim light or at night) and reduced visual acuity. Individuals typically experience progressive decline in central vision, and many meet the criteria for legal blindness by the fourth decade; some progress to profound visual loss (including no light perception) by mid-adulthood.

In RPE65-related juvenile RP, onset of visual manifestations typically occurs in late childhood or adolescence. Individuals often present with nyctalopia, progressive peripheral visual field loss, and relatively preserved central visual acuity in earlier stages. Affected individuals often maintain central vision into early adulthood; however, many meet the criteria for legal blindness by age 40 to 50 years, and some experience further decline in later decades, occasionally progressing to very poor vision, including no light perception.

Diagnosis/testing.

The diagnosis of autosomal recessive RPE65-related retinal degeneration is established in a proband with suggestive findings and biallelic pathogenic variants in RPE65 identified by molecular genetic testing.

Management.

Targeted therapy: Subretinal gene supplementation therapy for individuals between ages 12 months and 65 years with retinal degeneration known to be associated with biallelic RPE65 pathogenic variants.

Supportive treatment: Healthy balanced diet to reach the minimum reference daily intake (RDI) for nutrients. Docosahexaenoic acid / eicosapentaenoic acid supplements up to 500 mg/day as well as lutein supplements up to 10 mg/day can be considered if dietary intake is not sufficient.

Children with autosomal recessive RPE65-related retinal degeneration are usually of normal intellect but may experience learning delays due to visual impairment. Overarching principles should include involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired and early referral to low vision services to access low vision aids, especially with improving technologies, such as the refreshable Braille display. Advice on learning / intellectual disability / educational issues will vary from country to country, or even region to region within a country, depending on support services available.

Surveillance: Routinely scheduled follow up with the treating ophthalmologist.

Agents/circumstances to avoid: Children should be discouraged whenever possible from repeatedly poking and pressing on their eyes, 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 apparently unaffected older and younger at-risk sibs in order to identify those who have biallelic RPE65 pathogenic variants and may benefit from early evaluation, counseling, and timely consideration of subretinal gene supplementation therapy.

Genetic counseling.

RPE65-related retinal degeneration is inherited in an autosomal recessive manner. If both parents of a child diagnosed with autosomal recessive RPE65-related retinal degeneration are known to be heterozygous for an RPE65 pathogenic variant, each sib of an affected individual has at conception 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 and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Autosomal recessive RPE65-related retinal degeneration should be suspected in individuals with the following clinical, electroretinographic, and imaging findings and family history.

Clinical findings

• Symptomatic onset between birth and age five years
• Roving eye movements or nystagmus
• Poor pupillary light responses (in some)
• Profound nyctalopia
• Central visual acuity decreased to the 20/100 range (which can be variably preserved if initial manifestations are between ages one and five years). Generally, central visual acuity is worse when onset is before age one year compared to onset between ages one and five years.
• Fundus examination can be quite variable and can appear normal at presentation. Associated findings include retinal pigment epithelium (RPE) mottling, pigmentary retinopathy with attenuated vessels, optic nerve pallor, white spots at the level of the RPE, parafoveal RPE loss as a bull's-eye maculopathy, and optic disc drusen (see Nonsyndromic Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview).

Full-field electroretinogram (ERG) findings. An ERG is an electrophysiologic test that assesses the functional status of the photoreceptors and proximal neuronal layers of the retina. The ERG represents a composite response of millions of retinal cells. In RPE65-related Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD), the ERG is severely reduced or non-recordable [Lorenz 2025]. When onset of clinical manifestations is later (i.e., between ages one and five years), variable ERG findings can include residual activity on dark-adapted scotopic (rod) ERGs as well as light-adapted photopic (cone) ERGs.

Imaging findings

• Fundus autofluorescence (FAF) can detect autofluorescent material within the RPE and choroid (e.g., lipofuscin and melanin) that is indicative of retinal health. Severely diminished or absent short-wavelength (SW) fundus autofluorescence (FAF) is observed because of the enzymatic blockade in the visual cycle. A relatively preserved central retinal structure by optical coherence tomography (OCT) and near-infrared FAF in the presence of very abnormal or undetectable SW-FAF signals is nearly pathognomonic of RPE65-related LCA [Lorenz et al 2004]. SW-FAF can be performed on young children often without anesthesia.
• Optical coherence tomography (OCT) is a light-based imaging technology that uses tissue differences in optical interference to create cross-sectional high-resolution (micron-scale) images to measure retinal thickness and to determine which outer layers of the retina are involved in retinal degeneration [Huang et al 1991, Huang et al 1998]. OCT findings in RPE65-related LCA and EOSRD can be variable and can include a preserved central foveal region with thinning of the outer nuclear layer (ONL) that surrounds the fovea [Jacobson et al 2005, Jacobson et al 2007, Maeda et al 2009].
  Note: While two studies suggested that OCT in RPE65-related LCA and EOSRD reveals an age-related decreased thickness in the foveal ONL layer [Jacobson et al 2007, Cideciyan et al 2013], a third study (which measured overall retinal thickness at the fovea) did not find a relationship between foveal ONL layer thickness and age [Chung et al 2019].

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of autosomal recessive RPE65-related retinal degeneration is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in RPE65 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic RPE65 variants of uncertain significance (or of one known RPE65 pathogenic variant and one RPE65 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome or genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of RPE65, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

The three phenotypes of autosomal recessive RPE65-related retinal degeneration, from most severe to mildest, are Leber congenital amaurosis (LCA), early-onset severe retinal dystrophy (EOSRD), and juvenile retinitis pigmentosa (RP).

Systemic manifestations have not been reported in autosomal recessive RPE65-related retinal degeneration.

RPE65-related LCA is a severe inherited retinal degeneration with onset of visual manifestations frequently within in the first year of life [Cideciyan 2010]. Visual function is generally poor (but in some instances central vision is variably preserved) and is often accompanied by nystagmus and sluggish or near-absent pupillary responses.

• Visual impairment. Central vision can be variable, but most affected individuals have severe visual impairment (mean visual acuity of 20/126 measured in children ages four to ten years in largest case series) [Chung et al 2019]. While vision is relatively stable in the first decade of life, it begins to decline again starting in the teens.
  Fifty percent of affected individuals are legally blind (visual acuity of 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, vision loss is more rapidly progressive: all affected individuals are legally blind by the fourth decade and many have complete loss of vision (i.e., no light perception).
• Other ophthalmic findings
  • Oculodigital sign (i.e., poking, rubbing, or pressing on the eye to stimulate phosphenes for visual perception) is occasionally observed but is not specific to RPE65-related LCA.
  • Late-stage findings can include keratoconus and cataract.
  • Refractive error is common; most affected individuals are myopic [Chung et al 2019].

RPE65-related EOSRD describes individuals whose manifestations begin slightly later than those of RPE65-related LCA, typically in early childhood rather than in infancy. Affected children often present with nyctalopia, reduced visual acuity, and lower electroretinogram responses. Fundus examination may show mottled retinal pigment epithelium (RPE) or early macular changes, and optical coherence tomography (OCT) often demonstrates reduced (but preserved) retinal structures. Central visual acuity and visual fields gradually decline. Although residual retinal function is often present in childhood, progressive degeneration occurs, and many individuals meet criteria for legal blindness in their fourth decade; some progress to profound visual loss (including no light perception) by mid-adulthood.

RPE65-related juvenile RP, representing the mildest end of the phenotypic spectrum, is characterized by a later onset of manifestations, typically in late childhood or adolescence. Individuals often present with nyctalopia, progressive peripheral visual field loss, and relatively preserved central visual acuity in earlier stages. Fundus findings may include subtle bone spicule-like pigmentation, vascular attenuation, or mottled RPE changes, while OCT scans commonly show a retained foveal structure with peripheral outer retinal thinning. Affected individuals frequently retain useful central vision into early adulthood, but peripheral visual field loss is progressive. Many meet the criteria for legal blindness by age 40-50 years, and some experience further decline in later decades, occasionally progressing to very poor vision, including no light perception.

Genotype-Phenotype Correlations

Genotype-phenotype correlations in autosomal recessive RPE65-related retinal degeneration do not allow reliable prediction of disease severity in an individual [Chung et al 2019]; however, certain variant classes have been associated with milder or more severe phenotypes.

The severe early-onset phenotypes (LCA and EOSRD) are more often associated with null variants (e.g., nonsense, frameshift, canonical splice).

RPE65-related EOSRD. Compared to LCA, EOSRD reflects partial retention of isomerohydrolase activity and is generally associated with biallelic missense or hypomorphic variants that allow some residual RPE65 function.

RPE65-related juvenile RP is most often associated with biallelic hypomorphic RPE65 variants that provide greater residual enzymatic activity, consistent with its slower progression and milder early presentation. Hypomorphic alleles (e.g., p.Arg91Trp and p.Ala132Thr) are observed in individuals with later-onset or milder disease, including juvenile-onset rod-cone dystrophy or fundus albipunctatus-like changes. Individuals with at least one such allele may retain useful central vision into adulthood (see Table 6) [Perrault et al 2004, de Freitas Cenachi et al 2025, Lorenz 2025].

Nomenclature

Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are clinical diagnoses that do not have well-agreed-upon definitions; consequently, different designations may be variably applied to an affected individual. With nomenclature moving away from clinical descriptive terms to gene-based terms, RPE65-related LCA/EOSRD is considered the more appropriate term for these phenotypes when caused by pathogenic variants in RPE65.

The term "autosomal recessive RPE65-related retinal degeneration" encompasses RPE65-related LCA/EOSRD and RPE65-related juvenile RP [Lorenz 2025]. RPE65-related retinal degeneration may also be referred to as RPE65-related retinal dystrophy.

Prevalence

Autosomal recessive RPE65-related retinal degeneration is rare. RPE65-related LCA/EOSRD is thought to account for approximately 3%-16% of LCA/EOSRD depending on the population studied [Sallum et al 2022, de Freitas Cenachi et al 2025, Lorenz 2025]. In the United States, this corresponds to an estimated 1,000-2,000 affected individuals.

RPE65-related juvenile RP represents approximately ~0.2%-4% of autosomal recessive RP [Sallum et al 2022].

Founder variants have been identified in a small Dutch isolate, in Costa Rica, and in the North African Jewish (Sephardic) population [Banin et al 2010] (see Table 6).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of individuals diagnosed with autosomal recessive RPE65-related retinal degeneration, the evaluations included in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended, and their purpose summarized.

Note that some evaluations may be indicated only in individuals considering subretinal gene supplementation therapy (see Table 4).

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended. Note: No consensus surveillance guidelines exist; the intervals shown are based on expert opinion and clinical practice.

Agents/Circumstances to Avoid

Children should be discouraged whenever possible from repeatedly poking and pressing on their eyes, which may cause damage to the cornea and/or retina.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently unaffected older and younger at-risk sibs in order to identify those who have biallelic RPE65 pathogenic variants and may benefit from early evaluation, counseling, and timely consideration of gene supplementation therapy.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Clinical investigations of variations of the FDA-approved gene replacement therapy treatment for autosomal recessive RPE65-related retinal degeneration (i.e., subretinal injection of an AAV2 vector expressing full-length RPE65-encoded protein, retinoid isomerohydrolase) have been completed. A Phase I/IIb clinical trial (NCT02781480) of an AAV2/5 vector with codon-optimized RPE65 has been completed, but no peer-reviewed outcomes have yet been published.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

RPE65-related Leber congenital amaurosis (LCA), early-onset severe retinal dystrophy (EOSRD), and juvenile retinitis pigmentosa (RP) – collectively referred to as autosomal recessive RPE65-related retinal degeneration – are inherited in an autosomal recessive manner.

Parents of a proband

• The parents of a child diagnosed with autosomal recessive RPE65-related retinal degeneration are presumed to be heterozygous for an RPE65 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an RPE65 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Autosomal recessive RPE65-related retinal degeneration resulting from uniparental isodisomy has been reported [Lee et al 2025].
• Heterozygous parents of a proband with autosomal recessive RPE65-related retinal degeneration are not at risk of developing autosomal recessive RPE65-related retinal degeneration.

Sibs of a proband

• If both parents of a child diagnosed with autosomal recessive RPE65-related retinal degeneration are known to be heterozygous for an RPE65 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygous sibs of a proband with autosomal recessive RPE65-related retinal degeneration are not at risk of developing autosomal recessive RPE65-related retinal degeneration.

Offspring of a proband. Unless an affected individual's reproductive partner also has autosomal recessive RPE65-related retinal degeneration or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in RPE65.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an RPE65 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the RPE65 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with autosomal recessive RPE65-related retinal degeneration, particularly if both partners are of the same ancestry. Founder variants associated with autosomal recessive RPE65-related retinal degeneration have been identified in several populations (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Once the RPE65 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Normally, photoreceptors sense light through the isomerization of the visual chromophore 11-cis retinal to all-trans retinal by photons of light. This chromophore binds rod and cone opsins to form rhodopsin and other visual pigments and plays an essential part of photo transduction. All-trans retinal then needs to be converted back to 11-cis retinal for continued phototransduction via a pathway called the visual cycle. Retinoid isomerohydrolase, encoded by RPE65, is a key rate-limiting enzyme required for the regeneration of 11-cis retinal from all-trans retinal. Without retinoid isomerohydrolase function, 11-cis retinal cannot be regenerated from all-trans retinal, resulting in lack of phototransduction in photoreceptors as well as subsequent retinal degeneration, presumably due to accumulation of retinyl esters.

Mechanism of disease causation. Most RPE65 pathogenic variants are loss-of-function alleles that result in absent or severely reduced enzymatic activity, causing autosomal recessive disease.

Author Notes

Dr Mark Pennesi is the Director of the Inherited Retinal Degeneration division at the Retina Foundation in Dallas, Texas, and an Adjunct Professor of Ophthalmology at Oregon Health and Science University's Casey Eye Institute in Portland, Oregon.

Brooke Koritala is a Clinical Research Assistant at the Retina Foundation in Dallas, Texas. Her research focuses on pediatric ophthalmology and the lived experiences of children with eye conditions. Current projects focus on quality of life in children with inherited retinal diseases and pediatric cataracts.

Author History

Amanda Burr, MS, CGC; Oregon Health & Science University (2019-2026)
Daniel L Chao, MD, PhD; University of California, San Diego (2019-2026)
Brooke A Koritala, BS, BA (2026-present)
Mark Pennesi, MD, PhD (2019-present)

Revision History

• 8 January 2026 (bp) Comprehensive update posted live
• 14 November 2019 (bp) Review posted live
• 26 March 2019 (dc) Original submission

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