{ "id": "ep35f455pt", "slug": "leber-congenital-amaurosis", "title": "Leber congenital amaurosis", "updated": "2026-10-21", "topic_path": [ { "id": "life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/topics/life" }, { "id": "life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health" }, { "id": "life.health.conditions", "label": "Diseases and injuries", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions" }, { "id": "life.health.conditions.neural", "label": "Nervous and sensory conditions", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.neural" }, { "id": "life.health.conditions.neural.ophthalmic_sensory", "label": "Eye and neuro-ophthalmic conditions", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.neural.ophthalmic_sensory" }, { "id": "life.health.conditions.neural.ophthalmic_sensory.macular-and-inherited-retinal-dystrophies", "label": "Macular and inherited retinal dystrophies", "api_url": "https://www.edgepedia.org/api/v1/topics/life.health.conditions.neural.ophthalmic_sensory.macular-and-inherited-retinal-dystrophies" } ], "geo": [ { "id": "geo.us.t2001.life.health.conditions.neural", "label": "United States · 2001 to 2020: Nervous and sensory conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001.life.health.conditions.neural", "path": [ { "id": "geo.us", "label": "United States", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us" }, { "id": "geo.us.t2001", "label": "United States · 2001 to 2020", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001" }, { "id": "geo.us.t2001.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001.life" }, { "id": "geo.us.t2001.life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001.life.health" }, { "id": "geo.us.t2001.life.health.conditions", "label": "Diseases and injuries", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001.life.health.conditions" }, { "id": "geo.us.t2001.life.health.conditions.neural", "label": "Nervous and sensory conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.us.t2001.life.health.conditions.neural" } ] }, { "id": "geo.weu.t1800.life.health.conditions.neural.ophthalmic_sensory", "label": "Western Europe · 1800 to 1945: Eye and neuro-ophthalmic conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life.health.conditions.neural.ophthalmic_sensory", "path": [ { "id": "geo.weu", "label": "Western Europe", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu" }, { "id": "geo.weu.t1800", "label": "Western Europe · 1800 to 1945", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800" }, { "id": "geo.weu.t1800.life", "label": "Life and health", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life" }, { "id": "geo.weu.t1800.life.health", "label": "Human health and medicine", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life.health" }, { "id": "geo.weu.t1800.life.health.conditions", "label": "Diseases and injuries", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life.health.conditions" }, { "id": "geo.weu.t1800.life.health.conditions.neural", "label": "Nervous and sensory conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life.health.conditions.neural" }, { "id": "geo.weu.t1800.life.health.conditions.neural.ophthalmic_sensory", "label": "Eye and neuro-ophthalmic conditions", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.weu.t1800.life.health.conditions.neural.ophthalmic_sensory" } ] } ], "excerpt": "Leber congenital amaurosis (LCA, amaurosis congenita of Leber) is a group of inherited retinal dystrophies causing severe vision loss or blindness in the first year of life, usually autosomal recessive, involving over 20 genes including CEP290, GUCY2D, CRB1, and RPE65; RPE65-related disease is treatable with Luxturna gene therapy.", "snippet": "Leber congenital amaurosis (LCA, amaurosis congenita of Leber) is a group of inherited retinal dystrophies causing severe vision loss or blindness in the first year of life, usually autosomal recessive, involving over 20 genes including CEP290, GUCY2D, CRB1, and RPE65; RPE65-related disease is treatable with Luxturna gene therapy.", "node": "life.health.conditions.neural.ophthalmic_sensory.macular-and-inherited-retinal-dystrophies", "markdown": "# Leber congenital amaurosis\n\n**Leber congenital amaurosis** (LCA) is a family of [inherited retinal dystrophies](https://www.edgepedia.org/inherited-retinal-dystrophies) that cause severe vision loss at or within the first year of life, defined by blindness and electroretinogram (ERG) responses below threshold on Ganzfeld (diffuse full-field light stimulation used for ERG eye testing) testing.[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) It is among the leading genetic causes of severe vision loss in infants and one of the most severe forms of inherited retinal disease.[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) Since 2017, when the first ocular gene therapy was approved for one genetic subtype, LCA has also become a central condition in ophthalmic gene therapy.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis)\n\n| Key fact | Detail |\n|---|---|\n| Definition | Retinal dystrophy with blindness and Ganzfeld ERG responses below threshold, severe visual impairment within the first year of life[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) |\n| Frequency | 2 to 3 per 100,000 newborns; Orphanet gives 1 in 50,000 to 1 in 33,000 live births[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) • [1](https://www.orpha.net/en/disease/detail/65?mode=orpha) |\n| Inheritance | Usually autosomal recessive; some genes (for example CRX, IMPDH1) act in an autosomal dominant manner[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) • [4](https://www.ncbi.nlm.nih.gov/sites/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_genes_and/) |\n| Genes | Variants in over 20 genes can cause LCA; CEP290 (15%-20%), GUCY2D (10%-20%), CRB1 (10%), RDH12 (10%), and RPGRIP1 (6%) are among the most common[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) • [4](https://www.ncbi.nlm.nih.gov/sites/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_genes_and/) |\n| Approved therapy | Voretigene neparvovec-rzyl (Luxturna), FDA-approved in 2017 for biallelic RPE65 mutation-associated retinal dystrophy, the first FDA-approved gene therapy product for the eye[5](https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna) • [3](https://eyewiki.aao.org/Leber_congenital_amaurosis) |\n| Prognosis | Vision commonly declines with age until complete blindness, most often by the third or fourth decade of life[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) |\n| Burden | Accounts for about 20% of blindness in school-age children and 5% of all retinal dystrophies[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) |\n\n## Clinical features\n\nAffected infants present at or shortly after birth with severely reduced visual acuity (20/400 or worse) or blindness, nystagmus or roving eye movements, sluggish or near-absent pupillary responses, photophobia, and high hyperopia (extreme farsightedness).[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) • [3](https://eyewiki.aao.org/Leber_congenital_amaurosis) The fundus may look normal in infancy, or show vessel attenuation, disc pallor, maculopathy, or pigmentary changes that develop over time.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC5574398/)\n\nFranceschetti's oculo-digital sign, in which a child repeatedly pokes, presses, and rubs the eyes with a knuckle or finger, is described as pathognomonic; the behavior produces flashes of light called phosphenes and may contribute to deep-set eyes and to keratoconus, a thinning and bulging of the cornea.[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) • [2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) [Esotropia](https://www.edgepedia.org/esotropia) (inward-turning eyes) is the most common form of strabismus seen in affected children.[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/)\n\nThe course depends on the genetic subtype. Longitudinal studies show that most patients remain stable, some deteriorate, and rare cases improve.[7](https://www.sciencedirect.com/science/article/abs/pii/S0039625704000839) Vision commonly declines until complete blindness, most often by the third or fourth decade of life.[1](https://www.orpha.net/en/disease/detail/65?mode=orpha)\n\n## Genetics\n\nLCA is genetically heterogeneous. Pathogenic variants in one of over 20 different genes can cause the disorder, and these genes act in several retinal pathways: photoreceptor development ([CRB1](https://www.edgepedia.org/crb1), CRX), phototransduction (GUCY2D), ciliary function ([CEP290](https://www.edgepedia.org/cep290)), and the visual cycle, the process that recycles light-sensitive molecules (RPE65, LRAT, RDH12).[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) Reviews report disease-causing variants in 24 to 25 genes associated with LCA and the related early-onset severe retinal dystrophy (EOSRD), accounting for 70% to 80% of cases, with more genes still to be identified.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC5574398/) • [8](https://www.ncbi.nlm.nih.gov/books/NBK531510/) Despite advances in testing, a pathogenic variant is not found in 20% to 30% of affected people.[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/)\n\n**Inheritance is usually autosomal recessive**, meaning both copies of the gene must carry a pathogenic variant; parents are typically unaffected carriers. Some cases follow an autosomal dominant pattern, arising from an inherited variant or a new (de novo) variant.[2](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/) Gene-specific frequencies illustrate the spread: CEP290 accounts for 15% to 20% of cases, GUCY2D for 10% to 20%, CRB1 and RDH12 for about 10% each, RPGRIP1 for 6%, and IMPDH1 for 5%, while RPE65 mutations account for only a minority of patients with LCA.[4](https://www.ncbi.nlm.nih.gov/sites/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_genes_and/) • [3](https://eyewiki.aao.org/Leber_congenital_amaurosis)\n\nSome genes also cause syndromic disease: CEP290 variants are associated with [Joubert syndrome](https://www.edgepedia.org/joubert-syndrome), [Bardet-Biedl syndrome](https://www.edgepedia.org/bardet-biedl-syndrome), nephronophthisis, and Senior-Løken syndrome, and NMNAT1 variants with SHILCA syndrome.[4](https://www.ncbi.nlm.nih.gov/sites/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_genes_and/)\n\n## Diagnosis\n\nDiagnosis rests on clinical observation, fundus examination, and a sedated full-field ERG that is close to or below threshold; molecular diagnosis is indispensable.[1](https://www.orpha.net/en/disease/detail/65?mode=orpha) The non-recordable ERG was identified as an essential diagnostic feature in 1957, the year the disease received its name.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) [Next-generation sequencing](https://www.edgepedia.org/next-generation-sequencing) is the preferred molecular method, covering up to 90% of patients, compared with 50% to 70% for older arrayed primer extension chips.[1](https://www.orpha.net/en/disease/detail/65?mode=orpha)\n\nFollowing diagnosis, GeneReviews recommends baseline full-field ERG and full-field stimulus threshold testing to measure residual rod- and cone-mediated function, multiluminance mobility testing to determine the minimum luminance at which a person can complete a standard course, developmental assessment, genetic counseling, and family support evaluation.[9](https://www.ncbi.nlm.nih.gov/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_recommend/?report=objectonly) [Genetic testing](https://www.edgepedia.org/genetic-testing) is critical for genotype-specific treatment, trial eligibility, prognostication, and family planning.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC8961750/)\n\n## History\n\nThe German ophthalmologist Theodor Karl Gustav von Leber (1840 to 1917) first described the disease in 1869 in a blind child with wandering nystagmus, amaurotic pupils, and congenital retinitis pigmentosa.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) It should not be confused with [Leber hereditary optic neuropathy](https://www.edgepedia.org/leber-hereditary-optic-neuropathy), a different condition described by the same physician in 1871.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) The first disease gene, LCA1, was localized to chromosome 17p13 in 1995 and ascribed in 1996 to mutations in the photoreceptor guanylate cyclase gene retGC1 (GUCY2D); RPE65 mutations were reported in 1997.[11](https://www.sciencedirect.com/science/article/pii/S1096719299929062)\n\n## Treatment\n\nFor the majority of LCA variants, no meaningful therapy or cure yet exists, and treatment that can alter the disease's course is offered to only a small fraction of the genetic subtypes.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) Regardless of genotype, affected individuals benefit from correction of refractive error, low-vision aids, treatment of associated ocular complications such as cataract, keratoconus, and cystoid macular edema, and access to educational and work-related opportunities.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC8961750/)\n\n**Gene therapy for RPE65.** The Briard dog was the first successful retinal gene therapy in animal models, with multiple studies reporting restored vision in Briard dogs with RPE65 mutation using recombinant adeno-associated virus (AAV) vectors.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis) The first human RPE65 gene therapy trials began in 2007.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC5574398/) In a phase 1-2 open-label trial of 12 participants treated with an rAAV2/2 vector carrying RPE65, improvements in retinal sensitivity were evident in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining.[12](https://www.nejm.org/doi/full/10.1056/NEJMoa1414221) In 2017 the FDA approved voretigene neparvovec-rzyl (Luxturna, [Spark Therapeutics](https://www.edgepedia.org/spark-therapeutics)) for confirmed biallelic RPE65 mutation-associated retinal dystrophy, the first FDA-approved gene therapy product for the eye.[5](https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna) • [3](https://eyewiki.aao.org/Leber_congenital_amaurosis) The recommended dose is 1.5 × 1011 vector genomes in 0.3 mL per eye, given subretinally on separate days at least 6 days apart.[8](https://www.ncbi.nlm.nih.gov/books/NBK531510/) Long-term phase 3 data show gains largely maintained at 3 to 4 years, with follow-up planned for 15 years.[3](https://eyewiki.aao.org/Leber_congenital_amaurosis)\n\n**Therapies for other subtypes.** Because RPE65 mutations account for only a minority of patients, trials target other genes. Sepofarsen, an antisense oligonucleotide for CEP290-related LCA10, is in the Phase III HYPERION trial (NCT06891443).[13](https://www.rarediseaseatlas.org/disease/65) • [14](https://www.reviewofophthalmology.com/CMSDocuments/2026/03/_MARCH%20RP.pdf) The first CRISPR-mediated retinal gene therapy trial (EDIT-101, NCT03872479) delivers *Staphylococcus aureus* Cas9 and CEP290-specific guide RNues by subretinal AAV5 injection.[15](https://bjo.bmj.com/content/bjophthalmol/106/4/445.full.pdf) In January 2026, Radboudumc treated the first Dutch patient with an antisense oligonucleotide \"genetic patch\" injected into the vitreous gel of the eye to mask a CEP290 DNA defect, as part of an international clinical study.[16](https://www.radboudumc.nl/en/news-items/2026/radboudumc-treats-first-dutch-patient-with-genetic-patch-for-hereditary-blindness) A gene therapy for LCA5 (OPGx-LCA5), an AAV8 vector delivering a functional LCA5 gene encoding the ciliary protein lebercilin, is in phase 1/2 with phase 3 dosing initiation expected in the fourth quarter of 2026.[17](https://www.sec.gov/Archives/edgar/data/1228627/000114036126039781/ef20083857_ex99-3.htm) A compassionate-use AAV8 gene therapy study for AIPL1-LCA in infants and young children is underway at [Great Ormond Street Hospital](https://www.edgepedia.org/great-ormond-street-hospital) and [Moorfields Eye Hospital](https://www.edgepedia.org/moorfields-eye-hospital) in London.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC8961750/)\n\n## References\n\n1. [Leber congenital amaurosis, Orphanet (ORPHA:65)](https://www.orpha.net/en/disease/detail/65?mode=orpha)\n2. [Leber congenital amaurosis, MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/)\n3. [Leber Congenital Amaurosis, EyeWiki, American Academy of Ophthalmology](https://eyewiki.aao.org/Leber_congenital_amaurosis)\n4. [Table 1. Nonsyndromic LCA/EOSRD: Genes and Distinguishing Clinical Features, GeneReviews, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/sites/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_genes_and/)\n5. [LUXTURNA (voretigene neparvovec-rzyl), US Food and Drug Administration](https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna)\n6. [Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol 2017](https://pmc.ncbi.nlm.nih.gov/articles/PMC5574398/)\n7. [Koenekoop RK. An overview of leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol 2004](https://www.sciencedirect.com/science/article/abs/pii/S0039625704000839)\n8. [Nonsyndromic Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview, GeneReviews, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK531510/)\n9. [Table 3. Nonsyndromic LCA/EOSRD: Recommended Evaluations Following Initial Diagnosis, GeneReviews](https://www.ncbi.nlm.nih.gov/books/NBK531510/table/lca-ov.T.nonsyndromic_lcaeosrd_recommend/?report=objectonly)\n10. [Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials. Br J Ophthalmol 2022](https://pmc.ncbi.nlm.nih.gov/articles/PMC8961750/)\n11. [Leber Congenital Amaurosis. Molecular Genetics and Metabolism 1999](https://www.sciencedirect.com/science/article/pii/S1096719299929062)\n12. [Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis. N Engl J Med 2015;372:1887-1897](https://www.nejm.org/doi/full/10.1056/NEJMoa1414221)\n13. [Leber congenital amaurosis, Rare Disease Research Atlas](https://www.rarediseaseatlas.org/disease/65)\n14. [Inherited Retinal Disease Pipeline, Review of Ophthalmology, March 2026](https://www.reviewofophthalmology.com/CMSDocuments/2026/03/_MARCH%20RP.pdf)\n15. [Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials (full PDF), Br J Ophthalmol](https://bjo.bmj.com/content/bjophthalmol/106/4/445.full.pdf)\n16. [Radboudumc treats first Dutch patient with 'Genetic Patch' for inherited blindness, 20 January 2026](https://www.radboudumc.nl/en/news-items/2026/radboudumc-treats-first-dutch-patient-with-genetic-patch-for-hereditary-blindness)\n17. [OPGx-LCA5 Gene Therapy program disclosure, SEC filing](https://www.sec.gov/Archives/edgar/data/1228627/000114036126039781/ef20083857_ex99-3.htm)\n\n---\n*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Nervous and sensory conditions › Eye and neuro-ophthalmic conditions › Macular and inherited retinal dystrophies*\n\n*Initially written Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/leber-congenital-amaurosis", "markdown_url": "https://www.edgepedia.org/leber-congenital-amaurosis.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Leber congenital amaurosis\", Edgepedia (EdgeChat), https://www.edgepedia.org/leber-congenital-amaurosis. Edgepedia Community License 1.0.", "credit_md": "\"[Leber congenital amaurosis](https://www.edgepedia.org/leber-congenital-amaurosis)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/leber-congenital-amaurosis](https://www.edgepedia.org/leber-congenital-amaurosis). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Leber congenital amaurosis\", Edgepedia (EdgeChat), https://www.edgepedia.org/leber-congenital-amaurosis. Edgepedia Community License 1.0.", "speakable": "Leber congenital amaurosis is a group of inherited retinal dystrophies causing severe vision loss or blindness in the first year of life, usually autosomal recessive, involving over 20 genes including CEP290, GUCY2D, CRB1, and RPE65; RPE65-related disease is treatable with Luxturna gene therapy." }