Leber Congenital Amaurosis

Key points at a glance

Key Points at a Glance

• Leber congenital amaurosis (LCA) is the most severe form of congenital retinal dystrophy, causing severe visual impairment from birth to infancy.
• Most cases are autosomal recessive, and about 27 causative genes have been identified to date.
• Nystagmus, reduced or absent pupillary response, and oculodigital sign are characteristic clinical findings.
• Electroretinography (ERG) showing absent or severely reduced rod and cone responses is key to diagnosis.
• Most patients have visual acuity of 0.1 or less, and about one-third have no light perception.
• Gene therapy (voretigene neparvovec/Luxturna®) for LCA2 due to RPE65 mutations was approved in Japan in 2023, but it applies to only about 8% of all LCA cases.
• For other types, no effective treatment has been established; management focuses on refractive correction, vision training, and low vision care.

1. What is Leber Congenital Amaurosis?

Leber congenital amaurosis (LCA) is the most severe form of congenital retinal dystrophy, causing severe visual impairment from birth to infancy. It is a major cause of childhood visual impairment and is known as a representative cause of congenital visual impairment. Clinical manifestations are diverse.

It was first reported in 1869 by the German ophthalmologist Theodor Karl Gustav von Leber (1840–1917). Note that Leber hereditary optic neuropathy (LHON), reported by the same Leber in 1871, is a mitochondrial disease that develops around age 20 and is completely different from LCA. In 1957, the absence of waveforms on electroretinography (ERG) was confirmed as a common feature of LCA diagnosis, establishing the disease name.

The estimated birth prevalence is 2–3 per 100,000 births (1/30,000 to 1/81,000)¹⁾. Some reports cite 1:80,000 to 1:200,000, showing variability²⁾. LCA accounts for about 5% of all retinal dystrophies, and about 20% of visually impaired children attending schools for the blind have LCA¹⁾. Currently, about 27 LCA-associated genes have been identified²⁾, and causative genes are identified in about 70–80% of cases²⁾. The inheritance pattern is mainly autosomal recessive, but autosomal dominant and X-linked inheritance have also been reported.

Q When is Leber congenital amaurosis usually detected?

A

Parents often notice nystagmus or lack of fixation around 6 weeks of age³⁾. When severe poor visual response (complete inability to fixate or follow) is observed, LCA is suspected and confirmed by electroretinography.

2. Main Symptoms and Clinical Findings

Fundus photographs, fundus autofluorescence, and OCT of both eyes in Leber congenital amaurosis, showing retinal pigment epithelium changes and outer retinal damage

Higa N, et al. A novel RPE65 variant p.(Ala391Asp) in Leber congenital amaurosis: a case report and literature review in Japan. Front Med (Lausanne). 2024. Figure 1. PMCID: PMC11446184. License: CC BY.

A 27-year-old patient: (A) Fundus photographs of both eyes showing retinal pigment epithelium depigmentation and retinal vascular attenuation; (B) Fundus autofluorescence showing hyperautofluorescence and signal loss in affected areas; (C) OCT showing loss of the ellipsoid zone (EZ) in the right eye and minimal residual EZ at the fovea in the left eye. Corresponds to retinal pigment epithelium degeneration and retinal vascular attenuation discussed in section “2. Main symptoms and clinical findings”.

Subjective symptoms

Severe visual impairment is present from birth or early infancy.

• Visual acuity loss: Most patients have visual acuity of 0.1 or less, and about one-third have no light perception. Visual impairment is generally stable or progresses very slowly.
• Photophobia: Many patients show sensitivity to light.
• Night blindness: Visual function in dark conditions is further reduced.

Parents often notice nystagmus or lack of fixation around 6 weeks of age ³⁾.

Clinical findings (findings confirmed by physician examination)

• Nystagmus: Appears at birth or soon after. It is pendular or wandering and present in all gaze positions. This is an important distinguishing feature from early-onset severe retinal dystrophy (EOSRD), which does not involve nystagmus ²⁾.
• Abnormal pupillary response: The pupillary light reflex is sluggish or absent. This is called “amaurotic pupils.”
• Oculo-digital sign: Poking, pressing, or rubbing the eyes, thought to be an attempt to mechanically stimulate the retina to elicit visual sensations. The main sequela is enophthalmos due to orbital fat atrophy.
• Refractive error: High hyperopia (>5 diopters) is common, thought to result from impaired emmetropization due to early visual impairment.

Retinal findings

In infancy, the fundus often appears normal, but various findings appear later. Fundus findings range from normal to typical retinitis pigmentosa-like appearance. In advanced cases, the optic disc becomes pale, blood vessels become extremely attenuated, the overall fundus color darkens, and the foveal reflex disappears.

• Optic disc pallor and retinal vascular attenuation
• Salt-and-pepper fundus: retinal pigment epithelium degeneration with small white spots and depigmentation
• Bone-spicule pigmentation and subretinal flecks (marbled fundus)
• Macular degeneration and Coats-like exudation
• Pigmented nummular lesions

OCT and FAF findings

On OCT, the outer retinal layers are almost absent, with thinning to loss of the ellipsoid zone (IS/OS junction) being characteristic. Findings vary by genotype:

• CRB1 mutation: paradoxical finding of increased retinal thickness (coarse lamination)¹⁾
• RPE65 mutation: absence of FAF (fundus autofluorescence)²⁾
• GUCY2D mutation: preserved normal FAF²⁾
• NMNAT1 mutation: macular coloboma-like atrophy

Complications

Keratoconus, cataracts, and glaucoma increase in frequency with age.

Systemic findings

LCA is classified into simple type with only ocular symptoms and complex type with systemic involvement.

Simple type

Ocular symptoms only: Visual impairment is the main feature, without systemic abnormalities.

Moderate to high hyperopia: Common in cases without systemic abnormalities.

Complex type

Central nervous system abnormalities: Cerebellar vermis hypoplasia, brainstem malformations.

Psychomotor retardation: Some cases have intellectual disability.

Renal impairment: May be associated with cystic kidney disease.

Others: Hearing loss, skeletal abnormalities, liver disease, metabolic disorders, epilepsy.

Q What is the purpose of the oculo-digital sign (eye rubbing)?

A

This is a characteristic behavior in LCA patients, thought to mechanically stimulate the retina by poking or pressing the eyes with fingers, attempting to evoke visual sensations. Repeated over time, it leads to atrophy of orbital fat and causes enophthalmos.

3. Causes and Risk Factors

LCA is a group of inherited retinal degenerative diseases, most of which follow an autosomal recessive inheritance pattern²⁾. Rarely, mutations in CRX, IMPDH1, or OTX2 show autosomal dominant inheritance²⁾. X-linked inheritance has also been reported.

Currently, 19 types (LCA1 to LCA19) and 8 additional related genes have been reported²⁾. The causative genes are involved in multiple pathways related to retinal development and function, including photoreceptor morphogenesis, phototransduction cilia, and the visual cycle.

LCA-associated genes are classified into five major functional networks²⁾:

1. Retinoid metabolism / rod visual cycle (RPE65, LRAT, RDH12)
2. Retinal homeostasis maintenance / photoreceptor maintenance (AIPL1, SPATA7, TULP1, USP45, CRB1, LCA5)
3. Retinal development / morphogenesis (RD3, CEP290)
4. Light detection / visual perception (GUCY2D, CNGA3)
5. Photoreceptor connecting cilium / outer segment maintenance (CEP290, RPGRIP1, RPGR)

The most frequently mutated genes worldwide and their proportions are as follows:

Gene	Proportion	Pathway involved
CEP290	Approximately 15%	Ciliary function
GUCY2D	Approximately 12%	Phototransduction (cGMP synthesis)
CRB1	Approximately 10%	Cell polarity maintenance
RPE65	Approximately 8%	Retinoid metabolism

In a Japanese cohort (34 families), NGS analysis showed a detection rate of about 56%, with the most frequent mutated genes reported as CRB1, NMNAT1, and RPGRIP1¹⁾.

Identification of the causative gene directly determines treatment eligibility. In particular, confirmation of RPE65 mutation is essential for determining eligibility for gene therapy (voretigene neparvovec)²⁾.

AIPL1 functions as a specific chaperone for phosphodiesterase 6 (PDE6), which is responsible for cGMP degradation in phototransduction. AIPL1 deficiency leads to a dramatic reduction in PDE6 protein levels, resulting in cGMP metabolic disruption, photoreceptor degeneration, and early blindness²⁾. AIPL1 mutations account for approximately 5–10% of all LCA cases²⁾.

About genetic counseling

In autosomal recessive inheritance, siblings of an affected child have a 25% chance of being affected and a 50% chance of being asymptomatic carriers. If the causative mutation is known, carrier testing and prenatal diagnosis are possible. It is recommended to undergo genetic counseling.

Q What is the probability that the next child will also have LCA?

A

In autosomal recessive inheritance, if both parents are carriers, the probability that the next child will be affected is 25%, the probability of being a carrier is 50%, and the probability of being unaffected and non-carrier is 25%. If the causative gene is identified, prenatal diagnosis or preimplantation genetic diagnosis are options.

4. Diagnosis and testing methods

The diagnosis of LCA is made clinically, and confirmation requires electroretinography for definitive diagnosis and genetic testing for molecular genetic confirmation²⁾.

LCA is suspected when there is a congenital marked lack of visual response (lack of fixation and tracking). In infants with severe visual impairment and high hyperopia, molecular genetic testing for LCA is the first choice⁴⁾.

The main diagnostic tests are shown below.

Test	Findings/Features
Electroretinogram (ERG)	Non-recordable to severely reduced in both scotopic and photopic conditions. Essential.
OCT (Optical Coherence Tomography)	Retinal atrophy, loss of outer layers, loss of ellipsoid zone.
FAF (Fundus Autofluorescence)	Varies by subtype (absent in RPE65 type, normal in GUCY2D type).
Genetic testing (NGS, etc.)	Required for definitive diagnosis and subtype identification.

• Electroretinogram: Both rod and cone responses are absent to severely reduced. A normal ERG rules out LCA.
• OCT: The outer retinal layers and ellipsoid zone are mostly absent. CRB1 mutations show paradoxical retinal thickening (coarse lamination) ¹⁾. Handheld OCT is useful for examining awake infants or young children under anesthesia ⁴⁾.
• FAF: Findings vary by subtype. GUCY2D mutations show preserved autofluorescence, while RPE65 mutations show absent autofluorescence ²⁾.
• Genetic testing: Next-generation sequencing (NGS), DNA microarrays, and linkage analysis are used. The overall detection rate is approximately 70–80% ²⁾. Since 2023, a panel test for 82 IRD causative genes (PrismGuide IRD Panel) has been covered by insurance and is applied to young-onset patients suspected of having RPE65-related IRD.

Caution regarding fundus findings in infancy

In infancy, the fundus often appears normal, and fundus abnormalities appear later in life. There are no retinal lesions that are pathognomonic for LCA or specific to a particular subtype. Due to the diversity of clinical phenotypes and genetic overlap with other inherited retinal diseases, genetic testing is essential for a definitive diagnosis.

Differential Diagnosis

• Early-onset retinitis pigmentosa (RP): Onset is later than LCA, and central vision is well preserved. It is not accompanied by nystagmus.
• Early-onset severe retinal dystrophy (EOSRD): Severe vision loss after the first year of life without nystagmus ²⁾.
• Achromatopsia: Shows photophobia and characteristic electroretinogram changes.
• Congenital stationary night blindness: Accompanied by myopia, better visual acuity than LCA, and a characteristic electroretinogram pattern.
• Joubert syndrome: Associated with cerebellar vermis hypoplasia, nephronophthisis, and early-onset retinal dystrophy.

5. Standard Treatment

For most types of LCA, no substantial treatment has been established. Current management is as follows.

• Correction of refractive errors: Provide appropriate refractive correction for high hyperopia, etc. Since strong refractive errors may be present, prescribe glasses and strive for vision training.
• Vision training: Provide visual rehabilitation to maximize the use of residual visual function.
• Vision substitution training: Because visual function is severely impaired, consider Braille instruction, white cane walking training, use of magnifying reading devices, etc.
• Low vision care: Support the use of low vision aids and optimal access to education and employment opportunities.
• Genetic counseling: Recommended for families and patients. Carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis may be possible.
• Management of photophobia: Use of tinted glasses and reduction of light exposure are recommended.
• Regular follow-up: Perform ophthalmologic follow-up including electroretinography, and refer to a low vision clinic as needed.

Family Support

When diagnosed in early childhood, parents often have strong anxiety about the future, so care by a specialist for the family is also necessary. Although there is currently no curative treatment, advances in gene therapy, artificial vision, and regenerative medicine are expected, and appropriate information provision and psychological support for patients and families are important.

Gene therapy (voretigene neparvovec)

In 2017, the US FDA approved voretigene neparvovec-rzyl (brand name Luxturna) as a treatment for LCA2 associated with biallelic RPE65 mutations. This is the first FDA-approved gene therapy product in ophthalmology. In 2023, it was also approved in Japan (product name: Luxturna® injection).

A recombinant adeno-associated virus (rAAV2) vector delivers a normal copy of the RPE65 gene to the retinal pigment epithelium via subretinal injection. The procedure is performed in a vitreous surgery operating room.

Phase III 301 trial (Russell 2017)⁵⁾:

• Subjects: 31 patients with RPE65-associated IRD
• Primary endpoint: MLMT (multi-luminance mobility test; an observational test of mobility under various light levels)
• Significant improvement was also observed in full-field stimulus threshold (FST)

Phase I/III long-term results (Maguire 2019)⁶⁾:

• Retinal sensitivity, visual acuity, and functional gains that peaked at 6–12 months after treatment showed a tendency to progressively decline thereafter
• Improvement in night blindness and visual field can be expected due to increased retinal sensitivity

Domestic Phase III trial (A11301 trial) (Fujinami 2025)⁷⁾:

• Subjects: 4 Japanese patients with RPE65-associated IRD
• Significant sensitivity increase in FST (full-field stimulus threshold) (defined as a sensitivity increase of more than 10-fold)
• Visual field expansion was confirmed at 1 year after administration
• Main adverse events: ocular disorders including eye pain (presumed to be related to the administration procedure)

Administration protocol:

• The second eye is administered at least 6 days after the first eye.
• Immunosuppression: Start steroids 3 days before administration and continue for 14 days after administration.

However, RPE65 mutations account for only about 8% of all LCA patients. For other mutation types, there is currently no proven treatment.

Limitations of gene therapy

Long-term follow-up of Phase I/III studies has shown that the clinical benefit, which peaks at 6–12 months after treatment, progressively declines⁶⁾. In addition, perifoveal chorioretinal atrophy has been reported as a long-term complication⁸⁾. Since gene therapy-associated uveitis (GTAU) can occur in up to 50% of cases postoperatively, appropriate immunosuppression and follow-up are necessary⁹⁾.

Q Can gene therapy be used for all LCA patients?

A

Currently, the approved gene therapy (voretigene neparvovec / Luxturna® injection) is indicated only for LCA2 caused by biallelic RPE65 mutations. RPE65 mutations account for about 8% of all LCA cases, so the majority of patients are not eligible. Treatments for other genotypes are still in the research stage.

Q How can I receive gene therapy in Japan?

A

Eligibility requires confirmation of biallelic RPE65 mutations and sufficient viable retinal cells. Genetic diagnosis using a gene panel test (PrismGuide IRD panel) is the first step. Referral to a specialized facility with experience in treating inherited retinal diseases is recommended.

6. Pathophysiology and detailed mechanism of onset

The pathophysiology of LCA is related to the disruption of the visual cycle, which prevents the eye from transmitting light information.

The visual cycle is a series of enzymatic reactions between the retinal pigment epithelium (RPE) and the neurosensory retina, metabolizing dietary vitamin A to produce 11-cis retinal, which generates photopigments. Without 11-cis retinal, the phototransduction cascade cannot be initiated, and visual nerve signals are not transmitted to the visual cortex. Mutations in any of the genes encoding proteins involved in this cascade can block the visual cycle and cause LCA symptoms.

Histopathologically, involvement of the outer retina and photoreceptors has been demonstrated, suggesting that LCA is a degenerative process rather than a malformation.

Major causative genes and their functions

• GUCY2D (LCA1): Encodes retinal-specific guanylate cyclase (GC-E). Catalyzes cGMP synthesis and is key to phototransduction. Over 140 disease-associated mutations have been identified, 88% causing autosomal recessive LCA. Amino acid 838 is known as a mutation hotspot ²⁾.
• RPE65 (LCA2): Belongs to the carotenoid cleavage oxygenase superfamily. It is a bifunctional enzyme that catalyzes O-alkyl ester cleavage from all-trans-retinyl ester and isomerization of the retinyl moiety (all-trans-retinol → 11-cis-retinol) ²⁾. Essential for both rod and cone function, and recent studies suggest it may also be involved in the isomerization of lutein to meso-zeaxanthin ²⁾. It is the only approved indication for gene therapy.
• CRB1 (LCA8): Homologous to the Drosophila crumbs protein, expressed in photoreceptor inner segments and Müller cells. Important for maintaining cell polarity, located on chromosome 1q31.3 ¹⁾.
• CEP290 (LCA10): Involved in ciliary function of photoreceptors. It has the highest mutation frequency among LCA-associated genes (approximately 15%).
• NMNAT1 (LCA9): Encodes a key enzyme in NAD (nicotinamide adenine dinucleotide) biosynthesis ²⁾.
• LCA5: Encodes lebercilin, involved in ciliary function and intraflagellar transport ²⁾.
• AIPL1: Functions as a specialized chaperone for PDE6 (phosphodiesterase 6). AIPL1 deficiency leads to PDE6 instability → cGMP metabolism disruption → channel abnormalities → photoreceptor degeneration ²⁾.

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7. Latest research and future perspectives (reports at research stage)

For patients: Please read

The following content is currently at the research stage or in clinical trials, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Long-term outcomes of gene therapy

Long-term follow-up evaluations of voretigene neparvovec (NCT00481546, NCT00643747) have reported that after an initial peak at 6–12 months post-treatment, clinical benefits including retinal sensitivity, visual acuity, and functional gains progressively decline ⁶⁾. The PERCEIVE study (prospective registry study) reported 2-year safety and efficacy data in real-world clinical practice, with GTAU (gene therapy-associated uveitis) observed in up to 50% of cases ⁹⁾.

CRISPR/Cas9 therapy for CEP290 (EDIT-101)

Developed by Editas Medicine. An AAV5 vector carrying S. aureus-derived Cas9 and two guide RNAs targets the deep intronic mutation (c.2991+1655A>G) in intron 26 of CEP290 ³⁾. Safety was confirmed in a first-in-human trial, showing good tolerability even at relatively high doses ³⁾.

Optogenetics for visual function restoration

As a gene-independent approach, a method to express light-responsive channelrhodopsin in remaining inner retinal neurons is being studied ³⁾. It may be applicable to all LCA types (regardless of genotype), and early clinical trials are ongoing.

Gene therapy for other genotypes

Gene therapy for GUCY2D and AIPL1 mutations is progressing in animal models, showing promising results in rescuing rod and cone photoreceptors.

Prognosis

The course of LCA is classified into three patterns: stable (about 75%), progressive worsening (about 15%), and improvement (about 10%). AIPL1 mutations are associated with progressive worsening, while RPGRIP1 mutations are associated with a stable course. In the future, halting progression or treatment through artificial vision, gene therapy, and regenerative medicine is expected.

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8. References

1. Duan W, Zhou T, Jiang H, Zhang M, Hu M, Zhang L. A novel nonsense variant (c.1499C>G) in CRB1 caused Leber congenital amaurosis-8 in a Chinese family and a literature review. BMC Med Genomics. 2022;15(1):197.
2. Mordà D, Alibrandi S, Scimone C, et al. Decoding pediatric inherited retinal dystrophies: Bridging genetic complexity and clinical heterogeneity. Prog Retin Eye Res. 2025;109:101405.
3. Botto C, Rucli M, Tekinsoy MD, et al. Early and late stage gene therapy interventions for inherited retinal degenerations. Prog Retin Eye Res. 2022;86:100975.
4. Gurnani B, et al. Clinical approach to pediatric nystagmus: a comprehensive diagnostic algorithm. Clin Ophthalmol. 2025;19:1617-1636.
5. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849-860.
6. Maguire AM, Russell S, Wellman JA, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019;126:1273-1285.
7. Fujinami K, Akiyama K, Tsunoda K, et al. Efficacy and safety of voretigene neparvovec in RPE65-retinopathy: results of a phase 3 trial in Japan. Ophthalmol Sci. 2025;5:100876.
8. Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis. Ophthalmol Retina. 2022;6:58-64.
9. Fischer MD, Simonelli F, Sahni J, et al. Real-world safety and effectiveness of voretigene neparvovec: results up to 2 years from the prospective, registry-based PERCEIVE study. Biomolecules. 2024;14:122.