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- Overview
- Clinical phenotype
- Genetics
- Key investigations
- Diagnosis
- Management
- Current research
- Further information and support
- References
- LCA: for patients
Overview
Prevalence |
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Inheritance | |
Genes involved (OMIM No.) | 26 genes identified to date with the most common being: |
Symptoms |
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Ocular features |
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Systemic features | Joubert syndrome (CEP290)
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Key investigations |
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Molecular diagnosis | Next generation sequencing
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Management | Ocular
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Therapies under research |
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Clinical phenotype
Presenting features
LCA/EOSRD form part of a spectrum of inherited retinal dystrophies (IRDs) that cause severe visual loss at an early age. LCA is the most severe phenotype with visual dysfunction evident at birth or within the first year of life. It is characterised by the following features:
- Roving nystagmus
- Amaurotic pupils
- Absent or severely reduced electroretinogram (ERG) signals
- Oculodigital sign (poking, rubbing or pressing of the eye to create a sensation of light) but this is not pathognomonic for LCA
EOSRD is a less severe phenotype which presents after infancy but before the age of five years. Visual function is usually more preserved compared to LCA and ERG signals are minimally detectable.[1]
26 genes have been identified currently that cause LCA/EOSRD and as a result, there is significant inter- and intrafamilial phenotypic variability in terms of signs and symptoms of visual dysfunction, disease progression and clinical findings. Some genes are associated with a severe but stable disease course such as GUCY2D or CEP290 while others gradually progress like those with AIPL1 mutations. In general, visual function remains stable over time in 75% of cases while it can deteriorate in 15% of cases.[2]
Although early onset visual loss and nystagmus are the most prominent features, some children may have other accompanying symptoms like nyctalopia, photophobia or photo-attraction.[2]
Fundal appearance
Due to the genetic heterogeneity, the fundal features are highly variable as well but patients usually have symmetrical ocular findings. It may appear normal in the early stages or display a range of abnormalities which can be indistinguishable from other IRDs. These include:
- Bone-spicule hyperpigmentation, nummular pigmentation, granular appearance, salt-and-pepper appearance, intraretinal white dots, subretinal flecks, retinal pigment epithelium (RPE) mottling/atrophy in the periphery
- Certain genotypes such as CRB1, RDH12, AIPL1 are associated with early onset maculopathies which include pigmentation, atrophy, pseudocoloboma, and/or oedema
- The optic disc may appear normal or there might be pallor, peripapillary atrophy, drusen, papilloedema or pseudopapilloedema
- Blood vessel attenuation

Other ocular features
Apart from the retinal changes, patients may present with the following ocular features which can lead to further visual deterioration:
- High hypermetropia (common in LCA while high myopia is less frequent)
- Keratoconus
- Cataracts
- Enophthalmos
- Strabismus
Associated extraocular features
Syndromic forms of LCA can occur with the following genes:
- CEP290 mutations are associated with Joubert syndrome with renal involvement[3], Senior-Loken syndrome[3] and Meckel Gruber syndrome[4]
- IQCB1 mutations are associated with Senior-Loken syndrome[5]
Clinicians should also be aware that children with such early onset profound visual loss are at risk of developmental delays.
Genetics
Pathogenic mutations in 26 genes have been identified so far that account for 80-90% of cases.[6-8] The most common causative genes are:
- CEP290 (15-20% of cases)
- GUCY2D (10-20% of cases)
- RPE65 (3-16% of cases)
- RDH12 (3.4-10.5% of cases)
- CRB1 (10% of cases)
All the identified causative genes encode proteins that play important roles in several retinal developmental and physiological pathways.
General Function | Genes |
Photoreceptor morphogenesis | AIPL1, CRB1, CRX, GDF6, PRPH2, USP45 |
Photoreceptor differentiation | OTX2 |
Visual cycle | LRAT, RPE65, RDH12 |
Phototransduction | CABP4, GUCY2D, KCNJ13 |
Photoreceptor ciliary transport | CEP290, CLUAP1, IFT140, IQCB1, LCA5, RPGRIP1, SPATA7, TULP1 |
Protein synthesis | IMPDH1, NMNAT1, RD3 |
Stabilisation of protein folding and transport | CCT2 |
Further information about each gene can be found on OMIM and Medline Plus.
Key investigations
Ocular
1) Electrophysiology
Absent or severely reduced rod and cone responses on full-field ERG are diagnostic of LCA. Pattern ERG should be performed to assess macular function.
2) Optical coherence tomography (OCT)
The overall macular structure including the photoreceptor outer segment and RPE integrity can be ascertained through OCT. This will help determine if patients are eligible for retinal gene therapy such as those with biallelic RPE65 mutations.
Furthermore, certain genotypes have specific macular features which can be easily identified on OCT which can direct genetic testing. For instance, patients with CRB1 mutations have a characteristic thickened retinal appearance.

3) Fundus autofluorescence imaging (FAF)
FAF is done to assess RPE integrity. Similar to OCT, it can also aid in guiding genetic investigation. Patients with RDH12 mutations display radial hypoautofluorescent regions of RPE atrophy with a surrounding rim of hyperautofluorescence, along with the sparing of para-arteriolar and peripapillary AF.
Patients harbouring mutations in the genes involved in the visual cycle (RPE65 and LRAT) usually have diffusely reduced or absent AF due to the lack of chromophore production.


4) Kinetic perimetry
To establish baseline visual field.
Systemic
Due to potential extraocular manifestations in certain genotypes of LCA/ESORD, babies and children should be referred to a paediatrician for a general paediatric work up which usually include:
- General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
- MRI brain imaging (e.g. classic molar tooth sign in Joubert syndrome)
- Echocardiogram if suspicious of heart abnormalities
- Renal ultrasound
- Developmental assessment
Diagnosis
New patients should be under joint care with a paediatrician to investigate for any syndromic associations and monitoring the child’s development. Genetic testing should be undertaken to obtain a molecular diagnosis and direct future management.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (retinal)
- Whole exome sequencing
- Whole genome sequencing
Related links
- Genomics England PanelApp for inherited retinal dystrophies
- Clinical genetic testing: for professionals
Management
Ocular
1) Supportive management
- Correcting any refractive errors
- Referral to low vision services
- Directing patients to supporting organisations
- Encourage the use of assistive technology that may improve quality of life
- Monitoring for associated complications such as cataracts and keratoconus
- Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
- UV protected sunglasses
- Blue light screen protectors on mobile devices or computer screens*
*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.
2) Gene Therapy
Patients with confirmed biallelic RPE65 mutations in the UK (and other countries around the world) are now able to receive retinal gene therapy with voretigene neparvovec (Luxturna) under the National Health Service (NHS). A normal healthy copy of the RPE65 gene is packaged into a recombinant adeno-associated virus (AAV) serotype 2 vector which is then injected sub-retinally to replace loss-of-function variants in the photoreceptors.

This followed the success of a phase 3 trial which demonstrated that 65% of participants injected with Luxturna were able to navigate around an obstacle course at reduced light levels compared to controls. This improvement has been sustained up to 4 years after vector administration according to this report.
The safety profile of sub-retinal AAV2 injections has been well established in numerous trials (Hauswirth et al 2008, Bainbridge et al 2008, Jacobson et al 2012 and Weleber et al 2016). The side effects frequently reported in trials are related to the surgical procedure itself, which include:
- Subconjunctival haemorrhage
- Ocular hyperaemia
- Post-operative ocular inflammation
- Ocular hypertension
Treatment centres in the UK currently offering Luxturna treatment:
- Great Ormond Street Hospital for Children, London (for children below 10 years of age)
- Moorfields Eye Hospital, London (for children and adults)
- Manchester Royal Eye Hospital
- Oxford Eye Hospital
Systemic
A multidisciplinary approach is recommended for children affected by LCA (syndromic and non-syndromic). Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.
The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.
Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.
Family management and counselling
Most cases of LCA/EOSRD display an autosomal recessive inheritance pattern but autosomal dominant cases have been reported with de novo pathogenic variants in CRX, OTX2 and IMPDH1 genes.[9-11]
Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.
Emotional and social support
Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.
Related links
Referral to a specialist centre
In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.
In the UK, patients with confirmed biallelic RPE65 mutations can be referred to one of the four Luxturna centres to evaluate if they are suitable for treatment.
Current research in LCA/EOSRD
1) Gene therapy
RPE65
A second-generation gene therapy candidate utilising AAV5 vectors called AAV2/5-OPTIRPE65 has been developed to increase the efficiency of transferring the normal RPE65 gene copy into the retinal cells. A phase 1/2 clinical trial (NCT 02781480) has been conducted and the 6-month interim data showed that it was generally well tolerated with a safety profile consistent with other approved and investigational ocular gene therapies.
GUCY2D
A phase 1/2 trial (NCT 03920007) investigating the safety and tolerability of ascending doses of unilateral subretinal SAR439483 (AAV5-GUCY2D) injections is currently ongoing.
2) Antisense RNA oligonucleotides (AONs)
AONs are small molecules that bind complementarily to their target messenger RNAs (mRNA) to block the transcription of a mutant allele or correcting splice defects at the pre-mRNA level.[12] It is being trialled in a phase 1/2 setting (NCT 03140969) on patients with the most common CEP290 mutation causing LCA in Europe and the US, which is the c.2991+1655 A>G mutation in intron 26.[13,14] This mutation introduces a pseudo-exon with a premature stop codon to about 50–75% of the CEP290 mRNA transcripts.[13]
In the trial, the AON, also known as QR-110 (Sepofarsen) is injected intravitreally on a 3-monthly basis. The interim results suggested that it was well tolerated and a visual benefit was observed at 3 months for most participants. This improvement was maintained at 6 months for those who received a second dose at month 3. Due to such promising results, this trial has been expanded to a phase 2/3 study (ILLUMINATE)
3) CRISPR/Cas9 genome editing system
CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9) is a recently discovered RNA-based genome editing technology that works like a pair of molecular “scissors”. Directed by complementary guide RNAs (gRNAs), it is able to cut a mutated DNA sequence at the precise location and introduce the normal sequence.
This system is currently being investigated in a phase 1/2 trial (NCT 03872479) for patients with the common c.2991+1655 A>G mutation in CEP290. Known as EDIT-101, a pair of staph aureus Cas9 gRNAs are used to direct the Cas9 enzyme to cut the two flanking regions of the mutated sequence which corrects the splice defect. The gRNAs and Cas9 are delivered sub-retinally with an AAV5 vector.
Related links
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
Further information and support
References
- 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;101(9):1147-1154
- den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27(4):391-419
- Valente EM, Silhavy JL, Brancati F, et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet. 2006;38(6):623-625
- Frank V, den Hollander AI, Brüchle NO, et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Human Mutation. 2008;29(1):45-52
- Yu PH, Kuo YR, Altmuller J, Hwang DY. Senior-Loken syndrome with IQCB1 mutation in Taiwan. Kaohsiung J Med Sci. 2018;34(10):588-589
- Yi Z, Ouyang J, Sun W, et al. Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. J Med Genet. 2019;56(5):325-331
- Thompson JA, De Roach JN, McLaren TL, et al. The genetic profile of Leber congenital amaurosis in an Australian cohort. Molecular genetics & genomic medicine. 2017;5(6):652-667
- Bernardis I, Chiesi L, Tenedini E, et al. Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing. BioMed research international. 2016;2016:6341870-6341870
- Perrault I, Hanein S, Gerber S, et al. Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele. Journal of Medical Genetics. 2003;40(7):e90-e90
- Bowne SJ, Sullivan LS, Mortimer SE, et al. Spectrum and Frequency of Mutations in IMPDH1 Associated with Autosomal Dominant Retinitis Pigmentosa and Leber Congenital Amaurosis. Investigative Ophthalmology & Visual Science. 2006;47(1):34-42
- Henderson RH, Williamson KA, Kennedy JS, et al. A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction. Mol Vis. 2009;15:2442-2447
- Collin RW, Garanto A. Applications of antisense oligonucleotides for the treatment of inherited retinal diseases. Curr Opin Ophthalmol. 2017;28(3):260-266
- den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79(3):556-561
- Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2007;28(4):416