Overview
Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy, accounting for 5% of all retinal dystrophies and 20% of children attending schools for the blind. It presents at birth or within the first year of life with profound visual impairment, nystagmus, and absent or severely reduced ERG responses. LCA is caused by mutations in at least 26 genes involved in phototransduction, retinal development, and photoreceptor maintenance.
Genetics
LCA is predominantly autosomal recessive, with 26 causative genes identified. RPE65 and GUCY2D are the most common, each accounting for approximately 6–16% of cases.
| Gene | Locus | Inheritance | Notes |
|---|---|---|---|
| RPE65 | 1p31.2 | AR | Retinal pigment epithelium 65 kDa protein; first gene therapy target (LUXTURNA®) |
| GUCY2D | 17p13.1 | AR/AD | Retinal guanylate cyclase 2D; most common LCA gene |
| CEP290 | 12q21.32 | AR | Centrosomal protein 290; most common LCA gene in some populations |
| CRX | 19q13.33 | AD/AR | Cone-rod homeobox; transcription factor for photoreceptor development |
| AIPL1 | 17p13.2 | AR | Aryl hydrocarbon receptor interacting protein-like 1 |
| NMNAT1 | 1p36.22 | AR | Nicotinamide nucleotide adenylyltransferase 1 |
Clinical Presentation
Neonatal/Infancy
- Profound visual impairment from birth
- Nystagmus (involuntary eye movements)
- Oculodigital sign (eye poking/pressing)
Early childhood
- Photophobia (light sensitivity)
- Hyperopia (farsightedness)
- Absent or severely reduced ERG
Long-term
- Variable progression depending on genotype
- Keratoconus in some patients
- Associated systemic features in syndromic forms
Diagnosis
- Electroretinogram (ERG): Absent or severely subnormal responses — essential for diagnosis
- Clinical examination: Nystagmus, poor visual behavior, oculodigital sign
- Refraction: High hyperopia common
- Genetic testing: Comprehensive NGS panel covering all 26 LCA genes
- OCT: Variable retinal structure depending on genotype and age
- Fundus: May appear normal early; pigmentary changes develop over time
Current Research & Treatment
LCA caused by RPE65 mutations has the first FDA-approved gene therapy for an inherited retinal disease: voretigene neparvovec (LUXTURNA®, Spark Therapeutics), approved in 2017. Multiple additional gene therapy programs are in clinical trials for CEP290, GUCY2D, and NMNAT1 mutations. Antisense oligonucleotide therapy (sepofarsen) for CEP290 c.2991+1655A>G mutation showed significant visual improvement in trials.
Active Clinical Trials
The following active clinical trials are investigating treatments for Leber Congenital Amaurosis. Trial status and enrollment may change; always verify directly on ClinicalTrials.gov.
Sepul Bio · ASO targeting CEP290 c.2991+1655A>G
Atsena Therapeutics · AAV gene therapy (GUCY2D)
Supporting Organizations
The following nonprofit organizations fund research, support patients, and advocate for advances in the treatment and cure of Leber Congenital Amaurosis.
Foundation Fighting Blindness
VisitThe world's leading funder of IRD research since 1971.
$954M+ raised since 1971Retinal Degeneration Fund (RD Fund)
VisitBridging nonprofit research and commercial IRD therapy development.
$86M deployed in 17 companiesResearch to Prevent Blindness (RPB)
VisitThe leading nonprofit supporting all forms of eye disease research.
$400M+ in total research fundingFighting Blindness Canada
VisitLeading the fight against blindness by funding IRD research in Canada.
Canada's leading IRD research funderFighting Blindness Ireland
VisitDriving IRD research and supporting patients in Ireland.
Target 5000: Ireland's national IRD registry