What is Leber Congenital Amaurosis?
Leber Congenital Amaurosis (LCA) is a family of congenital retinal dystrophies that results in severe vision loss at an early age leading to blindness by the age of one. Various phenotypes (LCA1 to LCA19) with at least 29 genotypes have been identified in around 70-80% of cases of LCA. Dystrophy is a heterogeneous recessive disease and is estimated to affect 1 in 30,000- 81,000 individuals.
Key Takeaways
- Leber Congenital Amaurosis (LCA) is a congenital retinal dystrophy resulting in nystagmus and significantly reduced vision.
- Franceschetti’s oculo-digital sign is characteristic of LCA.
- Luxturna, a gene therapy drug, was approved by the FDA in 2017 for LCA patients with a RPE65 mutation.
Understanding Leber Congenital Amaurosis
Leber Congenital Amaurosis (LCA) is also known as congenital retinitis pigmentosa (RP). Significant visual impairment and nystagmus is usually present from birth in individuals with LCA. One-third of those with LCA have no perception of light. In the early stages, a mild degree of visual improvement can be observed, but may be followed by progressive degradation. It is suggested that LCA is a degenerative process involving the outer retina and photoreceptors. LCA accounts for almost 5% of all retinal dystrophies, and 20% of children with visual impairment in special schools. Cataracts, keratoconus, and oculodigital reflex (eye rubbing or poking) are commonly associated with LCA.
Franceschetti’s oculo-digital sign is characteristic of LCA. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Studies suggest this behavior contributes to deep-set eyes in children with the dystrophy.
Risk Factors for Leber Congenital Amaurosis
The risk factor for LCA is an affected parent and/or parents who are carriers of a mutated gene responsible for one of the 17 LCA subtypes. Genes with known mutations are GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, NMNAT1, CEP290, IMPDH1, RD3, RDH12, LRAT, TULP1, KCNJ13, GDF6, CABP4, CNGA3, ALMS1, IQCB1, and MYO7A. The other genes causing LCA are unknown. CEP290 (15%), GUCY2D (12%), and CRB1 (10%) and RPE65 (8%) are the most frequently mutated LCA genes.
Leber Congenital Amaurosis Symptoms
The symptoms of Leber Congenital Amaurosis may include:
- Nystagmus
- Sluggish or near-absent pupillary responses
- Decreased vision in infancy (20/200 to complete blindness)
- Photophobia
- High hyperopia (>5 diopters)
- Keratoconus
- Nyctalopia
Diagnosing Leber Congenital Amaurosis
When a doctor views the retina in these individuals, it initially appears normal. Over time, a variety of abnormalities may develop. These findings may include chorioretinal degeneration and atrophy centered around the fovea, “bone-spicule” like pigmentation, subretinal flecks, “marbled” fundus, pigmented nummular lesions at the level of the retinal pigment epithelium (RPE), optic disc abnormalities, and a “Coats like” reaction. In advanced cases of LCA, retinal arterioles are attenuated reflecting the metabolic status of the retina. Though rare, LCA may be seen in association with neurodevelopmental delay, intellectual disability, and oculomotor apraxia-type behavior.
Advanced testing can be used to confirm diagnosis. A non-recordable/extinguished or severely reduced scotopic and photopic electroretinogram (ERG) is typical in LCA. Normal ERG responses rule out a diagnosis of LCA. Visual evoked responses are variable. Autofluorescence can measure lipofuscin accumulation in RPE which is related to shed photoreceptor disc elements. The amount of autofluorescence in LCA varies by subtype; autofluorescence is normal in GUCY2D mutation but absent in RPE65 mutations. OCT can be used to see retinal atrophy which is common in LCA. Visual fields can be detectable in some patients, but these are small central islands and on occasion, peripheral islands with the largest and brightest target. Genetic testing may also help with the diagnosis.
Leber Congenital Amaurosis Treatment
There is no treatment or cure for most gene types of LCA. Individuals with the dystrophy can benefit from refractive error correction (glasses or contact) and low-vision aids. There are several ongoing clinical trials for treating LCA, including gene replacement therapy or photo pigment supplementation.
In 2017, The FDA approved voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug for treating patients with confirmed biallelic RPE65 mutation-associated LCA.
