Abstract
Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.
Highlights
Inherited retinal dystrophies (IRDs) are a group of diseases caused by genetic mutations that are characteristic of photoceptor dysfunction and eventual death of retinal cells
A non-detectable electroretinogram (ERG) response is typical in Leber’s congenital amaurosis (LCA), a residual cone response could be detected with mutation in GUCY2D, and a residual rod response in RPE65 [10]
The common phenotype of RPE65-associated LCA includes profound nyctalopia at birth; some residual cone-mediated vision has been observed in these cases
Summary
Inherited retinal dystrophies (IRDs) are a group of diseases caused by genetic mutations that are characteristic of photoceptor dysfunction and eventual death of retinal cells. Among the diverse phenotypes and genotypes within IRDs, Leber’s congenital amaurosis (LCA) is one of the earliest and most severe forms of IRDs. In 1869, Dr Theodore Leber first described severe visual impairment in infants with nystagmus and poor pupillary light reflex, which were recognized as typical presentations of the later-named LCA [2]. A milder phenotype of LCA with relative visual preservation has been considered as early-onset severe retinal dystrophy, their genetic basis overlaps significantly [7]. Owing to the diversity in genetic background, disease presentation, and early onset in infancy, it is challenging but important for ophthalmologists to obtain a definitive diagnosis in preliminary consultations. This review aims to summarize the clinical manifestations and genetic updates of LCA, as well as show the genotype-phenotype correlations in LCA to promote early diagnosis and facilitate bridging therapies in the near future
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