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Leber Congenital Amaurosis: Clinical, Genetic, and Therapeutic Perspectives 

Leber Congenital Amaurosis: Clinical, Genetic, and Therapeutic Perspectives
Chapter:
Leber Congenital Amaurosis: Clinical, Genetic, and Therapeutic Perspectives
Author(s):

Robert K. Koenekoop

, Frans P.M. Cremers

, Irma Lopez

, and Anneke I. den Hollander

DOI:
10.1093/med/9780195326147.003.0034
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date: 29 March 2020

Much has changed in our understanding of LCA in the past 12 years and since our last writing of this chapter in 1998. Today, we know through genetic analysis that there are at least 16 LCA genes, encoding proteins with heterogeneous retinal functions. The currently known genes and mutations are responsible for the disease in about 70% of the patients. We suspect that there are many more causal genes for LCA, and that most will be mutated in a small number of patients; they will be harder to find. These genetic discoveries have thus far allowed us to identify proteins, pathways, and functions that have led to understanding of some of the pathophysiologic mechanisms underlying LCA. LCA is a unique group of disorders with relatively well-defined molecular boundaries that is distinct from systemic disorders associated with a phenocopy of the retinal disorder. Animal models, as well as retinal protein and biochemical studies have demonstrated that LCA is a group of diseases unified by the clinical triad of congenital or very early onset of visual loss, nystagmus, and non-detectable ERG responses. LCA can be caused by defects in at least five retinal pathways. Defects in phototransduction (GUCY2D, AIPL1, RD3), retinoid cycle (RPE65, LRAT, RDH12), photoreceptor development (CRX, CRB1), ciliary transport function (CEP290, NPHP5, LCA5, TULP1, RPGRIP1, SPATA7), guanine synthesis (IMPDH1), and phagocytosis by the RPE (MERTK1) have all been described. Clinical studies suggest that photoreceptors in specific genetic types are viable but dormant and not responding to visual stimuli. If therapy is to be instituted before photoreceptors eventually die, early diagnosis is necessary, and rapid and accurate genetic testing needs implementation, so that patients can be prepared for clinical trials and eventual treatments. Clinical experience and genotype-phenotype correlations suggest that the gene defect may be predictable from the retinal appearance and other characteristic features of the phenotype. Gene augmentation and new drug studies in mice, dogs, and recently humans with LCA have shown remarkable and long-term recovery of photoreceptor function and rescue of visual function. Currently, several LCA trials are testing gene and drug therapy in humans, and early safely and success have been reported.

In 12 years, LCA has gone from an obscure, important, devastating, incurable retinal dystrophy to a model disease for understanding mendelian inheritance, the importance of genetic testing, and normal retinal development and physiology. Foremost, LCA has become the prototype retinal dystrophy that is amenable to therapy.

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