Major reviewAn overview of leber congenital amaurosis: a model to understand human retinal development
Introduction
The purpose of this review article is to summarize recent advances in our understanding of Leber congenital amaurosis (LCA), a rare but important juvenile retinal dystrophy. LCA was first described in 1869 by Theodor Leber42 and is at the center of an international attempt to understand its clinical and molecular features and their correlations. In the past decade, nine genetic loci for LCA have been discovered,13., 16., 26., 36b., 48., 50., 60., 67., 71. of which six genes have been identified. The three main points in this review are to provide evidence that LCA is a model for ophthalmologists and scientists to gain a greater understanding of normal and aberrant human eye development, in particular the molecular events that participate in retinal development. Also, LCA illustrates the complexities created by clinical and genetic heterogeneity of a retinal disorder, and thirdly, recent studies have led to a new view that LCA is not one disorder, but multiple disorders, which may be classified into three types of disease categories: an aplasia, with abnormal embryological formation of photoreceptors; a degeneration, with early, progressive photoreceptor cell death; and a dysfunction, in which the retinal anatomy remains normal, but a key biochemical message is missing, although the evidence for the existence of a dysfunction is scanty. Evidence for the existence of three LCA disease categories comes from four sources: 1) Data from longitudinal clinical studies of visual function; 2) Histopathological reports on adult LCA globes; 3) New molecular genetic information; and 4) Insights gained from LCA animal models with targeted disruptions of the LCA genes. This information is brought together in this review to test the hypothesis that at least three types of LCA disease exist. Future therapies for retinal cell rescue, in the form of retinal cell transplants, gene replacement, or medical therapies will be discussed in the context of LCA. Therapies may not be far off, as gene-therapy of the Briard dog has shown proof of principle. LCA may therefore be approached in a gene-therapy trial. Probably, these therapies will be gene, cell, and/or disease type specific, making genotype-phenotype correlation studies vital.
Section snippets
Clinical description of the LCA phenotype and its variability
Leber congenital amaurosis (LCA, MIM 204000) is an important congenital retinal form of blindness with a worldwide prevalence of 3 in 100,000 newborn babies.5 It accounts for ≥ 5% of all inherited retinopathies and approximately 20% of children attending schools for the blind around the world.64 LCA was first described by a German ophthalmologist named Theodor Leber over 130 years ago (in 1869) while working as an ophthalmic consultant for the Ilvesheim school for the blind in Germany.42 His
Differential diagnoses of congenital retinal blindness
As in other eye diseases the differential diagnosis of congenital blindness, which includes LCA, can be difficult. Differentiating these various entities is especially important for four separate reasons: 1) Some forms of congenital blindness are associated with systemic disease, others are confined to the eye; 2) Some forms of disease are stationary, others are progressive; 3) Future potential therapies with gene replacement, cell transplants, or drugs will be disease-specific; and 4) For
Longitudinal natural history studies of visual function in LCA
Most retinal dystrophies such as RP are slowly progressive with loss of visual field, increase in nightblindness and eventually legal blindness, when central visual loss ensues. Other retinal dystrophies such as achromatopsia and CSNB are stationary. The prognosis for patients with LCA is more complex, as it may be possible to divide the natural history of visual function of LCA patients into three groups. Three longitudinal studies of visual function in LCA are available in the literature.
Retinal anatomy
The retina is an exquisitely delicate diaphanous nervous membrane of neuro-ectodermal origin and is made up of a single layer of cuboidal cells: the retinal pigment epithelium (RPE) and a three layered neurosensory retina. The RPE is a layer of pigmented cells and provides the outer blood-retinal barrier, nourishes the photoreceptors, recycles vitamin A, commences phagocytosis of the photoreceptor disks and other wastes, induces retinal development during embryogenesis, and is involved in
Retinal physiology
In the retina, photoreceptor cells convert light energy into an electrical signal through a phototransduction process (Fig. 3) that consists of an enzymatic cascade, and is similar for rods and cones, but the details are better worked out in the rods. In summary, this cascade is a sequence of enzymatic reactions, that captures a photon of light and converts this electromagnetic stimulus into biochemical messengers and ultimately into a neurological excitation and visual cortex stimulation.
Histopathological features of LCA and its variability
Histopathological studies of LCA are important to understand the disease process and before potential therapies such as cell transplants, gene replacement, and drugs are tested, it is imperative to recognize possible disease subtypes. By studying the pathological changes of the LCA retinas, it may be possible to discern which cell type or which retinal layer is affected by the disease process and which is spared. Different therapeutic strategies may not be universally effective and may be
Genetic aspects of LCA
LCA has a multigenic basis, and is proving central to our understanding of the molecular developmental biology of the retina and the human eye. LCA is usually inherited in an autosomal recessive manner.5., 42. but autosomal dominant cases have been reported.9., 23., 70.
Ever since the report of Waardenburg of normal sighted children from two LCA parents, it has been suspected that LCA has a multigenic basis,81 and since 1996, six genes with disparate functions have been implicated in LCA. Table 4
Biochemical aspects of LCA
GUCY2D encodes the protein retinal guanylate cyclase, RetGC-1, which is a photoreceptor specific enzyme that is involved in the recovery of the phototransduction cascade (see section VI and Fig. 3). Two membrane guanylyl cyclases, RetGC-1 and RetGC-2, have been identified in human photoreceptor cells. Their function is to replenish cGMP in the retina which has been depleted by light-activated phosphodiesterase. GUCY2D is expressed in the photoreceptor outer segments, but at higher levels in
Animal models for LCA
Animal models have been developed recently to study hereditary eye diseases at the cellular and biochemical level (Table 5). This is important for human diseases because histological and/or biochemical analyses of the retina can be done in the animal models at different stages of the disease's evolution, especially before all the cells have died. Intervention and/or manipulation can be attempted at different stages (cell transplants of rods, cones, or RPE cells, neurotrophic factors, and gene
Therapeutics of hereditary retinal degenerations
Recent research in the field of retinal degenerations has prompted the cautious expectation that photoreceptor cell diseases may become treatable in the near future. It is generally agreed that these treatments may be divided into three separate therapeutic groups: photoreceptor cell and/or RPE cell transplantation or replacement, gene replacement, and pharmacological intervention. Each group will be discussed in detail. Although animal studies are very promising, none of the therapies have
Method of literature search
The author conducted searches of PubMed and OMIM (1964–2003). Search words included Leber congenital amaurosis, LCA, juvenile retinal dystrophies, retinitis pigmentosa, retinal gene therapy, retinal cell transplantation, and artificial vision. Only those articles that covered the clinical, molecular, and therapeutic aspects of the above topics were selected.
Acknowledgements
The author gratefully acknowledges the help and support from Ms. Claudine Robert and Ms. Emily Simmonds. This work could not have been done without the LCA children and their parents and families. The author also acknowledges the MRC Canada (now CIHR), FRSQ from Quebec, and the Foundation Fighting Blindness of Canada for their financial support. The author reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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