Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision

Cideciyan, Artur V.; Jacobson, Samuel G.

doi:10.1167/iovs.19-26672

Cited by 60 publications

(61 citation statements)

References 99 publications

(230 reference statements)

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“…For IRD, a key driver for genetic testing is the advent of gene-directed interventions including gene augmentation therapies and antisense oligonucleotide treatments. 41 Clinical trials for multiple IRD subtypes are in progress and genetic analysis is required to identify those for whom these treatments might be relevant. Furthermore, IRD can be one of the first presenting features of a syndromic condition such as a ciliopathy (e.g., Bardet-Biedl, Alström [MIM 203800], or Senior-Løken syndrome) or a neurometabolic disorder (e.g., Refsum [MIM 266500] or Batten [MIM 204200] disease).…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Lenassi

Clayton‐Smith

Douzgou

et al. 2020

Genetics in Medicine

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Purpose A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

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Section: Discussionmentioning

confidence: 99%

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Lenassi

Clayton‐Smith

Douzgou

et al. 2020

Genetics in Medicine

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“…Quantitative relation between structure and function. Understanding the relationship between colocalized retinal structure and visual function is key for determining vision improvement potential with treatments in IRDs 40 . Studies of rod-mediated function and retinal structure in extra-foveal regions dominated by rods have been mostly qualitative 10,12,38,39,64,[96][97][98][99][100] .…”

Section: Natural History Of Rod Photoreceptor Dysfunction In Human Irdsmentioning

confidence: 99%

Rod function deficit in retained photoreceptors of patients with class B Rhodopsin mutations

Cideciyan

Jacobson

Román

et al. 2020

Sci Rep

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A common inherited retinal disease is caused by mutations in RHO expressed in rod photoreceptors that provide vision in dim ambient light. Approximately half of all RHO mutations result in a Class B phenotype where mutant rods are retained in some retinal regions but show severe degeneration in other regions. We determined the natural history of dysfunction and degeneration of retained rods by serially evaluating patients. Even when followed for more than 20 years, rod function and structure at some retinal locations could remain unchanged. Other locations showed loss of both vision and photoreceptors but the rate of rod vision loss was greater than the rate of photoreceptor degeneration. This unexpected divergence in rates with disease progression implied the development of a rod function deficit beyond loss of cells. The divergence of progression rates was also detectable over a short interval of 2 years near the health-disease transition in the superior retina. A model of structure-function relationship supported the existence of a large rod function deficit which was also most prominent near regions of health-disease transition. Our studies support the realistic therapeutic goal of improved night vision for retinal regions specifically preselected for rod function deficit in patients. Vision is initiated with the absorption of photons by opsin molecules located in the outer segment antenna of retinal photoreceptor cells. Resulting hyperpolarization of the photoreceptor plasma membrane activates inter-neuronal signaling pathways which reach the visual cortex culminating in perception. Any number of defects along the complex visual pathway can give rise to loss of vision. Monogenic defects causing inherited retinal diseases (IRDs) act primarily at retinal photoreceptors and provide an opportunity to understand detailed mechanism of vision loss. One of the most common IRDs is due to mutations in Rhodopsin (RHO) associated with autosomal dominant retinitis pigmentosa (adRP) 1-4. RHO encodes the opsin molecules expressed only in rod photoreceptors which provide night vision. Thus, the primary consequence of the molecular defect in RHO-adRP is abnormal night vision. Day vision mediated by cone photoreceptors are often affected secondarily through non-cell-autonomous mechanisms. There are currently no approved treatments for RHO-adRP, but promising therapeutic approaches directed to the rod photoreceptors include knock-down-and-replace gene therapy 5 , anti-sense oligonucleotides 6 , and modification of proteasomal activity 7. The human RHO-adRP disease phenotype is well represented by only two classes of mutations 8-13 despite the hypothesized existence of a variety of pathomechanisms in vitro 14,15. Patients with Class A phenotype have severe, early and retina-wide loss of rod photoreceptors with residual visual function originating only from cone cells. In Class B RHO phenotypes on the other hand, loss of rods is limited to certain retinal regions, or sectors, but rods (and cones) are retained in neighboring regi...

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“…LCA is known as the most severe type of IRDs originating at birth . To date, 25 genes have been identified that contribute to the pathogenesis of LCA, both in recessive and dominant modes of inheritance .…”

Section: Discussionmentioning

confidence: 99%

RPE65 and retinal dystrophy: Report of new and recurrent mutations

Safari

Zare‐Abdollahi

Bushehri

et al. 2020

The Journal of Gene Medicine

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Bachground Leber congenital amaurosis (LCA) is a severe and congenital or early onset form of inherited retinitis pigmentosa (RP). To date, approximately 25 genes have been introduced in relation to LCA. In this regard, retinal pigment epithelium‐specific 65 kDa (RPE65) is a well‐known gene mutation that plays a role in the pathogenesis of 5–10% of LCA cases. Methos Two individuals fromseparate families were subjected to ehole exome sequencing (WES). Causativevariants were searched further assessed using Sanger sequencing. Results Here, two families with mutations in the RPE65 gene show severe and early onset LCA, as expected. In addition to the characterization of the phenotype, by reporting a new mutation (c.1451‐1G>A), we further expand the mutation spectrum of RPE65. Likewise, as an interesting aspect of our study, we report on a previously reported RP‐linked mutation associated with severe early onset LCA (c.T200G:p.L67R). Conclusions Considering this variant in different populations, it is likely that it represents a hotspot and affects the function of the coded protein. The variable expressivity of the phenotype can be assumed by the presence of the modifier allele(s) as a result of a different genetic background or the effect of different environments on phenotype expression.

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Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision

Cited by 60 publications

References 99 publications

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Rod function deficit in retained photoreceptors of patients with class B Rhodopsin mutations

RPE65 and retinal dystrophy: Report of new and recurrent mutations

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