Clinical phenotypes in carriers of Leber congenital amaurosis mutations

doi:10.1016/j.ophtha.2004.08.023

Ophthalmology

Volume 112, Issue 2, February 2005, Pages 349-356

https://doi.org/10.1016/j.ophtha.2004.08.023 Get rights and content

Objective

To determine the clinical phenotypes in carriers with probable disease-causing sequence variations in 1 of 6 genes established to cause Leber congenital amaurosis (LCA).

Design

Observational prospective comparative study.

Participants

Thirty carriers with various probable disease-causing sequence variations in 1 of 6 genes known to cause LCA.

Methods

After the establishment of various disease-causing sequence variations in 37 (33.6%) of 110 patients with LCA, we examined a number of carriers who were either parents or offspring and who were willing to participate in our study. Evaluations included assessment of visual acuity, slit-lamp biomicroscopy, dilated fundus examination, and full-field electroretinogram (ERG) measurements.

Main outcome measures

Dilated fundus examination and full-field ERGs.

Results

Of the 30 carriers with probable disease-causing sequence variations for LCA, 5 (16.7%) carriers had an AIPL1 variation, 4 (13.3%) CRB1, 0 (0%) CRX, 5 (16.7%) GUCY2D, 9 (30%) RPE65, and 7 (23.3%) carriers had a RPGRIP1 variation. Twenty-nine (96.7%) carriers had 20/20 or better visual acuity in their better seeing eye with correction. Drusenlike deposits were more selectively observed in carriers with mutations in the AIPL1, CRB1, RPE65, and RPGRIP1 genes, whereas mild peripheral chorioretinal atrophy was only observed in AIPL1 and RPE65 carriers. A reduced dark-adapted isolated rod ERG response and/or maximal combined cone and rod response was recorded in carriers with mutations in the AIPL1, GUCY2D, and RPGRIP1 genes. A reduced light-adapted ERG response to a single-flash and/or 32-Hz flicker was recorded in carriers with mutations in the AIPL1, CRB1, GUCY2D, and RPGRIP1 genes. Overall, our cohort of LCA carriers did not describe significant subjective visual difficulties, including nyctalopia and/or photosensitivity.

Conclusions

The variation of phenotypic expression in carriers among 5 LCA genotypes indicates that there is considerable phenotypic overlap. However, phenotypic trends were noted in carriers' fundus findings and ERG responses for each genetic subtype. Observations of phenotypic associations with specific disease-causing sequence variations in carriers have potential practical value for molecular screening strategies of patients with LCA.

Section snippets

Patients and methods

Informed consent was obtained from all carriers or their legal guardians in accordance with the Declaration of Helsinki. The Institutional Review Board at the University of Illinois Medical Center approved this project. Two of the authors (JAG, GAF) examined 30 carriers from families with various LCA genotypes for both fundus and ERG abnormalities.

Electroretinograms were obtained by either of 2 procedures previously described.14, 15 All ERGs were performed according to International Society for

Results

Classical genetic teaching dictates that recessive mutations cause a phenotype in the affected patient, because both copies of the defective gene are present, but not in the carrier parents and/or children, who carry only 1 copy of the defective allele and are presumably protected by the wild-type allele. Nevertheless, in our cohort, we found that 22 of the 30 LCA carriers (73.3%) had a phenotype determined from detailed ERG measurements and/or careful retinal examination.

Thirty carriers, 17

Discussion

A limited number of reports have previously observed fundus and/or ERG abnormalities in LCA carriers associated with mutations in the AIPL1²² (Invest Ophthalmol Vis Sci 45:5109, 2004), GUCY2D,¹⁸ RPE6523, 24 (Invest Ophthalmol Vis Sci 41[suppl]:4, 2000), and the RPGRIP1 genes (Invest Ophthalmol Vis Sci 45:4728, 2004). As in previous reports, we observed a spectrum of clinical phenotypic expression in our cohort of 30 LCA carriers representing 5 different LCA genotypes. To date, reported

References (30)

M.M. Sohocki et al.
Prevalence of AIPL1 mutations in inherited retinal degenerative disease
Mol Genet Metab
(2000)
T.P. Dryja et al.
Null RPGRIP1 alleles in patients with Leber congenital amaurosis
Am J Hum Genet
(2001)
N.S. Peachey et al.
Rod and cone dysfunction in carriers of X-linked retinitis pigmentosa
Ophthalmology
(1988)
S.G. Jacobson et al.
Automated light- and dark-adapted static perimetry for evaluating retinitis pigmentosa
Ophthalmology
(1986)
R.S. Sitorus et al.
Analysis of three genes in Leber congenital amaurosis in Indonesian patients
Vision Res
(2003)
B.S. Fine
Lipoidal degeneration of the retinal pigment epithelium
Am J Ophthalmol
(1981)
T. Leber
Uber retinitis pigmentosa und angeborene amaurose
Albrecht Von Graefes Arch Ophthalmol
(1869)
A. Franceschetti et al.
Importance diagnostique et prognostique de l'electroretinogramme (ERG) dans les degenerescences tapeto-retiniennes avec retrecissement du champ visuel et hemeralopie
Confin Neurol
(1954)
M.M. Sohocki et al.
Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis
Nat Genet
(2000)
A.J. Lotery et al.
Mutations in the CRB1 gene cause Leber congenital amaurosis
Arch Ophthalmol
(2001)

A.I. den Hollander et al.

Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene

Am J Hum Genet

(2001)

C.L. Freund et al.

De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis

Nat Genet

(1998)

S.G. Jacobson et al.

Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene

Invest Ophthalmol Vis Sci

(1998)

E. Silva et al.

A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype

Invest Ophthalmol Vis Sci

(2000)

I. Perrault et al.

Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis

Nat Genet

(1996)

Cited by (31)

Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy
2021, Molecular Therapy
Citation Excerpt :
RPE65-IRDs thus serve as a model of a phenotypic continuum modulated by disease severity, a relatively common occurrence in IRDs. Individuals heterozygous for these loss-of-function RPE65 mutations can have minimal fundus changes (yellow-white dots, RPE depigmentation, localized peripheral chorioretinal atrophy), but otherwise normal vision.24 There are an estimated 1,000–2,000 individuals in the US with RPE65-IRDs.
Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the normal copy of the human RPE65 cDNA led to reversal of blindness first in animal models and then in humans. This led to the first US Food and Drug Administration (FDA)-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna). Luxturna was then approved by the European Medicines Association and is now available in the US through Spark Therapeutics and worldwide through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This review describes many of the considerations for administration of Luxturna and describes how lessons from experience with Luxturna could lead to additional gene-based treatments of blindness.
Leber congenital amaurosis: Current genetic basis, scope for genetic testing and personalized medicine
2019, Experimental Eye Research
Retinal dystrophies are one of the leading causes of pediatric congenital blindness. Leber's congenital amaurosis (LCA) encompasses one of the most severe forms of inherited retinal dystrophy responsible for early-onset childhood blindness in infancy. These are clinically characterized by nystagmus, amaurotic pupil response and markedly reduced or in most instances completely absent full-field electroretinogram. LCA exhibits immense genetic heterogeneity. With advances in next-generation genetic technologies, tremendous progress has been achieved over the last two decades in discovering genes and genetic defects leading to retinal dystrophies. Currently, 28 genes have been implicated in the pathogenesis of LCA and with initial reports of success in management with targeted gene therapy the disease has attracted a lot of research attention in the recent time. The review provides an update on genetic basis of LCA, scope for genetic testing and pharmacogenetic medicine in diagnosis and treatment of these diseases.
The ciliary protein Rpgrip1l in development and disease
2018, Developmental Biology
Citation Excerpt :
Interestingly, mutations in RPGRIP1L and RPGRIP1 result in different mouse and human ciliopathies (Tables S1, S2 and S3). RPGRIP1 mutations lead to eye defects in mice and humans (Abouzeid et al., 2016; Booij et al., 2005; Chen et al., 2013; Coppieters et al., 2014; Dryja et al., 2001; Fakhratova, 2013; Fernández-Martínez et al., 2011; Galvin et al., 2005; Gerber et al., 2001; Hameed et al., 2003; Han et al., 2017; Hanein et al., 2004; Huang et al., 2017, 2016, 2013; Imani et al., 2018; Kikuchi et al., 2015; Li et al., 2011, 2009; McKibbin et al., 2010; Neveling et al., 2013; Roepman et al., 2005; Sanchez-Navarro et al., 2018; Saqib et al., 2015; Seong et al., 2008; Suzuki et al., 2014; Tiwari et al., 2016; Vallespin et al., 2007; Verma et al., 2013; Walia et al., 2010; Wang et al., 2016, 2013; Won et al., 2009; Zernant et al., 2005; Zhao et al., 2003), RPGRIP1L mutations affect the development of the brain, the eyes, the lung, the heart, the kidneys, the liver, the limbs, and the skin (Alazami et al., 2012; Arts et al., 2007; Besse et al., 2011; Brancati et al., 2008; Chen et al., 2015; Delous et al., 2007; Doherty et al., 2010; Fahim et al., 2011; Gerhardt et al., 2013; Halbritter et al., 2012; Khanna et al., 2009; Laclef et al., 2015; Otto et al., 2011; Stratigopoulos et al., 2014; Summers et al., 2017; Szymanska et al., 2012; Vierkotten et al., 2007; Wolf et al., 2007). Patients bearing mutations in RPGRIP1 suffer from Retinitis Pigmentosa (RP), Cone Rod Dystrophy (CRD), Inherited Retinal Dystrophy (IRD) and Leber’s Congenital Amaurosis (LCA) (Abouzeid et al., 2016; Booij et al., 2005; Chen et al., 2013; Coppieters et al., 2014; Dryja et al., 2001; Fakhratova, 2013; Fernández-Martínez et al., 2011; Galvin et al., 2005; Gerber et al., 2001; Hameed et al., 2003; Han et al., 2017; Hanein et al., 2004; Huang et al., 2017, 2016, 2013; Imani et al., 2018; Kikuchi et al., 2015; Li et al., 2011, 2009; McKibbin et al., 2010; Neveling et al., 2013; Roepman et al., 2005; Sanchez-Navarro et al., 2018; Saqib et al., 2015; Seong et al., 2008; Suzuki et al., 2014; Tiwari et al., 2016; Vallespin et al., 2007; Verma et al., 2013; Walia et al., 2010; Wang et al., 2016, 2013; Zernant et al., 2005), while patients with mutations in RPGRIP1L suffer from Meckel syndrome (MKS), Joubert syndrome (JBTS), Cerebellar Vermis Aplasia Oligophrenia Congenital Ataxia Coloboma Hepatic Fibrosis (COACH), Nephronophtisis (NPHP), Bardet-Biedl syndrome (BBS), Retinitis Pigmentosa (RP) and Leber’s Congenital Amaurosis (LCA) (Alazami et al., 2012; Arts et al., 2007; Brancati et al., 2008; Chaki et al., 2011; Delous et al., 2007; Doherty et al., 2010; Fahim et al., 2011; Halbritter et al., 2012; Khanna et al., 2009; Otto et al., 2011; Summers et al., 2017; Szymanska et al., 2012; Wolf et al., 2007).
RPGRIP1L is an evolutionary highly conserved gene encoding a protein that localises at the transition zone of primary cilia. Mutations in RPGRIP1L result in ciliopathies, severe human diseases caused by dysfunctional cilia. Patients with mutations in this gene often suffer from an impaired development of not only one but various organs. To elucidate the function of Rpgrip1l in human development and the mechanisms underlying ciliopathies, different model organisms are used. In this review article, we summarise the findings of these investigations comprising novel functions of Rpgrip1l and the most promising therapeutic approaches.
Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D
2018, Progress in Retinal and Eye Research
Citation Excerpt :
An interesting question regarding the effect of GUCY2D mutation on retinal function is whether individuals who carry heterozygous recessive mutations develop any mild signs of retinal disease. Aiming to answer this question, clinical analysis of parents of LCA1 patients has been reported (Galvin et al., 2005; Koenekoop et al., 2002), with a total of four parents who are heterozygous for identified GUCY2D mutations (ages 40–55 years). Some of the patients reported mild and recent visual impairment (including difficulties driving at night and photoaversion during the day) with best-corrected visual acuity that was normal or subnormal and with normal appearance of the retina.
The GUCY2D gene encodes for the photoreceptor guanylate cyclase GC-E that synthesizes the intracellular messenger of photoreceptor excitation cGMP and is regulated by intracellular Ca²⁺-sensor proteins named guanylate cyclase-activating proteins (GCAPs). Over 140 disease-causing mutations have been described so far in GUCY2D, 88% of which cause autosomal recessive Leber congenital amaurosis (LCA) while heterozygous missense mutations cause autosomal dominant cone-rod degeneration (adCRD). Mutations in GUCY2D are one of the major causes of all LCA cases and are the major cause of adCRD. A single amino acid, arginine at position 838, is likely to be the most sensitive one in GC-E as four single mutations and two complex mutations were reported to affect R838.
The biochemical effect of 45 GC-E variants was studied showing a clear genotype-phenotype correlation: LCA-causing mutations either show reduced ability or complete inability to synthesize cGMP from GTP, while CRD-causing mutations are functional, but shift the Ca²⁺-sensitivity of the GC-E − GCAP complex.
Eight animal models of retinal guanylate cyclase deficiency have been reported including knockout (KO) mouse and chicken models. These two models were used for gene augmentation therapy that yielded promising results.
Here we integrate the available information on the genetics, biochemistry and phenotype that is related to GUCY2D mutations. These data clearly show that mutation type (missense versus null) and localization (dimerization domain versus other protein domains) are correlated with the pattern of inheritance, impact on enzymatic function and retinal phenotype. Such clear correlation is unique to GUCY2D while mutations in many other retinal disease genes show variable phenotypes and lack of available biochemical assays.
Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands
2016, Experimental Eye Research
Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. We have previously performed a mutational analysis of the known LCA-associated genes in probands with LCA by both Sanger and whole exome sequencing. In this study, whole exome sequencing was carried out on 66 new probabds with LCA. In conjunction with these data, the present study provides a comprehensive analysis of the spectrum and frequency of all known genes associated with retinal dystrophy in a total of 159 Chinese probands with LCA. The known genes responsible for all forms hereditary retinal dystrophy were included based on information from RetNet. The candidate variants were filtered by bioinformatics analysis and confirmed by Sanger sequencing. Potentially causative mutations were further validated in available family members. Overall, a total of 118 putative pathogenic mutations from 23 genes were identified in 56.6% (90/159) of probands. These mutations were harbored in 13 LCA-associated genes and in ten genes related to other forms of retinal dystrophy. The most frequently mutated gene in probands with LCA was GUCY2D (10.7%, 17/159). A series of mutational analyses suggests that all known genes associated with retinal dystrophy account for 56.6% of Chinese patients with LCA. A comprehensive molecular genetic analysis of Chinese patients with LCA provides an overview of the spectrum and frequency of ethno-specific mutations of all known genes, as well as indications about other unknown genes in the remaining probands who lacked identified mutations.
Pathobiology of the Outer Retina: Genetic and Nongenetic Causes of Disease
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
The outer retina is composed primarily of rod and cone photoreceptor (PR) cells and retina pigment epithelial cells. These cells serve as the main cells of the retina and initiate the process of phototransduction whereby light is converted and transmitted to the visual cortex of the brain to generate an image. The majority of the diseases of the outer retina are genetic (over 97%) and result from mutations in genes associated with photoreceptor development, phototransduction, and maintenance of normal photoreceptor function. The retinal pigment epithelium (RPE) functions to nourish the PR cells and provides a mechanism to recycle photoreceptor outer segments that are spent during phototransduction. Thus, mutations in RPE genes also cause outer retinal degeneration. Further, a small percentage of outer retinal diseases result from trauma or injury to the retina. This article provides an overview of the pathobiology of outer retinal diseases. While each case is unique, the biological processes that are disrupted are common and thus a common pathology primarily of rod and cone degeneration leads to debilitating vision loss.

View all citing articles on Scopus

: Manuscript no. 240288.

: Supported in part by a center grant from The Foundation Fighting Blindness, Owings Mills, Maryland (GAF, EMS); The Grant Healthcare Foundation, Chicago, Illinois; an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, New York; and Foundation Fighting Blindness Canada, Toronto, Canada, and FRSQ Canada, Montreal, Canada (RKK).

View full text

Original articleClinical phenotypes in carriers of Leber congenital amaurosis mutations

Objective

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Section snippets

Patients and methods

Results

Discussion

Mol Genet Metab

Am J Hum Genet

Ophthalmology

Ophthalmology

Vision Res

Am J Ophthalmol

Uber retinitis pigmentosa und angeborene amaurose

Albrecht Von Graefes Arch Ophthalmol

Importance diagnostique et prognostique de l'electroretinogramme (ERG) dans les degenerescences tapeto-retiniennes avec retrecissement du champ visuel et hemeralopie

Confin Neurol

Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis

Nat Genet

Mutations in the CRB1 gene cause Leber congenital amaurosis

Arch Ophthalmol

Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene

Am J Hum Genet

De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis

Nat Genet

Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene

Invest Ophthalmol Vis Sci

A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype

Invest Ophthalmol Vis Sci

Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis

Nat Genet

Original article
Clinical phenotypes in carriers of Leber congenital amaurosis mutations