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The Phenotype of Leber Congenital Amaurosis in Patients With AIPL1 Mutations
Sharola Dharmaraj, MD, FRCS;
Bart P. Leroy, MD;
Melanie M. Sohocki, PhD;
Robert K. Koenekoop, MD, PhD;
Isabelle Perrault, PhD;
Khalid Anwar, MD;
Shagufta Khaliq, PhD;
R. Summathi Devi, MD;
David G. Birch, PhD;
Elaine De Pool, MD;
Natalio Izquierdo, MD;
Lionel Van Maldergem, MD;
Mohammad Ismail, MD;
Annette M. Payne, PhD;
Graham E. Holder, PhD;
Shomi S. Bhattacharya, PhD;
Alan C. Bird, MD, FRCOphth;
Josseline Kaplan, MD, PhD;
Irene H. Maumenee, MD
Arch Ophthalmol. 2004;122:1029-1037.
ABSTRACT
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Objectives To describe the phenotype of Leber congenital amaurosis (LCA) in 26 probands with mutations in aryl hydrocarbon receptor interacting protein-like 1 protein (AIPL1) and compare it with phenotypes of other LCA-related genes. To describe the electroretinogram (ERG) in heterozygote carriers.
Methods Patients with AIPL1-related LCA were identified in a cohort of 303 patients with LCA by polymerase chain reaction single-strand confirmational polymorphism mutation screening and/or direct sequencing. Phenotypic characterization included clinical and ERG evaluation. Seven heterozygous carrier parents also underwent ERG testing.
Results Seventeen homozygotes and 9 compound heterozygotes were identified. The W278X mutation was most frequent (48% of alleles). Visual acuities ranged from light perception to 20/400. Variable retinal appearances, ranging from near normal to varying degrees of chorioretinal atrophy and intraretinal pigment migration, were noted. Atrophic and/or pigmentary macular changes were present in 16 (80%) of 20 probands. Keratoconus and cataracts were identified in 5 (26%) of 19 patients, all of whom were homozygotes. The ERG of a parent heterozygote carrier revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.
Conclusions The phenotype of LCA in patients with AIPL1 mutations is relatively severe, with a maculopathy in most patients and keratoconus and cataract in a large subset. Rod ERG abnormalities may be present in heterozygous carriers of AIPL1 mutations.
Clinical Relevance Understanding and recognizing the phenotype of LCA may help in defining the course and severity of the disease. Identifying the gene defect is the first step in preparation for therapy since molecular diagnosis in LCA will mandate the choice of treatment.
INTRODUCTION
Leber congenital amaurosis (LCA) was first described by Theodore Leber in 18691 as a congenital form of retinitis pigmentosa. It represents a clinically and genetically heterogeneous disorder with severe visual impairment from birth.2-3 Fundus examination results are not frequently initially normal, but chorioretinal atrophy, narrowing of the retinal vasculature, intraretinal pigment migration, white fundus flecks, and macular aplasia have been described.4-8 The retinal basis of the visual loss is shown by absent or severely diminished rod and cone responses on electroretinography (ERG).9 Nystagmus, enophthalmos, sluggish pupillary responses, keratoconus, cataracts, and hyperopia have also been described.10-12
Leber congenital amaurosis is usually inherited as an autosomal recessive trait, although dominant inheritance has been reported.13-16 Currently, mutations in 6 different retinal genes have been shown to cause LCA. The genes include (1) retinal guanylate cyclase (GUCY2D),17 (2) retinal pigment epithelium–specific 65kD protein (RPE65),18 (3) cone-rod homeobox (CRX),19-22 (4) crumbs gene homolog of CRB1,23-24 (5) retinitis pigmentosa GTPase regulator–interacting protein (RPGRIP-1),25-26 and (6) AIPL1, encoding the aryl hydrocarbon receptor interacting protein-like 1 protein.27-28
The AIPL1 gene consists of 6 exons and encodes a protein of 384 amino acids. This sequence includes 3 tetratricopeptide repeat motifs thought to be associated with protein-protein interaction, and its similarity with aryl hydrocarbon interacting protein is suggestive of a protein folding function.27-28 The exact functions of the AIPL1 gene are not fully understood. However, recent data suggest that the protein may be involved in photoreceptor differentiation during development and subsequent survival of photoreceptors.29 Indeed, through interaction with the NUB1 protein, it might be involved in regulation of the cell-cycle progression during photoreceptor maturation.29 Mutations in AIPL1 account for 7% of LCA.28
Clinical outcomes differed for patients with LCA and GUCY2D mutations when compared with those with RPE65 defects30-33 in terms of the natural history of this disorder. In addition, some heterozygous carriers of GUCY2D mutations, who have offspring with LCA, have been shown to have significant cone abnormalities on ERG results, with essentially normal rod ERG findings.34 Most heterozygotes with RPE65 mutations have normal ERG findings.32
The purpose of this large study is to describe the phenotype of LCA in patients with AIPL1 mutations and compare it with the known phenotypes of patients with mutations in other LCA genes. The phenotype of 26 patients with LCA of different ethnic origins with mutations in AIPL1 is described. The genotype of most patients has previously been published.15, 28 The ERG and clinical findings in a female heterozygous carrier are also reported.
METHODS
Informed consent was obtained from all patients involved in this study or from their legal guardians in accordance with the Declaration of Helsinki. The review and ethics boards of the institutions approved this study.
OPHTHALMIC EVALUATIONS
The clinical diagnosis of LCA was made on the basis of the following diagnostic criteria: severe visual impairment from birth or during early infancy accompanied by nystagmus, absent or very sluggish pupillary responses, and absent or markedly reduced rod and cone ERGs. All ERGs were performed according to the International Society for Clinical Electrophysiology of Vision standards.35 The examinations were undertaken in 5 centers and included slitlamp biomicroscopy, retinoscopy, and indirect ophthalmoscopy following pupillary dilation (Table 1). Clinical pictures were taken, and keratometry was performed.
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Table 1. Clinical and Genetic Characteristics of 26 Probands With AIPL1 Mutations
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GENETIC EVALUATIONS
DNA was extracted from peripheral blood leukocytes or cheek swabs. A cohort of 303 patients with LCA was screened for mutations in AIPL1. Patients were from a wide range of racial and ethnic backgrounds. The 6 exons of AIPL1 were screened using single-strand conformation polymorphism analysis (SSCP) followed by direct sequencing when an aberrant migration pattern was noted on the SSCP gels. In 39 probands, direct sequencing was used to screen for mutations in AIPL1, while in the others, SSCP was initially undertaken using primers and conditions previously described.27 The genotype of most of the patients with AIPL1-related LCA in this study has been published previously (Figure 1).27-28
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Figure 1. Structure of the AILPL1 gene with the relative locations of the mutations in the 26 probands.
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RESULTS
Mutations in AIPL1 were detected in 26 probands with LCA (Figure 1). Seventeen probands were homozygotes, while 9 were compound heterozygotes. Twenty-four of the 52 mutated AIPL1 alleles carried the W278X mutation. All sequence changes identified in our patients were absent in 205 control samples.
NIGHT BLINDNESS, PHOTOATTRACTION, AND PHOTOAVERSION
Night blindness was reported in 13 probands and photoaversion in 4. Photoattraction (staring at lights) was noted in 2 probands (Table 1).
VISUAL ACUITIES AND CYCLOPLEGIC REFRACTIONS
Visual acuities were found to vary between probands and ranged from 20/400 to light perception. Nine patients had light perception. Seven patients had hand motion vision (Table 1). Cycloplegic refractions performed in 10 patients showed hyperopia in 8 (+3.00 diopters [D] to +7.00 D) and myopia in 2 (–0.50 D to –2.75 D).
RETINAL AND MACULAR APPEARANCE
Twenty-four probands with an AIPL1-related LCA genotype had some form of pigmentary retinopathy that ranged from mild midperipheral salt and pepper-like retinopathy to diffuse and severe chorioretinopathy (Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7). The youngest patient with pigmentary changes was 4 months old. Two patients, a 2-year-old and a 3-year-old, had essentially normal retinas with indistinct foveal reflexes. A maculopathy of variable appearance was noted in a significant number of patients (Figure 2, Figure 3, Figure 4, Figure 5, and Figure 7). Information about the macular appearance was available in 20 of the 26 probands. Maculopathy was noted in 16 (80%) of 20 probands. In 4 probands, all young children (ranging from ages 2-6 years), an abnormal indistinct foveal reflex was noted, which likely represents an early stage of maculopathy. This strongly suggests that a significant number of patients with LCA and AIPL1 mutations develop a maculopathy. The maculopathy ranged in appearance from mild foveal atrophy with variable degrees of macular stippling to aplasia. The youngest patient with macular atrophy was 8 years old (Table 1).
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Figure 2. W287X/W278X mutation, proband 12 at 25 years of age. Posterior pole, right eye, showing atrophic macular area optic nerve pallor and pigmentary changes.
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Figure 3. W287X/W278X mutation, proband 8 at 8 years of age. Left eye, early macular changes showing retinal pigmentary epithelium disruption.
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Figure 4. W88X/W88X mutation, proband 2 at 30 years of age. Posterior pole, left eye, showing atrophic macular and retinal pigment epithelium disruption and optic nerve pallor.
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Figure 5. W88X/W88X mutation, proband 2 at 30 years of age. Superior midperiphery, left eye, showing intraretinal pigment accumulation, optic nerve pallor, and atrophic macula with pigmentary changes.
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Figure 6. T114I/P376S mutation, proband 20 at 8 years of age. Peripheral retinal mottling.
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Figure 7. T114I/P376S mutation, proband 20 at 8 years of age. Right eye, showing macular coloboma-like atrophy and mild optic nerve pallor.
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KERATOCONUS AND CATARACTS
Information about the presence of keratoconus was available in 19 probands (Table 1). Keratoconus was diagnosed in 6 probands (32%), and cataracts were noted in association with the keratoconus in 5 of these 6 patients. Distinct hydrops with scarring and breaks in the Descemet membrane were noted in proband 17. The cataracts ranged from cortical changes to posterior subcapsular cataracts. Of interest, keratoconus and cataracts were only seen in patients who were homozygous for AIPL1 mutations. Keratoconus was not observed in patients with compound heterozygous mutations. The youngest patient with keratoconus and cataract was aged 10 years.
OPTIC DISC APPEARANCE
Varying degrees of optic nerve pallor were noted in all patients after the age of 6 years. The optic nerve head appeared normal in children younger than 6 years, except in an infant (Table 1).
ERG FINDINGS
The ERG findings obtained in the 3 sets of clinically normal parents of probands 7, 10, and 26 who carry the AIPL1 mutation in a heterozygous state did not show any abnormalities. However, the ERG of 1 carrier parent of proband 2 with the W88X mutation showed significant rod abnormalities (Figure 8). She did not have any ocular complaints, and her clinical examination findings were normal. This 47-year-old mother had vision of 20/20 OU. Although her retinal examination results were unremarkable, full-field flash ERG showed rod b-wave amplitudes to be reduced to approximately one third of normal, with no change in implicit time. This is well below the lower limit of normal. The 30-Hz flicker and single flash cone responses were within normal limits (Figure 8). The ERG responses were reproducible on repetition.
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Figure 8. Top row, Electroretinogram (ERG), right eye, of the 47-year-old, heterozygous carrier parent of proband 2 carrying the W88X AIPL1 mutation. It shows a significantly reduced amplitude of rod-specific scotopic to one third of normal values and of maximal combined rod and cone response; cone-specific 30-Hz flicker and single flash cone ERGs are within normal limits. Second row, ERG of proband 2 at 27 years of age (carrying the W88X/W88X mutation) showing no measurable responses. Third row, ERG of proband 2's 30-year-old affected sister (carrying the W88X/W88X mutation) showing no measurable responses. Fourth row, Typical normal findings in a 45-year-old control.
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COMPARING THE LCA PHENOTYPES
The LCA phenotypes with mutations in the other LCA genes (GUCY2D, RPE65, CRX, CRB1, and RPGRIP1) were compared with the LCA phenotypes of the current study and tabulated in Table 2, Table 3, Table 4, Table 5, and Table 6. The AIPL1-related LCA phenotype is severe in nature, with pronounced macular involvement in individuals older than 6 years with varying degrees of optic nerve pallor. Additional findings of keratoconus and cataract could be present.
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Table 2. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With GUCY2D Mutations vs Patients With AIPL1 Mutations
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Table 3. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With RPE65 Mutations vs Patients With AIPL1 Mutations
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Table 4. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With CRX Mutations vs Patients With AIPL1 Mutations
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Table 5. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With CRB1 Mutations vs Patients With AIPL1 Mutations*
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Table 6. Comparisons of Leber Congenital Amaurosis Phenotypes: Patients With RPGRIP1 Mutations vs Patients With AIPL1 Mutations
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Both GUCY2D-related and AIPL1-related LCA phenotypes have markedly decreased visual acuities, visual fields, and ERGs.30-31,33 However, maculopathy, remarkable peripheral pigmentary changes, cataract, and significant optic disc pallor were not detected in patients with mutations in GUCY2D. 30-31,33 Keratoconus was reported by El-Shanti et al36 in a Jordanian pedigree. Compared with the reported GUCY2D phenotype,30-31,33 the AIPL1 phenotype appears to be similar in severity of visual loss. Phenotypical differences exist in the pattern of pigmentary changes, cataract, and keratoconus, which are more frequent in AIPL1-related LCA (Table 2).
The RPE65 phenotype reported in earlier studies30-32,37-38 shows that the visual acuities, visual fields, and ERG measurements were better than in the AIPL1 phenotype. Patients with RPE65-related LCA may develop a mild maculopathy, and the documented peripheral retinal changes are characterized as grainy and/or salt and pepper-like. The maculopathy of patients with AIPL1-related LCA appears to be more pronounced in all probands older than 6 years, while the peripheral retinal changes range from mottling to bone spicule-like formation. Cataract and keratocunus were present in one third of the patients with AIPL1-related LCA. Lorenz et al32 conclude that patients with LCA and RPE65 mutations are distinguishable on clinical grounds, based on their measurable visual acuities, their transient visual improvement in childhood followed by deterioration in later life, measurable cone ERGs (which also diminish in later life), measurable visual fields, and significant night blindness. The data from our study suggest that patients with LCA and mutations in AIPL1 do not have a similar course (Table 3).
From the several reported cases of patients with LCA and CRX mutations, visual acuities of 20/300 to light perception, with 1 case of 20/80, were described.15-16,19-22,31, 33, 39-43 Marked atrophy in the macula was recorded in 71% of CRX-related LCA, while in AIPL1-related LCA, maculopathy was pronounced in 80% of the patients after 6 years of age. Marked pigmentary retinopathy was noticed in 84% of patients with AIPL1-related LCA unlike in CRX-related LCA, where it was observed in 33% (Table 4).
Compared with that of patients with CRB1 mutations, the phenotype of our patients with AIPL1 mutations appears to be less variable and more severe. Small white dots and zonal retinal/choroidal hypoplasia were seen in the patients with CRB1-related LCA23 but not in patients with AIPL1-related LCA (Table 5). The presence of cataract, keratoconus, and optic disc pallor were not reported in the CRB1-related LCA phenotype. The constant features reported in the CRB1-related phenotype were moderate to high hyperopia, the relatively early appearance of white spots, and nummular pigment clumps in the retina.23
The RPGRIP1-related LCA phenotype has been reported in 3 patients.25 Visual acuity was light perception. Hyperopia and absence of intraretinal pigment migration were noted in 2 patients. However, bone spicule-like pigmentary deposits in the midperipheral zone were noted in a third patient. No evidence of maculopathy as seen in the patients with AIPL1-related LCA was observed (Table 6).
COMMENT
The retinal phenotype of AIPL1-related LCA is that of a severe, congenital retinal dystrophy with a notable maculopathy. The retinal appearances in our patients ranged from near normal (in a 3-year-old and a 6-year-old) to severely atrophic (and in all patients older than 6 years) with marked maculopathy and pigmentary retinopathy. Varying degrees of intraretinal pigment migration culminating in bone spicule-like pigment and gross pigment clumps in the retinas were observed. Overall, a high prevalence of macular lesions was observed in our patients compared with patients with LCA caused by mutations in the other 5 genes implicated in this disease. Atrophic macular lesions were particularly frequent and were observed in 16 (80%) of 20 patients; 11 harbored a premature stop-codon mutation, either in a homozygous or a heterozygous state. Macular involvement as seen on ophthalmoscopy likely begins with an indistinct dull or irregular foveal reflex and progresses to a diffuse ill-defined area of retinal pigment stippling and atrophy, leading to a marked atrophic maculopathy. Owing to the differences in age at the time of first examination, it was not possible to determine the accurate age of onset of the maculopathy.
The heterozygous carrier parent of the W88X mutation was found to have a significant and reproducible rod ERG abnormality with essentially normal cone ERG results. These ERG findings are significantly different from the heterozygous carriers of GUCY2D mutations, who have significant cone ERG abnormalities but relatively normal rod ERG findings.34 The rod ERG abnormalities in the AIPL1 carrier correlate with recent reports showing AIPL1 expression exclusively in rod photoreceptors in the differentiated retina.44 However, more ERGs in carriers of AIPL1 mutations need to be studied to better understand the role of AIPL1 in relation to rod function.
The presence of keratoconus in patients with LCA has been well documented.45-48 The high incidence of keratoconus in patients with a homozygous sequence change of AIPL1 in our cohort may well be significant. Keratoconus was observed in 6 probands, all with homozygous mutations. There is no definitive consensus about the origin of keratoconus in patients with LCA. The incidence of keratoconus has been reported to be as high as 54.5 cases per 100.0 in the general population, and it has been noted in 29% of children with LCA and 2% of all children with blindness.10, 49 Keratoconus in patients with LCA occurred in 2% of 0- to 14-year-olds and in 30% of 15- to 45-year-olds, further illustrating the later onset of the pathologic corneal features in comparison with the retinal dysplasia.50 The absence of keratoconus prior to 9 years of age also has been well documented46 and is the case in our cohort too.
Cataract has been associated with many different types of retinal dystrophy. Its association with retinitis pigmentosa has been well documented.51-52 Cataract has been noted at or beyond the second decade of life in patients with LCA.46 In this study, cataracts were observed in 5 probands (27%). Progressive retinal degenerative changes in association with keratoconus and cataract have been reported during the course of the disorder.46-47 The incidence of both keratoconus and cataract increased with increasing age in our cohort.
The LCA phenotypes are highly variable15, 23, 31-32 and change with age,46 and the phenotypes associated with the currently known LCA genes overlap.31-33 Comparisons between the reported LCA phenotypes of different studies23, 25, 30-33 are hampered by a lack of uniform assessment strategies, age matching, and uniform follow-up. Despite these obvious difficulties, it is important to study these LCA phenotypes in an effort to understand the evolution of disease based on genotype.
In summary, patients with AIPL1-related LCA appear to have a particularly severe phenotype, characterized by marked visual impairment, nondetectable fields and ERGs, optic disc pallor, maculopathy, peripheral retinal bone spicule-like pigmentation, and a significant prevalence of keratoconus and cataract.
Mutations in AIPL1 disrupt the normal function of photoreceptors. AIPL1 is not only expressed in mature rod photoreceptors44 but also during development in both rods and cones.29 The dysfunctional role of AIPL1 in photoreceptor cell cycle progression leads to photoreceptor cell death during development by disrupting the normal regulation of the cell cycle.29 More detailed understanding of the pathogenesis of each molecular subtype of LCA will provide further insight into treatment.
AUTHOR INFORMATION
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Correspondence: Sharola Dharmaraj, MD, FRCS, The Johns Hopkins Center for Hereditary Eye Diseases, Maumenee 517, Wilmer Eye Institute, Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287-9237 (sdharmaraj{at}jhmi.edu).
Submitted for publication October 10, 2002; final revision received April 3, 2003; accepted June 6, 2003.
This research was supported by grants from the Foundation for Retinal Research, Highland Park, Ill; the Edel & Krieble Funds of the Johns Hopkins Center for Hereditary Eye Diseases, Baltimore, Md; the Grousbeck Family Foundation, Stanford, Calif; the Fonds voor Research in Oftalmologie/Fonds de la Recherche en Ophtalmologie, Edegem, Antwerp, Belgium (Dr Leroy); the Bijzonder Onderzoeksfonds of Ghent University, Ghent, Belgium (Dr Leroy); the Foundation Fighting Blindness-Canada, Toronto, Ontario (Dr Koenenkoop); the Canadian Institutes of Health Research, Ottawa, Ontario (Dr Koenenkoop); Fonds de la recherche en Santé du Québéc, Montréal, Québéc (Dr Koenenkoop); the Kirchgessner Foundation, Los Angeles, Calif (Dr Sohocki); the Knights Templar Eye Foundation, Chicago, Ill (Dr Sohocki); the Foundation Fighting Blindness, Owings Mills, Md (Dr Sohocki); Fight for Sight, New York (Dr Sohocki); the Research Division of Prevent Blindness America, Schaumburg, Ill (Dr Sohocki); and William R. Acquavella (Dr Sohocki).
Dr Sohocki is the William R. Acquavella Scholar of Ophthalmic Research, Columbia University, New York.
These authors contributed equally to the study: Sharola Dharmaraj, MD, FRCS, and Bart P. Leroy, MD.
We thank the families for support and cooperation. We also thank the photography departments of all the institutes for their professional assistance and to Olof Sundin, PhD, for reviewing the manuscript.
From the Johns Hopkins Center for Hereditary Eye Diseases, Baltimore, Md (Drs Dharmaraj, De Pool, and Maumenee); the Departments of Molecular Genetics (Drs Leroy, Payne, and Bhattacharya) and Clinical Ophthalmology (Drs Bird and Leroy), Institute of Ophthalmology, University College of London, London, England; the Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium (Dr Leroy); the Departments of Ophthalmology and Pathology, Columbia University, New York, NY (Dr Sohocki); McGill Ocular Genetics Lab, Montreal Children's Hospital, Montreal, Quebec (Dr Koenekoop); Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Inserm U393, Hôpital des Enfants Malades, Paris, France (Drs Perrault and Kaplan); the Biomedical and Genetic Engineering Division, Dr AQ Khan Research Laboratories, Islamabad, Pakistan (Drs Anwar, Khaliq, and Ismail); Stanley Medical College, University of Madras, Madras, India (Dr Devi); The Retinal Foundation of the Southwest Dallas, Tex (Dr Birch); Instituto de Glaucoma y Genetic a Ocular, Rio Piedras, Puerto Rico (Dr Izquierdo); Centre de Génétique Humaine Institut de Pathologie et de Génétique, Loverval, Belgium (Dr Van Maldergem); the Department of Biological Sciences, Brunel University, London (Dr Payne); the Electrophysiology Department, Moorfields Eye Hospital, London (Dr Holder). The authors have no relevant financial interest in this article.
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