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At least 199 records · Page 11Linked to original sources
PubMed2000

Clinical and electroretinographic findings of female carriers and affected males in a progressive X-linked cone-rod dystrophy (COD-1) pedigree.

OBJECTIVE: To study the clinical and electroretinographic findings of affected males and female carriers in a family with X-linked cone-rod dystrophy (COD-1). DESIGN: Observational case series. PARTICIPANTS: Twenty-five members of a five-generation pedigree were examined. METHODS: A history of visual impairment including age at onset, loss of acuity, color vision abnormalities, photophobia, and nyctalopia was obtained. A complete ophthalmologic examination was performed, including kinetic perimetry with a Goldmann perimeter, FM 100-hue testing, and standardized Ganzfeld electroretinography following the ISCEV protocol. MAIN OUTCOME MEASURES: Patients were classified as affected or unaffected on the basis of the clinical examination. All carrier females had affected sons. RESULTS: Nine affected males and seven female carriers were identified. Affected males noted decreased visual acuity and poor color vision within the first two decades of life. Early in the disease, macular retinal pigment epithelial (RPE) changes were found that progressed to an atrophic macular scar by the fifth decade. Evidence of progression from macular pigment mottling to an atrophic macular lesion over a 13-year period was identified in one patient. The photopic, single-flash, b-wave amplitude was low in all affected males and declined with age. The 30-Hz flicker b-wave implicit times were abnormally prolonged in all affected males. Female carriers were asymptomatic although three had slightly abnormal color vision and small paracentral field defects and subtle RPE defects were found in three carriers. Carriers demonstrated prolongation of the 30-Hz flicker b-wave implicit time and interocular asymmetry. Five of seven carriers and two affected males demonstrated reduced oscillatory potentials and an abnormal-appearing flattened photopic a-wave. Five men and two women demonstrated a characteristic tapetal-like retinal sheen. CONCLUSIONS: Affected patients in this pedigree demonstrate early loss of visual acuity and poor cone function with late rod involvement. Female carriers may appear clinically normal or may be identified by subtle color vision defects, fundus abnormalities, prolongation of the 30-Hz flicker implicit time with interocular asymmetry, or an abnormal flattened photopic a-wave. Genetic linkage analysis of this family was recently reported and the disease-causing gene has been mapped to an approximately 1-Mb interval on chromosome Xp11.4.

Adolescent↗
PubMedDate not supplied

Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the GUCY2D gene in Japanese patients.

PURPOSE: To describe the clinical phenotypes of two Japanese families with autosomal dominant cone-rod dystrophy (CORD) caused by an R838H or R838C mutation. METHODS: Complete ophthalmological examinations were performed on three affected individuals from two Japanese families with autosomal dominant CORD. One family had an R838H mutation, and the other family had an R838C mutation in the GUCY2D gene. The tests included best-corrected visual acuity, slit-lamp and fundus examinations, fundus photography, electroretinography, Goldmann kinetic perimetry, and automated light- and dark-adapted static perimetry. RESULTS: The three patients showed essentially normal fundus or little pigmentary change in the maculae by indirect ophthalmoscopy, and only fluorescein angiography revealed clear atrophy of the retinal pigmented epithelium around the fovea. Central or paracentral scotoma was detected by the Goldmann kinetic visual field test. Electroretinography as well as light-adapted and dark-adapted two-color perimetry showed more severe impairment of cone than of rod function. The clinical features in our patients resembled those in Caucasian families with R838H or R838C mutations. CONCLUSIONS: The R838H and R838C mutations in GUCY2D cause CORD in the Japanese population. These mutations can cause a similar clinical phenotype in other races.

Adult↗
PubMedDate not supplied

Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.

Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology.

ATP-Binding Cassette Transporters↗
PubMed2001

Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene.

Mutations in the ABCA4(ABCR) gene cause autosomal recessive Stargardt disease (STGD). ABCR mutations were identified in patients with cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) by direct sequencing of all 50 exons in 40 patients. Of 10 patients with RP, one contained two ABCR mutations suggesting a compound heterozygote. This patient had a characteristic fundus appearance with attenuated vessels, pale disks and bone-spicule pigmentation. Rod electroretinograms (ERGs) were non-detectable, cone ERGs were greatly reduced in amplitude and delayed in implicit time, and visual fields were constricted to 10 degrees diameter. Eleven of 30 (37%) patients with CRD had mutations in ABCR. In general, these patients showed reduced but detectable rod ERG responses, reduced and delayed cone responses, and poor visual acuity. Rod photoresponses to high intensity flashes were of reduced maximum amplitude but showed normal values for the gain of phototransduction. Most CRD patients with mutations in ABCR showed delayed recovery of sensitivity (dark adaptation) following exposure to bright light. Pupils were also significantly smaller in these patients compared to controls at 30 min following light exposure, consistent with a persistent 'equivalent light' background due to the accumulation of a tentatively identified 'noisy' photoproduct.

ATP-Binding Cassette Transporters↗
PubMed2024

Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.

BACKGROUND: Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals. METHODS: Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022. RESULTS: All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis. CONCLUSIONS: Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.

Adult↗
PubMedDate not supplied

Dark choroid in cone-rod dystrophy.

An unusual pattern of dark choroid in an eight-year-old girl is described. The ophthalmoscopic, fluorescein angiographic and functional changes were indicative of progressive cone-rod dystrophy.

Child↗
PubMed2001

Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder caused by a CAG repeat expansion. To determine the mechanism of neurotoxicity, we produced transgenic mice and observed a cone-rod dystrophy. Nuclear inclusions were present, suggesting that the disease pathway involves the nucleus. When yeast two-hybrid assays indicated that cone-rod homeobox protein (CRX) interacts with ataxin-7, we performed further studies to assess this interaction. We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. In SCA7 transgenic mice, electrophoretic mobility shift assays indicated reduced CRX binding activity, while RT-PCR analysis detected reductions in CRX-regulated genes. Our results suggest that CRX transcription interference accounts for the retinal degeneration in SCA7 and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disease.

Age Factors↗
PubMed2004

Spondylometaphyseal dysplasia with cone-rod dystrophy.

The co-occurrence of ophthalmologic abnormality and intrinsic skeletal dysplasia is uncommon. We describe eight instances of a unique form of spondylometaphyseal dysplasia (SMD) associated with cone-rod dystrophy (although documentation is insufficient to be certain of that diagnosis in some). This is a new, syndromic form of SMD for which there is evidence for autosomal recessive transmission. Recognition of the specific bony features described here should precipitate comprehensive ophthalmologic assessment, since vision impairment becomes significantly disabling with age.

Bones of Upper Extremity↗
PubMed1996

Cleft lip and cone-rod dystrophy in a consanguineous sibship.

Three siblings from a consanguineous marriage were found to have a cleft lip. Two of them developed a progressive retinopathy which was identified as a cone-rod dystrophy. It is suggested that this association may represent a hitherto unreported entity with an autosomal recessive pattern of inheritance, although chance co-occurrence cannot be excluded.

Adult↗
PubMed2000

Thiamine-responsive megaloblastic anemia syndrome (TRMA) with cone-rod dystrophy.

Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive disease in which the active thiamine uptake into cells is disturbed. The molecular basis underlying the disorder has been related to mutations in the gene SLC19A2 on chromosome 1q23.3 that encodes a functional thiamine transporter. The protein is predicted to have 12 transmembrane domains. TRMA is characterized by sensorineural deafness, diabetes mellitus, megaloblastic anemia, and cardiomyopathy. Optic nerve atrophy and retinal dystrophy have been reported in a small number of patients. We report a 15-year-old girl with TRMA and cone-rod dystrophy and confirm that retinal dystrophy may form part of the syndrome. Differential diagnosis of syndromes with deafness, diabetes mellitus, and optic nerve atrophy or retinal dystrophy are discussed. The authors suggest that ERG be performed in all patients with TRMA.

Adolescent↗
PubMed2004

The cone dysfunction syndromes.

The cone dystrophies comprise a heterogeneous group of disorders characterised by visual loss, abnormalities of colour vision, central scotomata, and a variable degree of nystagmus and photophobia. They may be stationary or progressive. The stationary cone dystrophies are better described as cone dysfunction syndromes since a dystrophy often describes a progressive process. These different syndromes encompass a wide range of clinical and psychophysical findings. The aim is to review current knowledge relating to the cone dysfunction syndromes, with discussion of the various phenotypes, the currently mapped genes, and genotype-phenotype relations. The cone dysfunction syndromes that will be discussed are complete and incomplete achromatopsia, oligocone trichromacy, cone monochromatism, blue cone monochromatism, and Bornholm eye disease. Disorders with a progressive cone dystrophy phenotype will not be discussed.

Color Vision Defects↗
PubMed1998

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR.

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age-related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G->T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G->A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.

ATP-Binding Cassette Transporters↗
PubMed1996

Autosomal dominant cone-rod dystrophy associated with a Val200Glu mutation of the peripherin/RDS gene.

OBJECTIVE: Mutations of the peripherin/RDS gene have been reported in several kinds of retinal dystrophy, and they show a variety of manifestations. The authors identified a novel Val200Glu mutation of the peripherin/RDS gene in a Japanese family with autosomal dominant cone-rod dystrophy (CRD). This report describes a genotype-phenotype correlation of the Val200Glu mutation. PATIENTS AND METHODS: Fifteen members of one Japanese family with autosomal dominant CRD were screened for mutations in the peripherin/RDS and ROM 1 genes. Clinical features were identified by visual acuity, visual field testing, fundus examination, and electroretinography. RESULTS: A Val200Glu mutation was found in all of the affected family members examined and was segregated with the disease. No patient had a mutation in the ROM 1 gene. Phenotypic characteristics of each affected member in this family showed intrafamilial similarity. Characteristic features included cone function more severely impaired than rod function and degenerative change in the macular region associated with peripheral retinal degeneration. CONCLUSION: The mutation at codon 200 of the peripherin/RDS gene causes both cone and rod degeneration. The Val200Glu mutation results in a type of autosomal dominant CRD.

Adult↗
PubMed1986

Cone-rod dystrophy. A clinical and histopathologic report.

Clinical, histopathologic, and electron microscopic findings in two postmortem eyes from a 29-year-old black man and the clinical and electrophysiologic findings of his 33-year-old sister, both of whom had bilateral atrophic macular lesions, confirmed the diagnosis of cone-rod dystrophy in these two patients. Light microscopy revealed a loss of photoreceptor cells primarily in the peripheral retina and macula, with relative preservation of both rod and cone cells in the equatorial area. Electron microscopy showed abundant lipofuscin-like granules aggregated in the basal portion of the retinal pigment epithelial cells. In the macular area, many retinal pigment epithelial cells were atrophic. The phagocytic capacity of the retinal pigment epithelium appeared to remain intact. The accumulation of lipofuscin-like granules in the retinal pigment epithelium may be one of the significant pathologic changes of this dystrophy.

Adult↗
PubMed1997

Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration.

Crx is a novel paired-like homeodomain protein that is expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of a disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis of the proband from a family with autosomal dominant CORD revealed an Arg41Trp substitution in the third residue of the CRX homeodomain. The sequence change cosegregated with the disease phenotype and was not detected in 247 normal controls. Recombinant CRX homeodomain containing the Arg41Trp substitution showed decreased DNA binding activity. Analysis of another 169 CORD probands identified three additional CRX sequence variations (Arg41Gln, Val242Met, and a 4 bp deletion in codons 196/7) that were not found among the controls. This data suggests that mutations in the CRX gene are associated with photoreceptor degeneration and that the Crx protein is necessary for the maintenance of normal cone and rod function.

Adult↗
PubMed1997

Cone and rod function in cone degenerations.

Progressive cone dystrophy (CD) is usually marked in the initial stages by reduced visual acuity, color vision deficiency and alterations in the photopic electroretinogram, while morphological alterations can be very mild; in some forms rods are affected in a later stage as well. We examined 40 patients with progressive cone dystrophy to determine the extent of functional losses in the cone system with psychophysical tests. A great variety of visual acuity and fundus alterations was found. Myopia was present in 74% of the patients. An autosomal dominant pattern of inheritance predominated (32%). No prevalence of gender was found. The age of onset ranged between 10 and 30 yr. All patients had progression of their symptoms. The total error score in color arrangement tests, the saturated Farnsworth Panel D-15 and the Farnsworth-Munsell 100-hue test, was pathologic with a predominance of confusions along the tritan and scotopic axis. Especially if visual acuity was below 0.5, color vision defects increased, but color vision defects were also found in patients with normal visual acuity. A general decrease of sensitivity in all three cone mechanisms was observed in measurements of spectral sensitivity. Moreover, cone-cone interaction as tested by transient tritanopia measurements was usually disturbed. In the dark adaptation function the threshold of the cone branch was usually elevated. These tests provide a good means to ascertain the correct diagnosis in early stages of the disease and to monitor progression in patients suffering from cone dystrophy.

Adolescent↗