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ABSTRACT: To describe the clinical and histopathologic findings of a 72-year-old female with North Carolina macular dystrophy.
Observational case report with histopathologic correlation. Clinical examination includes slit-lamp biomicroscopy, indirect ophthalmoscopy, color fundus photography, and focal electroretinography. Histopathologic examination of the enucleated left eye performed with light microscopy.
Light microscopy demonstrated a discrete macular lesion characterized by focal absence of photoreceptor cells and retinal pigment epithelium with attenuation of the Bruch membrane and focal atrophy of the choriocapillaris. Adjacent to the macular lesion, some lipofuscin was identified in the retinal pigment epithelium.
North Carolina macular dystrophy has both clinical and microscopic appearances of a well-demarcated lesion confined to the macula, which involves the retina, pigment epithelium, and choriocapillaris.
American Journal of Ophthalmology 01/2002; 132(6):933-5. · 4.22 Impact Factor
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Ophthalmology 10/2001; 108(9):1516-7. · 5.45 Impact Factor
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E De Baere,
M J Dixon, K W Small,
E W Jabs,
B P Leroy,
K Devriendt,
Y Gillerot,
G Mortier,
F Meire,
L Van Maldergem, [......],
A Verloes,
N Udar,
V Yellore,
M Chalukya,
S Yelchits,
A De Paepe,
F Kuttenn,
M Fellous,
R Veitia,
L Messiaen
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ABSTRACT: Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.
Human Molecular Genetics 08/2001; 10(15):1591-600. · 7.64 Impact Factor
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ABSTRACT: To describe the clinical and histopathologic findings in a 72-year-old woman with North Carolina macular dystrophy.
Clinical examination was performed by slit-lamp biomicroscopy, indirect ophthalmoscopy, color fundus photography, and focal electroretinography. Histopathologic examination of the enucleated left eye consisted of light microscopy.
Light microscopy demonstrated a discrete macular lesion characterized by focal absence of photoreceptor cells and retinal pigment epithelium. Bruch's membrane was attenuated in the center of the lesion and associated with marked atrophy of the choriocapillaris. Adjacent to the central lesion, some lipofuscin was identified in the retinal pigment epithelium.
North Carolina macular dystrophy has both clinical and microscopic appearances of a well-demarcated retinal and pigment epithelial lesion confined to the macula. This is consistent with the clinical impression that it is a focal macular dystrophy.
Transactions of the American Ophthalmological Society 02/2001; 99:233-7; discussion 237-8.
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K W Small,
N Udar,
S Yelchits,
R Klein,
C Garcia,
G Gallardo,
B Puech,
V Puech,
D Saperstein,
J Lim,
J Haller,
C Flaxel,
R Kelsell,
D Hunt,
K Evans,
F Lennon,
M Pericak-Vance
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ABSTRACT: We previously reported linkage of North Carolina macular dystrophy in a single isolated family to a broad region on chromosome 6q16. In order to refine the localization of the MCDR1 gene (North Carolina macular dystrophy), additional families with this disease and new markers were studied.
We ascertained 10 families with the North Carolina macular dystrophy phenotype (MCDR1). These families were of various ethnic and geographic origins such as Caucasian, Mayan Indian, African-American, French, British, German, and American of European decent. Two hundred thirty-two individuals in these families underwent comprehensive ophthalmic examinations and blood was collected for genotyping. One hundred seventeen were found to be affected. Linkage simulation studies were performed. Two-point linkage, haplotype analysis, and multipoint linkage was performed using VITESSE and FASTLINK. HOMOG was used to test for genetic heterogeneity.
The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families. Multipoint linkage analysis indicates that the MCDR1 gene is in the interval between D6D249 and D6S1671 with a maximum LOD score of 41.52. There was no evidence of genetic heterogeneity among the families studied. Families 765, 768, 772, 1193, and 1292 shared the same chromosomal haplotype in this region.
This is the largest single data set of families with the MCDR1 phenotype. The single large family from North Carolina continues to be informative for the closest flanking markers and alone supports the minimal candidate region as suggested by previous studies. There remains no evidence of genetic heterogeneity in this disease. Most of the American families appear to have descended from the same ancestral mutation. The remaining families could each represent independent origins of the mutation in the MCDR1 gene.
Molecular vision 12/1999; 5:38. · 2.20 Impact Factor
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ABSTRACT: To describe the clinical findings of an autosomal dominant macular dystrophy in a family of Mayan Indian ancestry in Belize, Central America, and to determine its molecular genetic relationship with the original North Carolinian family.
We performed comprehensive ophthalmic examinations on 56 members of a single family living in Chicago, Illinois, and Belize, Central America. Fundus photography and fluorescein angiography were performed on 17 affected subjects and six affected family members were serially examined over a 12-year period. Blood was collected from 26 individuals, and DNA was extracted for genotyping. Two-point linkage, multipoint linkage, and haplotype analysis was performed.
In 17 affected individuals, the clinical features were consistent with the diagnosis of North Carolina macular dystrophy. Multipoint linkage analysis generated a peak lod score of 5.6 in the MCDR1 region. The haplotype associated with the disease was, however, different from that of the original North Carolinian family.
This family has an autosomal dominant macular dystrophy that is clinically indistinguishable from North Carolina macular dystrophy (MCDR1). Our findings indicate that the mutated gene in this Belizean family maps precisely to the same region as that of the North Carolina macular dystrophy (MCDR1) locus. This study provides evidence that MCDR1 occurs in various ethnic groups and that there is no evidence of genetic heterogeneity.
American Journal of Ophthalmology 05/1998; 125(4):502-8. · 4.22 Impact Factor
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ABSTRACT: To map the gene responsible for causing a macular degeneration in a Texan family that appears clinically similar to the North Carolina macular dystrophy (MCDR1) phenotype.
A single family in Texas had all the typical clinical features of the North Carolina macular dystrophy phenotype. Of 23 family members examined, 10 were affected. Blood was collected from all 23 members and fundus photographs were obtained on those affected. A detailed family history consisting of nine generations was obtained. Genotyping and likelihood analysis was performed using the closest linked MCDR1 markers.
The genealogic data showed no relation with the original North Carolina macular dystrophy pedigree. The dinucleotide repeat marker D6S283 yielded the highest 2-point LOD score with a Zmax = 4.1 at theta = 0. The peak LOD score generated from multipoint analysis was 6.0.
The linkage results indicate that the macular degeneration in this Texan family is due to a mutation in the same genomic region as that causing North Carolina macular dystrophy. Furthermore, haplotype analysis suggests that the original North Carolina family and the Texan family have the same mutation and a common founder.
Retina 02/1998; 18(5):448-52. · 2.81 Impact Factor
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K W Small
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ABSTRACT: To study the North Carolina macular dystrophy phenotype (MCDR1) in multiple families of different ethnic backgrounds, to determine the genetic relationships of these families, and to determine the minimal candidate region of the MCDR1 gene.
Thirteen families with the North Carolina MCDR1 were ascertained. These families were of various ethnic and geographic origins, such as Caucasian, Mayan Indian, African American, French, British, German, and American. Extensive genealogical investigations were performed for all families. A total of 232 members of these families underwent comprehensive ophthalmic examinations, including blood collection for genotyping. Of these, 117 were found to be affected with the disorder. Genetic linkage simulation studies were performed using the computer program SIMLINK. Two-point linkage analysis, haplotype analysis, and multipoint linkage analyses were performed using the computer programs M-LINK, VITESSE, and FASTLINK.
The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families studied. Multipoint linkage analysis and haplotype analysis indicate that the MCDR1 gene is in the 1.1-centimorgan (cM) interval between the genetic markers D6D249 and D6S1671, with a maximum LOD score of 40.03. There was no evidence of genetic heterogeneity. Families 765, 768, 772, 1193, and 1292 shared the same chromosomal haplotype in this region, suggesting they are the result of the same ancestral mutation. The remaining families each likely represent independent origins of the mutation in the MCDR1 gene. North Carolina macular dystrophy is present worldwide and does not emanate from a single founder from North Carolina.
Transactions of the American Ophthalmological Society 02/1998; 96:925-61.
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ABSTRACT: The short arm of chromosome 17 has emerged as a hot spot where several phenotypically distinct retinal disorders have been mapped in the past year. An autosomal dominant retinitis pigmentosa, Leber's congenital amaurosis, autosomal dominant cone degeneration, central areolar choroidal dystrophy and Sjogren-Larsson syndrome were all recently mapped to chromosome 17p. These disorders, their genetic linkage, possible candidate genes and the possibility that several of these disorders may share candidate genes are discussed.
Current Opinion in Neurology 03/1997; 10(1):31-5. · 4.94 Impact Factor
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ABSTRACT: To determine if a family in France, which manifests an autosomal dominant macular dystrophy, has North Carolina macular dystrophy (MCDR1) and to determine its possible molecular genetic relationship with the original North Carolina family.
A family from Northern France with a macular dystrophy underwent comprehensive ophthalmic examinations and were ascertained for genetic studies. Blood collection and examinations were performed on 38 individuals. Fundus photographs with a hand held KOWA camera were obtained on affected subjects. DNA was extracted and genotyping performed using new microsatellite genetic markers, which have recently been found in the MCDR1 (North Carolina macular dystrophy) region. Standard two - point linkage and haplotype analysis was performed.
Eleven individuals were found with the clinical manifestations of North Carolina macular dystrophy. Two - point linkage analysis generated a maximum peak LOD score of 4.5 with a recombination of 0% between D6S1717 and the macular dystrophy locus in the French family. The haplotype associated with the disease is, however, different from that of the original North Carolina family.
These findings indicate that the macular dystrophy gene in this French family maps to the same region as that of North Carolina macular dystrophy (MCDR1) locus but that independent mutations are involved. The disease in the French family is clinically and genetically similar to North Carolina macular dystrophy. Therefore MCDR1 occurs in various ethnic groups, is present world-wide, and there remains no evidence of genetic heterogeneity for this clinically distinct form of macular degeneration.
Molecular vision 02/1997; 3:1. · 2.20 Impact Factor
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ABSTRACT: The term "vestibulocerebellar ataxia" has been applied to a rare, autosomal dominant, late-onset disease with unusual ocular motility findings. We examined the ocular motility of 18 family members from two different kindreds and found 11 affected individuals. Both families in the present study, one of which was originally described by Farmer and Mustian, as well as the family reported by Farris et al., originated from Johnston County, North Carolina. We suspect that all three of these families have a common ancestral origin. The age of onset of the disorder was 31-60 years in the individuals examined. Ataxia, vertigo, diplopia, oscillopsia, and tinnitus were common complaints. Although a variety of eye movement abnormalities have previously been described in this disease, the most prominent and consistent findings in our patients were (a) abnormal smooth pursuits, (b) inability to suppress the vestibuloocular reflex (VOR), and (c) gaze-evoked nystagmus. These findings suggest that the cerebellar flocculus may be the primary site of pathology.
Journal of Neuro-Ophthalmology 07/1996; 16(2):91-5. · 1.45 Impact Factor
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ABSTRACT: To clarify the nosology of autosomal dominant central areolar pigment epithelial dystrophy (CAPED) as previously described.
The authors studied a family of 69 members spanning six generations with a macular dystrophy. Thirty-four patients were examined, and those found to be affected underwent further testing, including visual fields, electrophysiologic studies, and fluorescein angiography. Family history and medical records were used in three additional deceased patients.
Eleven patients were identified as having CAPED. The phenotype was inherited in an autosomal dominant fashion. Six of these patients were examined by us and had mid-life onset (at 32-53 years) of progressive visual loss (20/50--counting fingers), occurring over a 3- to 10-year period. These subjects had circumscribed hypopigmented maculae, retinal pigment epithelial window defects on fluorescein angiography, central scotomas, and electrophysiologic studies, ranging from normal to severely abnormal. Three deceased patients were presumed to have CAPED by review of records or family history. Two additional patients examined had mild macular changes but good visual acuity and no significant abnormalities on electrophysiologic studies. The latter two patients are presumed to have had early manifestations of CAPED.
This family demonstrates that CAPED is an autosomal-dominant hereditary macular dystrophy which has late-onset and variable expressivity.
Ophthalmology 04/1996; 103(3):406-15. · 5.45 Impact Factor
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ABSTRACT: Recently several autosomal dominant corneal stromal dystrophies have been mapped to chromosome 5q. Therefore, we tested whether Reis-Bücklers' corneal dystrophy, an autosomal dominant trait, was also linked to the same region.
Five generations of a single family with Reis-Bücklers' corneal dystrophy were ascertained. Twenty-two family members were examined, and 11 were found to be affected. Blood was obtained for genetic linkage analysis.
Several genetic markers on chromosome 5q were strongly suggestive of linkage or confirmed linkage (LOD score > 3.0). Multipoint analysis generated a maximum LOD score of 4.25 between D5S414 and IL-9.
Reis-Bücklers', lattice type 1, Avillino, and granular corneal dystrophies all map to the same genetic locus. This suggests that one of the following might be true: (1) that a corneal gene family exists in this region; (2) that these corneal dystrophies represent allelic heterogeneity (that is, different mutations within the same gene manifest as different phenotypes); or (3) that these are all the same disease.
American Journal of Ophthalmology 04/1996; 121(4):384-90. · 4.22 Impact Factor
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ABSTRACT: Autosomal dominant cone degeneration is an uncommon disorder characterized by progressive photophobia, hemeralopia, decreased central vision, and dyschromatopsia. To better understand the variable expressivity of autosomal dominant cone degeneration, we studied a single, large family.
We performed comprehensive ophthalmic examinations, full-field electroretinography, foveal electroretinography, and color vision studies on 73 family members.
Of the 73 family members, 34 were affected. Symptoms generally began in the first decade of life and slowly progressed into midlife. Ophthalmoscopic findings consisted primarily of macular granularity or central macular atrophy. The photopic full-field electroretinogram was important in establishing the diagnosis, although the results of the electroretinographic measurements varied across individuals. Either the foveal electroretinogram amplitudes were abnormally low or the foveal/parafoveal ratio was abnormal in all affected subjects.
No single test or finding was completely sensitive or specific for accurate diagnosis of autosomal dominant cone degeneration. Especially in the more mildly affected subjects, a constellation of symptoms, findings, and test results were used to diagnose autosomal dominant cone degeneration accurately.
American Journal of Ophthalmology 02/1996; 121(1):1-12. · 4.22 Impact Factor
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ABSTRACT: We studied a single, large family with autosomal dominant cone degeneration in order to map the disease-causing gene.
Seventy-three individuals in this family were examined, and 34 were found to be affected. Blood samples from 34 affected and unaffected family members were obtained for DNA analysis and linkage mapping. Fifty-three genetic markers were analyzed in this family by using short tandem repeat markers. These markers were primarily in candidate genomic regions.
Marker D17S796 generated a significantly positive LOD score of 4.21 (theta = .04; 10,000:1 odds in favor of linkage). Marker D17S513 gave a significant LOD score of 3.1 (theta = .096; 1,000:1 odds in favor of linkage). Other markers in the region generated suggestive findings, such as D17S786, with a LOD score of 2.7, and D17S945, with a LOD score of 2.41.
Our results indicate that a genetic defect that causes autosomal dominant cone degeneration is located on chromosome 17p in the region of recoverin. Recoverin, a retinal expressed gene, is an appealing candidate for this disease.
American Journal of Ophthalmology 02/1996; 121(1):13-8. · 4.22 Impact Factor
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ABSTRACT: Blepharophimosis syndrome (BPES, blepharophimosis eyelid syndrome) is a distinctive congenital eyelid malformation which can occur sporadically or be inherited in an autosomal dominant fashion. Previous reports have described associated cytogenetic abnormalities on chromosome 3q. We have ascertained and sampled two BPES families with apparent autosomal dominant inheritance and have tested for linkage with 17 polymorphic markers on 3q. Multipoint analysis generated a maximum LOD score of 3.23 using the markers RHO, ACPP and D3S1238. No evidence of genetic heterogeneity was observed. These studies provide the first non-cytogenetic evidence that a defective gene responsible for BPES is located on 3q22.
Human Molecular Genetics 04/1995; 4(3):443-8. · 7.64 Impact Factor
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ABSTRACT: A pyogenic granuloma of the cornea developed on the vascularized cornea of a 79-year-old woman after "snake oil" accidentally dripped in her eye. The snake oil was being used to relieve forehead pain, which may have been referred. The five previously reported examples of corneal pyogenic granuloma are similar to this case in that trauma preceded development of the lesion. However, the chemical trauma induced by the snake oil appears to be a unique mechanism of injury.
Cornea 06/1994; 13(3):284-6. · 1.73 Impact Factor
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K W Small
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ABSTRACT: With the new advances in molecular genetic technologies and methods has come great progress in mapping disease-causing genes. Many of these methods using polymerase chain reaction have made gene mapping much more efficient and effective. Herein is a brief review of some of the most recent advances in mapping genes causing eye diseases. Despite the technological advances, none of this progress would have been made had not the families been available for studies. Therefore, the clinician is the cornerstone of, essentially, all molecular genetic studies and it is imperative for the clinician to be aware of these diseases and the importance of ascertaining families with these disorders to continue such progress.
The Journal of the Florida Medical Association 05/1994; 81(4):264-7.
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ABSTRACT: The macular degenerations comprise a heterogeneous group of diseases, generally reported in small families. Single, large family studies of North Carolina macular dystrophy have aided in defining the spectrum of the phenotype of this disorder and its relationship to other macular degenerations. North Carolina macular dystrophy has many phenotypic similarities to age-related macular degeneration with the glaring exception of the early age of onset of North Carolina macular dystrophy. The authors initially reported mapping this disease by linkage to the long arm of chromosome 6. They now report additional data on a total of 247 individuals in the original North Carolina macular dystrophy family whom we ascertained for clinical and molecular genetic studies. Standard clinical ophthalmic examination revealed that 96 of these individuals were affected. Molecular genetic studies increased the LOD score to 23 and refined the genomic localization of the disease-causing gene to 6q14-q16.2.
Ophthalmic paediatrics and genetics 01/1994; 14(4):143-50.
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ABSTRACT: A genetic map of highly polymorphic microsatellite markers spanning the von Hippel-Lindau region (VHL) of 3p25 was constructed using the CEPH reference pedigrees. A greater than 1000:1 odds map of pter-D3S1038-RAF1-D3S651-D3S656-D3S110- D3S1255-cen was found. Genotyping of six multigenerational VHL families showed the region surrounding the D3S1038 marker to be the most likely location for the VHL gene with a peak location score of 10.04 with VHL completely linked to D3S1038. These data provide an initial high resolution genetic map of this region; D3S1038 appears to be a highly polymorphic marker that should prove useful in the future for presymptomatic diagnosis.
Journal of Medical Genetics 07/1993; 30(6):487-91. · 6.36 Impact Factor
