North Carolina macular dystrophy (MCDR1)

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.     

An early-onset autosomal dominant macular dystrophy (MCDR3) resembling North Carolina macular dystrophy maps to chromosome 5

PURPOSE: To characterize the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus. METHODS: Thirteen members of a four-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, fundus fluorescein angiography, and fundus autofluorescence imaging. After informed consent was obtained, blood samples were taken for DNA extraction, and genetic linkage analysis was performed. RESULTS: The retinal changes have an early age of onset and are confined to the macular region. The macular abnormalities vary from mild retinal pigment epithelium (RPE) pigmentary change to atrophy. Drusen-like deposits are present to various degrees and are characteristic of the phenotype. Subretinal neovascular membrane (SRNVM) is an established complication. Genetic linkage analysis established linkage to chromosome 5, region p13.1-p15.33 with a maximum LOD score of 3.61 at a recombination fraction of 0.00 for marker D5S630. The locus for this autosomal dominant macular dystrophy lies between flanking markers D5S1981 and D5S2031. CONCLUSIONS: A novel locus has been identified for early-onset autosomal dominant macular dystrophy on chromosome 5.     

North Carolina macular dystrophy, revisited

Progression of the maculopathy in North Carolina macular dystrophy (NCMD) was not well documented. Thus, the author recently examined 22 affected members of the original kindred. Evidence of progression of the macular disease was sought through comparison of the recent fundus findings with old fundus photographs and from subjective complaints of worsening visual acuity. Only 1 of the 22 affected subjects had evidence of such change. Additionally, two new findings of NCMD were observed: (1) severe macular lesions which were staphylomatous or excavated in appearance, not flat, and atrophic as previously described; and (2) peripheral retinal drusen variably present in affected subjects, in contrast to the "normal peripheral retina" originally described. These new findings, along with the generally stable course of the disease would seem to alter our understanding of the relationship of NCMD to other dominant macular dystrophies.     

North Carolina macular dystrophy: a hereditary macular dystrophy with good visual prognosis

Background: North Carolina macular dystrophy (NCMD) is a rare autosomal dominant maculopathy with highly variable expressivity. Genetic analysis of an American family consisting of 247 members out of which 96 were affected with NCMD allowed chromosomal assignment of the NCMD locus to 6q14-q16.2. Few families with NCMD are known in Europe, one of these is living in Germany. By routine investigation, a second family affected with NCMD was detected in Germany. As some authors still doubt the good prognosis of this disease, our results should be added to the experience of others. Patients and methods: In a total of 18 family members from three generations between the age of 2 and 65 years, clinical investigations and genetic analysis was carried out. Some individuals had additional examinations such as colour contrast sensitivity, EOG, ERG, and microperimetry. Results: Ten of 18 family members turned out to be affected. All grades of NCMD were present with great variability. Visual acuity ranged from 0.32 to 1.0 and did not correlate to the grade of the disease or to the age of the person. In those patients who underwent microperimetry, central fixation was confirmed. Genetic linkage analysis further narrowed the region harbouring the NCMD locus and supported the assumption that the central areolar pigment epithelial dystrophy (CAPED) is an allelic disorder. Conclusion: Similar visual acuity in three generations of NCMD patients supports the observation that NCMD is not a progressive disorder. If geographic atrophy is found in a patient with good visual acuity, NCMD should be considered and genetic analysis should be carried out.      

North Carolina macular dystrophy: clinicopathologic correlation

PURPOSE: To describe the clinical and histopathologic findings of a 72-year-old female with North Carolina macular dystrophy. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

A Korean family with an early-onset autosomal dominant macular dystrophy resembling North Carolina macular dystrophy

PURPOSE: To characterize and report the phenotype of a Korean family with an early-onset autosomal dominant macular dystrophy resembling North Carolina macular dystrophy (NCMD). METHODS: Five members of a Korean family were examined clinically and underwent fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, full field electroretinogram (ERG), multifocal ERG, electro-oculography (EOG), a color vision test, and a visual field test. RESULTS: Visual acuity ranged from 20/200 to 20/20. Fundus findings demonstrated varying degrees of involvement ranging from drusen only to chorioretinal involvement. Central scotoma corresponded to retinal lesions in two patients. Full field ERG was normal but multifocal ERG showed decreased amplitude and delayed implicit time in the macular area. EOG was normal except in one patient. Color vision tests were also normal. CONCLUSIONS: The phenotype of this Korean family is consistent with NCMD. Linkage analysis is required to confirm the diagnosis.     

Clinical characterization and genetic mapping of North Carolina macular dystrophy

North Carolina macular dystrophy (NCMD) is an autosomal dominant macular disease, was mapped to 6q14-q16.2, the disease-causing gene has yet not been identified. It shares phenotypic similarity with age-related macular degeneration including drusen and choroidal neovascularization. We collected six families with NCMD including 75 members, and conducted clinical characterization and genetic mapping for these families. Forty-five patients were diagnosed as NCMD; all six NCMD families were mapped to MCDR1 locus using genetic linkage analysis. MCDR1 interval was refined to 3 cM (1.8mb) between D6S1716 to D6S1671 via fine mapping using microsatellite markers in these six families, all eleven annotated genes within the interval were analyzed by mutation screening in coding regions, no mutation was found, suggesting a potential novel gene or a new pathological mechanism causing NCMD. The refinement of MCDR1 locus will aid the disease-causing gene identification. Functional studies of NCMD genes should provide important insights into pathogenetic mechanisms of NCMD and age-related macular degeneration.     

Subfoveal choroidal neovascularization in a 3-year-old child with North Carolina macular dystrophy

North Carolina macular dystrophy is characterized by nonprogressive atrophy of the choroid, choriocapillaris, and the retinal pigment epithelial layer. The characteristic retinal findings, ranging from scattered drusen to a posterior staphyloma, have been reported as early as infancy and usually reach their greatest magnitude in the second decade of life. Herein, we describe a case of a 3-year-old boy with a documented family history of North Carolina macular dystrophy who presented with a subfoveal choroidal neovascular membrane in addition to the macular dystrophic changes.     

Perifoveal function in patients with North Carolina macular dystrophy: the importance of accounting for fixation locus

PURPOSE: To quantify the extent of visual function losses in patients with North Carolina Macular Dystrophy (NCMD) and to demonstrate the importance of accounting for eccentric fixation when making comparisons with normal data. METHODS: Five patients with NCMD who were from a single family were examined. Multifocal electroretinograms (mfERGs) and psychophysical assessments of acuity and luminance visual field sensitivities were measured throughout the central retina. Comparisons of responses from equivalent retinal areas were accomplished by shifting normal templates to be centered at the locus of fixation for each patient. RESULTS: Losses of psychophysically measured visual function in patients with NCMD extend to areas adjacent to the locations of visible lesions. The multifocal ERG amplitude was reduced only within the area of visible lesion. Multifocal ERG implicit times were delayed throughout the entire central retinal area assessed. CONCLUSIONS: ERG timing is a sensitive assay of retinal function, and our results indicate that NCMD has a widespread effect at the level of the mid and outer retina. The findings also demonstrated that it is necessary to account for fixation locus and to ensure that equivalent retinal areas are compared when testing patients with macular disease who have eccentric fixation.     

An autosomal dominant bull's-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4

PURPOSE: To describe the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus. METHODS: Eleven members of a five-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, electrodiagnostic testing, fundus fluorescein angiography, and fundus autofluorescence imaging. Blood samples were taken for DNA extraction and linkage analysis was performed. RESULTS: The phenotype is characterized by bull's-eye macular dystrophy first evident in the first or second decade of life. There is mild visual impairment, central scotomata, and electrophysiological testing indicates that most affected individuals have disease confined to the central retina but older subjects have more widespread rod and cone abnormalities, demonstrated by flash ERG. Genetic linkage analysis established linkage to chromosome 4 at p15.2-16.3 with a maximum lod score of 3.03 at a recombination fraction of 0.00 for marker D4S391. The locus for this autosomal dominant macular dystrophy lies between flanking markers D4S3023 and D4S3022, and overlaps the Stargardt 4 locus. CONCLUSIONS: A new locus was identified for a bull's-eye macular dystrophy on the short arm of chromosome 4.     

A novel tandem duplication of PRDM13 in a Chinese family with North Carolina macular dystrophy

Graefe's Archive for Clinical and Experimental Ophthalmology - North Carolina macular dystrophy (NCMD) is a rare autosomal dominant inherited disorder characterized by macular impairment with a...     

Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q

AIMS—To document the phenotype of an autosomal dominant macular dystrophy diagnosed as having North Carolina macular dystrophy (NCMD) in this British family, and to verify that the disease locus corresponds with that of MCDR1 on chromosome 6q.
METHODS—37 family members were examined and the phenotype characterised. DNA samples from the affected members, 19 unaffected and five spouses, were used to perform linkage analysis with six microsatellite marker loci situated within the MCDR1 region of chromosome 6q.
RESULTS—Every affected family member had lesions characteristic of NCMD, which developed early in life and usually remain stable thereafter. Although fundus changes are evident in the periphery, all tests revealed that functional loss is restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion at 5° eccentricity. Significant linkage to the MCDR1 locus on chromosome 6q was obtained with three marker loci, with a maximum lod score of 5.9 (q = 0.00) obtained with D6S249.
CONCLUSION—This family has the typical phenotype NCMD, and the causative gene was linked to the disease locus (MCDR1) on chromosome 6q. Early onset and localisation of the disease to the central macula allow specialisation of eccentric retina in some eyes with resultant good visual acuity.

Keywords: macular dystrophy; linkage analysis; psychophysics     

Different clinical expressions in two families with Stargardt's macular dystrophy (STGD1)

PURPOSE: To describe the clinical expressions, with emphasis on electrophysiological examinations, in two Swedish families with Stargardt's macular dystrophy (STGD1). METHODS: Two pairs of siblings with STGD1, for whom diagnosis had been confirmed by genetic linkage to the ABCA4 gene region, were examined regarding visual acuity, kinetic perimetry, fundus photography, full-field ERG and multifocal ERG (MERG). Possible disease-causing mutations were screened for by DNA sequencing of selected regions of the ABCA4 gene. RESULTS: All STGD1 patients had visual acuity 0.07-0.1. The two families presented different fundus appearances, MERGs and implicit times on 30 Hz flicker white light full-field ERGs. Genetic analysis revealed one unique sequence variation in exon 19 of the ABCA4 gene, in one allele from the patients of one of the families. This point mutation causes the amino acid substitution T972N in the ABCR protein. CONCLUSION: Two pairs of siblings with STGD1 presented two different expressions of the disease regarding the distribution of the retinal dysfunction. One possible molecular explanation to the different clinical expressions may be the T972N substitution present in the ABCR protein in one of the STGD1 families investigated.     

Structural and functional assessment of the macular region in patients with glaucoma

PURPOSE: To investigate the correlation of a structural measure of the macular area (optical coherence tomography (OCT)) with two functional measures (10-2 Humphrey visual field (HVF) and multifocal visual evoked potential (mfVEP)) of macular function. METHODS: 55 eyes with open-angle glaucoma were enrolled. The 10-2 HVF was defined as abnormal if clusters of > or =3 points with p<5%, one of which had p<1%, were present. The mfVEP was abnormal if probability plots had > or =2 adjacent points with p<1%, or > or =3 adjacent points with p<5% and at least one of these points with p<1%. Two criteria were used for the macular OCT: (I) > or =2 sectors with p<5% or 1 sector with p<1% and (II) 1 sector with p<5%. RESULTS: 54 of the 55 eyes showed an abnormal 10-2 HVF and 50 had central mfVEP defects. The two OCT criteria resulted in sensitivities of 85% and 91%. When both functional tests showed a defect (in 49 eyes), the OCT was abnormal in 45. For the OCT the outer and inner inferior regions were the most likely to be abnormal, and both functional techniques were most abnormal in the superior hemifield. CONCLUSIONS: Good agreement exists between macular thickness and functional defects in patients with glaucoma. Study of the macular region may provide a quantitative measure for disease staging and monitoring.     

A vision specific functional index for use in patients with age related macular degeneration

AIM: To develop and evaluate a new vision specific functional index for use in individuals with age related macular degeneration (AMD). METHODS: Following consultation with patients with AMD and healthcare professionals, a questionnaire entitled the Daily Living Tasks Dependent on Vision (DLTV) was constructed. It was administered by interview to three separate groups of individuals aged 50 years or older: people with AMD, people with cataract, and people with no visual disability. The relations between DLTV, distance visual acuity, and disorder were examined using Pearson's product moment correlation coefficients, stepwise regression, and principal component analysis. RESULTS: There was a positive correlation between DLTV items and distance visual acuity in the better eye. Principal component analysis showed that the DLTV has a major single dimension within it. This first principal component accounted for 59% of the variation and correlated well with distance visual acuity in the better eye. Other components were found, one of which correlated with the difference in vision in the two eyes and one which featured in the differentiation of AMD subjects from individuals with cataracts. CONCLUSIONS: The DLTV provided information on visual impairment in patients over and above that obtained from a measure of visual acuity. It also showed that patients with AMD experience greater difficulty with daily living tasks for any given level of acuity than do patients with cataract.     

Multifocal electroretinography in patients with Stargardt's macular dystrophy

AIMS—To describe the topography of multifocal electroretinograms (ERGs) and to explore its diagnostic value in patients with Stargardt's macular dystrophy (SMD).
METHODS—51 patients with SMD were examined by means of the m-sequence technique to characterise the topography of electroretinographic responses in the central visual field. The results were compared with data from 30 normal volunteers.
RESULTS—In 49 of 51 patients with SMD, macular electroretinographic activity was markedly diminished or non-detectable. Towards more peripheral areas, ERG responses of the SMD patients approached those of normals. Implicit times were not markedly delayed at any eccentricity.
CONCLUSION—In contrast with Ganzfeld electroretinography, multifocal electroretinography is useful to detect foveal dysfunction in SMD. Areas of dysfunction were found to be usually larger than expected from psychophysical measurements and morphological alteration. In early stages of the disease it was possible to detect foveal dysfunction, even in patients lacking morphological fundus changes and with good visual acuity.

Keywords: Stargardt's macular dystrophy; fundus flavimaculatus; electroretinography