Alternative titles; symbols
SNOMEDCT: 312925009; ORPHA: 75327; DO: 0070439;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q16.2 | Macular dystrophy 1 | 136550 | Autosomal dominant | 3 | DHS6S1 | 616842 |
A number sign (#) is used with this entry because of evidence that retinal macular dystrophy-1 (MCDR1), also known as North Carolina macular dystrophy, is caused by heterozygous mutation in a DNase I (DNASE1; 125505) hypersensitivity site (DHS6S1; 616842) on chromosome 6q16, upstream of the PRDM13 gene (616741).
Heterozygous mutation in DHS6S1 also causes progressive bifocal chorioretinal atrophy (PBCRA; 600790), an ocular disorder with features that overlap those of MCDR1.
North Carolina macular dystrophy (NCMD, MCDR1) is a congenital autosomal dominant trait that appears to be completely penetrant. It is generally nonprogressive. The ophthalmoscopic findings are highly variable and are always much more dramatic than one would predict from the relatively good visual acuity level, which ranges from 20/20 to 20/400 (median, 20/60). Patients may have only a few drusen in the central macular region (grade I), confluent drusen confined to the central macular region (grade II), or a severe macular coloboma/staphyloma (grade III) involving 3 to 4 disc areas of the central macular region. Choroidal neovascular membranes develop in some patients. Color vision is normal. Electrophysiologic studies are also normal (summary by Small, 1998).
Genetic Heterogeneity of Retinal Macular Dystrophy
MCDR2 (608051) is caused by mutation in the PROM1 gene (604365) on chromosome 4p15. MCDR3 (608850) is caused by a duplication on chromosome 5p15. MCDR4 (619977) is caused by mutation in the CLEC3B gene (187520) on chromosome 3p21. MCDR5 (see 613660) is caused by mutation in the CDHR1 gene (609502) on chromosome 10q23.
See MAPPING for possible additional loci for MCDR.
Lefler et al. (1971) described a family from North Carolina in which members of 4 generations were affected with what the authors termed 'dominant macular degeneration and amino aciduria.' Onset was late in the first decade of life. Color vision remained intact, thus distinguishing the disorder, in the opinion of the authors, from Stargardt disease (see 248200). A random urine of 11 of 17 affected family members showed generalized amino aciduria and increased glycine in 2. It was not made clear whether members without macular dystrophy had amino aciduria. The authors thought the abnormality was different from other reported forms of macular dystrophy.
Frank et al. (1974) reported further on this North Carolina kindred and described their disorder as progressive foveal dystrophy. According to them, onset was under 1 year of age and the final stage was reached by the early teens at the latest. The fundus lesions consisted of pigmentary changes and drusen limited to the macula. Advanced foveal changes were always evident before a decrease in visual acuity took place. The amino aciduria was unrelated to the macular degeneration. The disorder is probably distinct from the dominant progressive foveal dystrophy described by Deutman (1971) in which onset and attainment of end stage are later, drusen are not seen, and decrease in visual acuity often precedes visible changes in the macula. The disorder is also distinct from dominant drusen of Bruch membrane (126700). Klein and Bresnick (1982) reported a mother and 3 children.
From studies of 22 affected members of the Lefler-Frank kindred with what was called North Carolina macular dystrophy by Gass (1987), Small (1989) concluded that the disorder shows little or no progression and that peripheral retinal drusen are variably present, in contrast to the original description of 'normal peripheral retina.' Small (1989) confirmed that Gass's patients were from the Lefler-Frank kindred. Both Gass (1987) and Small (1989) described some severe macular lesions which were staphylomatous or evacuated in appearance, not flat and atrophic as previously described. Visual acuity was much better than anticipated from the ophthalmoscopic appearance. The worst visual acuity was 20/200; the median was 20/40 to 20/50, and many mildly affected persons were completely asymptomatic with 20/20 vision. Small (1989) extended his examinations to many other members of the kindred with discovery of 68 affected persons. Progression occurred in only 2. Small et al. (1991) described a previously unreported branch of the North Carolina macular dystrophy family, adding another 17 affected members to the kindred. One of the 17 experienced a severe episode of deterioration of central vision with the development of a disciform lesion in the macula. The quality of the photographs in this publication was superior to that in earlier publications. Small et al. (1991) concluded that, contrary to its original description, North Carolina macular dystrophy is nonprogressive.
Fetkenhour et al. (1976) and Hermsen and Judisch (1984) had described families with what they considered to be distinct disorders, naming them 'central areolar pigment epithelial dystrophy (CAPED)' and 'central pigment epithelial and choroidal degeneration,' respectively. Small et al. (1992) found definitive genealogic connections of these families with the kindred reported by Lefler et al. (1971) and Frank et al. (1974). All were shown to be descendants of 3 Irish brothers in North Carolina. This finding demonstrated that choroidal neovascular membranes may occasionally develop in NCMD.
Small et al. (1992) stated that although the condition is named for the geographic region in which founder effect was observed, unrelated families with this disorder had been identified in Texas, Wisconsin, Canada, England, France, Spain, Belize, and Mexico.
Keithahn et al. (1996) studied a large 6-generation family originating from North Carolina in which 11 members had central areolar pigment epithelial dystrophy. Age at onset ranged from 32 to 53 years, and the presenting symptom in all patients was blurred central vision. Vision loss was progressive over a 3- to 10-year period in most affected individuals. Fundus findings ranged from patchy minimal atrophy of the central retinal pigment epithelium (RPE) to well-circumscribed hypopigmented macular lesions with loss of RPE and choriocapillaris. The peripheral retina appeared normal except in the oldest patient, who had atrophic changes without pigment clumping. Visual field examination showed central scotomas but full peripheral fields. Fluorescein angiography showed macular RPE window defects in all patients tested, as well as associated loss of the macular choriocapillaris in the oldest patient. Electrophysiologic studies ranged from normal to severely abnormal, with rod and cone function similarly affected when abnormal. Keithahn et al. (1996) noted differences between the phenotype in this kindred and descriptions of NCMD, including mid-life onset with progressive visual deterioration, usually abnormal results of electrophysiologic examination, and hypopigmented maculae with a normal peripheral retina. Small et al. (2016) included this family as part of the original North Carolina kindred described by Lefler et al. (1971).
Reichel et al. (1998) studied a British family in which 17 members over 5 generations exhibited 'typical' North Carolina macular dystrophy. Disease developed early in life and usually remained stable. Examination of 13 patients revealed that 8 had grade I disease, composed of drusen-like deposits in the peripheral fundus and normal visual acuity, with some eyes showing mild RPE changes. One patient showed grade II disease, with yellowish subretinal material at the macula and reduced visual acuity (20/40) in 1 eye. Grade III lesions were observed in the remaining 4 family members, including 2 patients in their 40s and 2 in their 20s. Visual acuities were asymmetric and ranged from 20/30 to 20/200. Funduscopy revealed deep large circumscribed excavated lesions up to 3 disc-diameters wide in the macular region. The authors noted that although fundus changes were evident in the periphery in some affected family members, all tests showed that functional loss was restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion, at 5 degrees eccentricity.
Voo et al. (2001) presented the clinical course and ocular histopathology of a woman with the same chromosome 6q16 haplotype as the original MCDR1 family. Light microscopy demonstrated a discrete macular lesion characterized by focal absence of photoreceptors and RPE with attenuation of the Bruch membrane and focal atrophy of the choriocapillaris. Adjacent to the macular lesion, some lipofuscin was identified in the RPE, corroborating previous reports of drusen surrounding the macular lesion.
Kiernan et al. (2011) reported a 2-stage 30-year follow-up of an African American family with MCDR1, the first from 1970 to 1982 in 10 patients (Leveille et al., 1982) and the second from 2005 to 2009 in 11 patients. Nine of 11 living family members had classic findings ranging from disease grade 2 (confluent foveal drusen, 8 eyes) to grade 3 (central coloboma-like lesion, 10 eyes). Two members developed choroidal neovascularization (CNV), requiring laser ablation, and 1 member developed nonclearing vitreous hemorrhage and underwent 25-gauge pars plana vitrectomy. Another family member developed exotropia and amblyopia in 1 eye by age 7 years. Those without CNV had no significant change in visual acuity over 30 years. Microperimetry analysis of the affected members with grade 3 MCDR1 revealed absent function in the region of the central coloboma-like lesions, corresponding to photoreceptor absence on optical coherence tomography (OCT), although there was preserved foveal function and intact photoreceptors adjacent to the lesion. Kiernan et al. (2011) suggested that eccentric viewing around impaired photoreceptors might explain good acuity in patients with clinical, severe-appearing macular lesions.
Bowne et al. (2016) examined 6 affected members over 3 generations of a family (RFS355) with NCMD. All had good to moderate visual acuity, ranging from 20/16 to 20/125. Evaluation of the 12 eyes showed Gass grade 1 and grade 2 changes in 1 eye each, whereas all other eyes had grade 3 Gass phenotypes with variably sized macular calderas. The calderas, consisting of a large central atrophic excavation of the retina and choroid, were centered in the macula at the site of the missing fovea. Despite the wide range of sizes, the distance between the disc and the nasal edge of the caldera were relatively similar, suggesting primarily temporal expansion during caldera formation. The preserved nasal retina typically contained the preferred locus of fixation, consistent with the good vision in these patients. The authors noted that the size and depth of the calderas were not age dependent, as the youngest individual examined had the largest lesion.
Manes et al. (2017) studied two 3-generation French families with the NCMD phenotype. In family A, 2 affected individuals from the first and second generations had visual acuities of 20/20 and displayed grades 1 and 2 NCMD, whereas 2 affected individuals from the second and third generations had grade 3 NCMD with visual acuities ranging from 20/25 to 20/60. In family B, 2 patients showed grade 1 disease and 3 patients showed grade 3 disease, with visual acuities ranging from 20/20 to 20/60. Full-field electroretinographic studies had been performed in 4 patients from family B, which showed a decrease in the amplitudes, and an increase in the latencies, of the OP3 and OP4 oscillatory potentials.
Small et al. (1991) presented linkage data on which an exclusion map was constructed; no evidence of linkage with 76 polymorphic markers was found. Using hypervariable microsatellite CA repeats, Small et al. (1992) found that 3 'Marshfield markers' (MFDs) located at 6q13-q21 were linked to the NCMD (MCDR1) locus. The highest lod score (for MFD 97) was 13.10 at theta = 0.017; MFD 171 gave a lod score of 8.42 at theta = 0.004. It may be noteworthy that chromosomal aberrations pointing to possible genes for retinal and macular degeneration located on 6q have been described (Small et al., 1992); also see 153700 and 180020. Small et al. (1992) gave a refined localization of 6q14-q16.2.
In a 5-generation family from northern Germany, Pauleikhoff et al. (1997) described an eye defect consistent with North Carolina macular dystrophy. Features included multiple drusen, choroidal neovascularization in 1 patient, and geographic atrophy in elderly patients. DNA analyses demonstrated linkage to 6q14-q16.2.
Small et al. (1997) studied a 5-generation family from northern France in which affected individuals exhibited the full range of classic findings of NCMD, with highly variable expressivity ranging from drusen in the central macular region to disciform macular lesions to macular colobomas associated with a congenital or infantile onset of decreased central vision. Analysis of microsatellite markers generated significantly positive lod scores (Zmax greater than 3.0) with markers D6S251 and D6S475, with a maximum lod score of 4.5 obtained at marker D6S1717. Small et al. (1997) noted that this family's history revealed no evidence of emigration to the United States or genealogic connection with the North Carolina family, but also stated that although the American family maintained that they were of Irish heritage, their surname was French Huguenot in origin. However, the haplotype associated with disease in the French family was different from that of the North Carolina family, suggesting that any common ancestor would have been in the far distant past.
Rabb et al. (1998) reported an autosomal dominant macular dystrophy in a family of Mayan Indian descent from Belize. The phenotype was clinically indistinguishable from NCMD. Multipoint linkage analysis generated a peak lod score of 5.6 in the MCDR1 region after genotyping 26 individuals of the 56-member family. The haplotype associated with the disease was different from that of the North Carolina family, suggesting that the mutations in MCDR1 occurred independently.
Small et al. (1998) reported a 6-generation family from southeast Texas in which 10 affected members exhibited an inherited maculopathy that was clinically the same as that of the original NCMD family, including 3 grades of severity and wide phenotypic variability. Linkage analysis yielded the highest 2-point lod score (Zmax = 4.7 at theta = 0) at marker D6S1671; multipoint analysis generated a peak lod score of 6.1, overlapping the original MCDR1 locus. Although genealogic data from the Texas family showed no relation with the North Carolina pedigree, the haplotype associated with disease in the Texas family was identical to that of the original North Carolina family, suggesting a common founder.
In a large 5-generation British family with NCMD, Reichel et al. (1998) performed linkage analysis and obtained significant linkage at 3 microsatellite markers, with a maximum lod score of 5.90 (theta = 0) at D6S249. Recombinant events narrowed the critical region to an approximately 28-cM interval, between markers D6S251 and D6S468, a region overlapping that previously assigned to MCDR1. The authors noted that although this family was of Irish origin, there was no direct link to the founders of the North Carolina pedigree who emigrated from Ireland in the 18th century.
Small et al. (1999) ascertained and examined 232 individuals from 10 families with the MCDR1 phenotype, including 7 families from the United States, 1 from Belize, 1 from northern France, and 1 from London. Analysis of chromosome 6q16 markers yielded the maximum 2-point lod scores for markers D6S249 and D6S1671 (32.00 and 35.71, respectively). Multipoint analysis in 8 of the families generated a maximum lod score of 41.52 when MCDR1 was placed between D6S249 and D6S1671, and that critical interval was confirmed by recombination events.
In a 4-generation African American family with North Carolina macular dystrophy, Kiernan et al. (2011) found linkage of the disorder to markers spanning D6S249 and D6S283 within the MCDR1 region of 6q16. This family shared the same haplotype as the originally described family from North Carolina and had clinical features similar to those in other reports of MCDR1 pedigrees.
In a large 4-generation family (RFS355) with NCMD, Bowne et al. (2016) performed linkage analysis and obtained a maximum lod score of 1.8 on chromosome 6. Chromosome 6q STR markers confirmed a consistent haplotype at 6q14-q16 that segregated fully with disease in the family.
In two 3-generation French families with NCMD, Manes et al. (2017) analyzed 13 microsatellite markers on chromosome 6q14-q16.2 and identified a haplotype in each family that segregated with disease. Recombination events defined a 16-Mb locus between D6S462 and D6S475 for family A, and a 19-Mb locus between D6463 and D6S475 for family B, both encompassing the previously reported 1.8-Mb MCDR1 locus. The authors noted that the families only shared 1 marker in common, suggesting that the 2 families could be unrelated.
Heterogeneity Pending Confirmation
Holz et al. (1995) reported clinical, angiographic, and electrophysiologic data from 5 affected members of a family of Indian origin with autosomal dominant macular dystrophy simulating the North Carolina variety. The fundus appearance in the proband simulated stage 3 North Carolina macular dystrophy. Affected relatives had features in common with pattern dystrophy, fundus flavimaculatus with a dark choroid, and dominantly inherited drusen. However, Holz et al. (1995) excluded linkage to loci assigned to a number of retinal dystrophies principally affecting the posterior pole, including the North Carolina macular dystrophy locus.
Francis et al. (2003) studied 8 affected and 4 unaffected members of a 4-generation English kindred segregating autosomal dominant macular disease, clinically similar to North Carolina macular dystrophy, and progressive adult-onset sensorineural deafness. The ocular phenotype was fully penetrant and exhibited variable expressivity, not only among different family members but also between the eyes of a single patient. Affected individuals had fine drusen-like subretinal deposits and pigmentary disturbance of the retinal pigment epithelium, centered on the macula. Others had, in addition, a well-demarcated subfoveal area of chorioretinal atrophy with pigment hypertrophy and fibrosis at the edge. The ocular phenotype was nonprogressive and in all but 1 individual was noted soon after birth; visual acuity was well preserved in those with the milder phenotype. Electroretinography in the 4 individuals who agreed to testing was normal, whereas electrooculography was mildly subnormal. The pattern of hearing loss segregating with the ocular phenotype was bilateral, symmetric, high frequency, and progressive, becoming significant in the fourth decade. Haplotype analysis indicated that this family is unrelated to the previously reported families with NCMD, and genotyping excluded linkage to the MCDR1 locus and suggested a potential locus on chromosome 14q (maximum lod score of 2.92 at theta = 0.0 for marker D14S261).
In a large 4-generation family (RFS355) with NCMD mapping to chromosome 6q14-q16, Bowne et al. (2016) analyzed the MCDR1 locus and identified a 68.9-kb tandem duplication (chr6:99,996,220-100,065,140; GRCH37) at chromosome 6q16.2 that duplicated the entire PRDM13 gene and the DNase hypersensitivity site as well as exons 1 to 9 of the CCNC gene, and included 5 bp of exogenous DNA (TCCTG) between the wildtype and duplicated regions. The duplication segregated fully with disease in the family. Noting that it was unlikely that any protein would be generated from the partial copy of CCNC, Bowne et al. (2016) stated that these results supported dysregulation of the PRDM13 gene as the cause of the MCDR1 phenotype.
By whole-genome sequencing in two 3-generation French families with MCDR1, negative for mutation in the DNase I hypersensitivity site or for a SNP or small indel at the locus, Manes et al. (2017) identified a large 98,389-bp tandem duplication that segregated with disease in both families (chr6:99,984,309-100,082,698, GRCh37). The duplication encompassed the DHS and the entire coding sequences of the CCNC (123838) and PRDM13 (616741) genes. Analysis of the orthologous genes in Drosophila melanogaster revealed that knockdown of either gene or overexpression of the CCNC ortholog did not cause any eye defect; however, overexpression of the PRDM13 ortholog resulted in strong loss of photoreceptors. The authors concluded that the phenotype observed in patients with the tandem duplication encompassing both CCNC and PRDM13 is likely due to overexpression of the PRDM13 transcription factor.
The transmission pattern of North Carolina macular dystrophy in the original family reported by Lefler et al. (1971) was consistent with autosomal dominant inheritance.
In the original North Carolina kindred with retinal macular dystrophy mapping to chromosome 6q16, negative for mutation in the 10 genes located within the MCDR1 locus, Small et al. (2016) performed whole-exome sequencing and identified a heterozygous point mutation (V1; 616842.0001) within a 255-bp DNase I (DNASE1; 125505) hypersensitivity site (DHS6S1; 616842) located upstream of both the PRDM13 (616741) and CCNC (123838) genes. The mutation segregated with disease in the family and was not found in 261 controls or in published variant databases. Analysis of 10 more MCDR1 families revealed heterozygosity for the V1 variant in all affected members of 5 of the families, including the family from southeast Texas reported by Small et al. (1998). In addition, affected members of 3 families, including the French family studied by Small et al. (1997), were heterozygous for a second point mutation within the same DHS (V2; 616842.0002), and affected members of another family were heterozygous for a third point mutation in the DHS (V3; 616842.0003). Whole-genome sequencing in the MCDR1 family from Belize, originally described by Rabb et al. (1998), revealed heterozygosity for a 123-kb tandem duplication (chr6:100,020,205-100,143,306; GRCh37) encompassing the entire coding region of the PRDM13 gene as well as the DNase hypersensitivity site. Collectively, the 4 variants were present in all 91 affected members of the 11 families, respectively; the variants were absent in 38 unaffected family members and in 261 unrelated controls, and were not found in public variant databases. Noting that PRDM13 is the only gene in the MCDR1 critical region that is solely expressed in the neural retina, and that PRDM13 expression in developing retinal cells revealed marked developmental regulation, Small et al. (2016) suggested PRDM13 is likely the responsible gene in MCDR1, although the mechanism of disease causation was not established.
In 2 British families (GC15416 and GC3722) with NCMD, one of which (GC3722) was originally reported by Reichel et al. (1998), Cipriani et al. (2017) identified heterozygosity for the V2 mutation at the MCDR1 locus (616842.0002).
In a mother and daughter with the North Carolina type of macular dystrophy, Ellingford et al. (2017) also identified heterozygosity for the V2 mutation at the MCDR1 locus.
In a 4-generation Georgian Jewish family (MOL1154) segregating markedly variable retinal maculopathy consistent with the North Carolina type, in which there was no correlation between age and disease severity, Namburi et al. (2020) identified heterozygosity for a point mutation within the DNase hypersensitivity site (DHS6S1; 616842.0006). A second variant, in the CFH gene (134370), was also present in 5 of the 6 affected individuals; the authors suggested that the CFH variant might have a modifier effect on the PRDM13 gene.
Exclusion Studies
Gehrig et al. (1998) found no disease-associated mutations in the IMPG1 gene (602870) in patients from 6q-linked multigenerational families diagnosed with MCDR1 and progressive bifocal chorioretinal atrophy (600790), or in a single patient from an autosomal dominant Stargardt disease (see 600110) family.
Manes et al. (2017) analyzed the Drosophila eye phenotype after knockdown or overexpression of D. melanogaster orthologs of the CCNC and PRDM13 genes (CycC and CG13296, respectively). Knockdown of either gene or overexpression of the CCNC ortholog did not cause any eye defect; however, overexpression of the PRDM13 ortholog resulted in strong loss of photoreceptors. In addition, overexpression of the PRDM13 ortholog in the third instar larva eye-antennal imaginal disc caused almost complete loss of the eye-antennal imaginal disc. The authors concluded that the NCMD phenotype observed in patients with duplications involving both genes is likely due to overexpression of the PRDM13 transcription factor.
Bowne, S. J., Sullivan, L. S., Wheaton, D. K., Locke, K. G., Jones, K. D., Koboldt, D. C., Fulton, R. S., Wilson, R. K., Blanton, S. H., Birch, D. G., Daiger, S. P. North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. Molec. Vision 22: 1239-1247, 2016. [PubMed: 27777503]
Cipriani, V., Silva, R. S., Arno, G., Pontikos, N., Kalhoro, A., Valeina, S., Inashkina, I., Audere, M., Rutka, K., Puech, B., Michaelides, M., van Heyningen, V., Lace, B., Webster, A. R., Moore, A. T. Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus. Sci. Rep. 7: 7512, 2017. Note: Electronic Article. [PubMed: 28790370] [Full Text: https://doi.org/10.1038/s41598-017-06387-6]
Deutman, A. F. The Hereditary Dystrophies of the Posterior Pole. Assen, The Netherlands: Van Gorcum (pub.) 1971.
Ellingford, J. M., Sergouniotis, P. I., Jenkins, E., Black, G. C. Genome sequencing identifies a non-coding variant in the MCDR locus as a cause of macular dystrophy. (Letter) Clin. Exp. Ophthal. 45: 297-320, 2017. [PubMed: 27551809] [Full Text: https://doi.org/10.1111/ceo.12825]
Fetkenhour, C. L., Gurney, N., Dobbie, J. G., Choromokos, E. Central areolar pigment epithelial dystrophy. Am. J. Ophthal. 81: 745-753, 1976. [PubMed: 937428] [Full Text: https://doi.org/10.1016/0002-9394(76)90357-3]
Francis, P. J., Johnson, S., Edmunds, B., Kelsell, R. E., Sheridan, E., Garrett, C., Holder, G. E., Hunt, D. M., Moore, A. T. Genetic linkage analysis of a novel syndrome comprising North Carolina-like macular dystrophy and progressive sensorineural hearing loss. Brit. J. Ophthal. 87: 893-898, 2003. [PubMed: 12812894] [Full Text: https://doi.org/10.1136/bjo.87.7.893]
Frank, H. R., Landers, M. B., III, Williams, R. J., Sidbury, J. B., Jr. A new dominant progressive foveal dystrophy. Am. J. Ophthal. 78: 903-916, 1974. [PubMed: 4440724] [Full Text: https://doi.org/10.1016/0002-9394(74)90800-9]
Gass, J. D. M. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. Vol. I. (3rd ed.) St. Louis: C. V. Mosby (pub.) 1987. Pp. 98-99.
Gehrig, A., Felbor, U., Kelsell, R. E., Hunt, D. M., Maumenee, I. H., Weber, B. H. F. Assessment of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene localised to 6q13-q15 in autosomal dominant Stargardt-like disease (ADSTGD), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1). J. Med. Genet. 35: 641-645, 1998. [PubMed: 9719369] [Full Text: https://doi.org/10.1136/jmg.35.8.641]
Hermsen, V., Judisch, G. F. Central areolar pigment epithelial dystrophy. Ophthalmologica 189: 69-72, 1984. [PubMed: 6472809] [Full Text: https://doi.org/10.1159/000309388]
Holz, F. G., Evans, K., Gregory, C. Y., Bhattacharya, S., Bird, A. C. Autosomal dominant macular dystrophy simulating North Carolina macular dystrophy. Arch. Ophthal. 113: 178-184, 1995. [PubMed: 7864750] [Full Text: https://doi.org/10.1001/archopht.1995.01100020062029]
Keithahn, M. A. Z., Huang, M., Keltner, J. L., Small, K. W., Morse, L. S. The variable expressivity of a family with central areolar pigment epithelial dystrophy. Ophthalmology 103: 406-415, 1996. [PubMed: 8600416] [Full Text: https://doi.org/10.1016/s0161-6420(96)30678-7]
Kiernan, D. F., Shah, R. J., Hariprasad, S. M., Grassi, M. A., Small, K. W., Kiernan, J. P., Mieler, W. F. Thirty-year follow-up of an African American family with macular dystrophy of the retina, locus 1 (North Carolina macular dystrophy). Ophthalmology 118: 1435-1443, 2011. [PubMed: 21310494] [Full Text: https://doi.org/10.1016/j.ophtha.2010.10.041]
Klein, R., Bresnick, G. An inherited central retinal pigment epithelial dystrophy. Birth Defects Orig. Art. Ser. 18(6): 281-296, 1982. [PubMed: 7171762]
Lefler, W. H., Wadsworth, J. A. C., Sidbury, J. B., Jr. Hereditary macular dystrophy and amino-aciduria. Am. J. Ophthal. 71 (suppl.): 224-230, 1971. [PubMed: 5100467] [Full Text: https://doi.org/10.1016/0002-9394(71)90394-1]
Leveille, A. S., Morse, P. H., Kiernan, J. P. Autosomal dominant central pigment epithelial and choroidal degeneration. Ophthalmology 89: 1407-1413, 1982. [PubMed: 7162784] [Full Text: https://doi.org/10.1016/s0161-6420(82)34621-7]
Manes, G., Joly, W., Guignard, T., Smirnov, V., Berthemy, S., Bocquet, B., Audo, I., Zeitz, C., Sahel, J., Cazevielle, C., Senechal, A., Deleuze, J.-F., and 9 others. A novel duplication of PRDM13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in Drosophila eye reproduces the human phenotype. Hum. Molec. Genet. 26: 4367-4374, 2017. [PubMed: 28973654] [Full Text: https://doi.org/10.1093/hmg/ddx322]
Namburi, P., Khateb, S., Meyer, S., Bentovim, T., Ratnapriya, R., Khramushin, A., Swaroop, A., Schueler-Furman, O., Banin, E., Sharon, D. A unique PRDM13-associated variant in a Georgian Jewish family with probable North Carolina macular dystrophy and the possible contribution of a unique CFH variant. Molec. Vision 26: 299-310, 2020. [PubMed: 32476814]
Pauleikhoff, D., Sauer, C. G., Muller, C. R., Radermacher, M., Merz, A., Weber, B. H. F. Clinical and genetic evidence for autosomal dominant North Carolina macular dystrophy in a German family. Am. J. Ophthal. 124: 412-415, 1997. [PubMed: 9439376] [Full Text: https://doi.org/10.1016/s0002-9394(14)70842-6]
Rabb, M. F., Mullen, L., Yelchits, S., Udar, N., Small, K. W. A North Carolina macular dystrophy phenotype in a Belizean family maps to the MCDR1 locus. Am. J. Ophthal. 125: 502-508, 1998. [PubMed: 9559736] [Full Text: https://doi.org/10.1016/s0002-9394(99)80191-3]
Reichel, M. B., Kelsell, R. E., Fan, J., Gregory, C. Y., Evans, K., Moore, A. T., Hunt, D. M., Fitzke, F. W., Bird, A. C. Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q. Brit. J. Ophthal. 82: 1162-1168, 1998. [PubMed: 9924305] [Full Text: https://doi.org/10.1136/bjo.82.10.1162]
Small, K. W., DeLuca, A. P., Whitmore, S. S., Rosenberg, T., Silva-Garcia, R., Udar, N., Puech, B., Garcia, C. A., Rice, T. A., Fishman, G. A., Heon, E., Folk, J. C., Streb, L. M., Haas, C. M., Wiley, L. A., Scheetz, T. E., Fingert, J. H., Mullins, R. F., Tucker, B. A., Stone, E. M. North Carolina macular dystrophy is caused by dysregulation of the retinal transcription factor PRDM13. Ophthalmology 123: 9-18, 2016. [PubMed: 26507665] [Full Text: https://doi.org/10.1016/j.ophtha.2015.10.006]
Small, K. W., Garcia, C. A., Gallardo, G., Udar, N., Yelchits, S. North Carolina macular dystrophy (MCDR1) in Texas. Retina 18: 448-452, 1998. [PubMed: 9801042]
Small, K. W., Hermsen, V., Gurney, N., Fetkenhour, C. L., Folk, J. C. North Carolina macular dystrophy and central areolar pigment epithelial dystrophy: one family, one disease. Arch. Ophthal. 110: 515-518, 1992. [PubMed: 1562260] [Full Text: https://doi.org/10.1001/archopht.1992.01080160093040]
Small, K. W., Killian, J., McLean, W. C. North Carolina's dominant progressive foveal dystrophy: how progressive is it? Brit. J. Ophthal. 75: 401-406, 1991. [PubMed: 1854692] [Full Text: https://doi.org/10.1136/bjo.75.7.401]
Small, K. W., Puech, B., Mullen, L., Yelchits, S. North Carolina macular dystrophy phenotype in France maps to the MCDR1 locus. Molec. Vision 3: 1, 1997. Note: Electronic Article. [PubMed: 9238090]
Small, K. W., Udar, N., Yelchits, S., Klein, R., Garcia, C., Gallardo, G., Puech, B., Puech, V., Saperstein, D., Lim, J., Haller, J., Flaxel, C., Kelsell, R., Hunt, D., Evans, K., Lennon, F., Pericak-Vance, M. North Carolina macular dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis. Molec. Vision 5: 38, 1999. Note: Electronic Article. [PubMed: 10617775]
Small, K. W., Weber, J. L., Hung, W.-Y., Vance, J., Roses, A., Pericak-Vance, M. North Carolina macular dystrophy: exclusion map using RFLPs and microsatellites. Genomics 11: 763-766, 1991. [PubMed: 1685483] [Full Text: https://doi.org/10.1016/0888-7543(91)90087-u]
Small, K. W., Weber, J. L., Roses, A., Lennon, F., Vance, J. M., Pericak-Vance, M. A. North Carolina macular dystrophy is assigned to chromosome 6. Genomics 13: 681-685, 1992. [PubMed: 1639395] [Full Text: https://doi.org/10.1016/0888-7543(92)90141-e]
Small, K. W., Weber, J. L., Roses, A., Lennon, F., Vance, J. M., Pericak-Vance, M. A. North Carolina macular dystrophy is localized to 6q14-q16.2. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A34 only, 1992.
Small, K. W. North Carolina macular dystrophy, revisited. Ophthalmology 96: 1747-1754, 1989. [PubMed: 2622620] [Full Text: https://doi.org/10.1016/s0161-6420(89)32655-8]
Small, K. North Carolina Macular Dystrophy. In: Traboulsi, E. I. (ed): Genetic Diseases of the Eye. New York: Oxford Univ. Press 1998. Pp. 367-371.
Voo, I., Glasgow, B. J., Flannery, J., Udar, N., Small, K. W. North Carolina macular dystrophy: clinicopathologic correlation. Am. J. Ophthal. 132: 933-935, 2001. [PubMed: 11730667]