North Carolina Macular Dystrophy

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Review:
Assigned status Update Pending
 by Sun Young (Sunny) Lee, MD, PhD on January 7, 2022.


Disease Entity

North Carolina Macular Dystrophy (MCDR1, PRDM13, MCDR3, OMIM 136,550)

Disease

North Carolina Macular Dystrophy (MCDR1, PRDM13, MCDR3, OMIM 136,550)

alias: Lefler, Wadsworth and Sidbury Syndrome, Hereditary Macular Degeneration and Amino-aciduria, Dominant Progressive Foveal Dystrophy, Central Areolar Pigment Epithelial Dystrophy (CAPED), Autosomal Dominant Central Pigment Epithelial and Choroidal Degeneration (all of these names were assigned to this one disease in one family)

phenocopies: congenital toxoplasmosis, Bests vitelliform macular dystrophy (BVMD), age-related macular degeneration, Torpedo maculopathy

Etiology

Inherited, autosomal dominant

Risk Factors

affected family memebers

General Pathology

To the best of our knowledge, there is only one report in the literature of a histopathological correlation. This report was by Small et al (Small KW, Vu I, Glasgow B, Flannary J. Histopathologic study of North Carolina macular dystrophy. American Journal Ophthalmology 132, 933-934, 2001). This was in a patient with a grade 2 macular lesion with confluent drusen centrally. Histopath showed the drusen to be typical appearing drusen with discrete loss of outer retina in the central macular area. In retrospect there was no abnormality of the Amacrine cell layer as might be expected after the mutations w were found.

Pathophysiology

This is a congenital developmental abnormality of the macula. Based on the mutations recently found by Small et and later confirmed by others, it would appear that the mutations cause malfunctioning of the DNASE1 hypersensitivity binding sites which then causes release of inhibition of the retinal transcription PRDM13 in the case of the MCDR1 locus. PRDM13 is a known factor involved in the development of the embryonic retina. In the case of the MCDR3 chromosome 5 locus, there are also duplications of another DNASE1 site but no known retinal transcription factor. One theory is that these mutations alter chromatin folding causing structural variants.

Primary prevention

Not applicable

Diagnosis

Clinical diagnosis: There is a great deal of variable expressivity in the appearance of the maculae. In general the macular lesions are congenital and bilaterally symmetrical. The appearance of the lesions range from central small / intermediate drusen (grade 1), to confluent drusen, to central vitelliform lesions (grade 2), to large central defects with atrophy that bows back into the choroid and sclera (grade 3) often with surrounding subretinal fibrosis (most likely from choroidal neovascularizations, CNVM). The visual acuity if generally better than would be expected given the appearance of the lesions. The visual acuity is stable throughout the patient’s lifetime unless they develop a CNVM in their area of the macula where they fixate (typically slightly nasal to the typical fovea).

Examining other family members is critical in appreciating the variable expressivity and greatly facilitates correctly diagnosing this disease. The diagnosis can be difficult when only one isolated individual is being examined. Examining other family members is important.

The diagnosis can now be made with DNA sequencing. Below are the published known mutations. If DNA sequencing is positive for one of these mutations, then that is pretty solid confirmatory evidence. If no mutation is found with DNA sequencing that does not necessarily mean that the person does not have NCMD; it means that either it was missed on sequencing or there is another mutation that has not yet been found / published. Below is a table of the known published mutations. Additionally the commercial labs are currently only sequencing the MCDR1 chromosome 6 locus and NOT sequencing the MCDR3 chromosome 5 locus that is more prevalent in the European population.

Variant Number phenotype Type of Variant Chromosomal Position (Hg19)   Nucleotide Change Geographic location Found by:  
           
      Chromosome 6      
V1 NCMD / MCDR1 SNP 6: 100040906 c.-14005G>T G>T USA Small et al 2017 F: 5'-GCATTCCCTAAAGCACTTGACC-3'

R: 5'-GATAGCTACCCCTCCTCTGAATG-3'

V2 NCMD / MCDR1 SNP 6: 100040987 c.-13924G>T G>C France/ Germany/ USA  /UK Small et al 2017 F: 5'-CTGATCATTTGAATCAAGGCAG-3'

R: 5'-CAGCACTTGCACATTTGTGTC-3'

V3 NCMD / MCDR1 SNP 6: 100041040 c.-13871C>T C>T China Small et al 2017 F: 5'-CACTGGAAAAATTATGTGGAAATC-3'

R: 5'-GAGTAATTAATGAAGTTGACAAGTTG-3'

V4 NCMD / MCDR1 Tandem DUP 6: 100020205-100143306   123,101 bp DUP Belize Small et al 2017 F: 5'-GATAAATCATATCTTAGACCGC-3'

R: 5'-CTCATGCCTATAATCCCAGCAC-3'

V6 NCMD / MCDR1 Tandem DUP 6: 99996226-100065137   69,912 bp DUP USA Brown et al 2019 F: 5'-TGTAAAACGACGGCCAGTCTGGCTCAGTACCAACTCCTG-3'

R: 5'-CAGGAAACAGCTATGACCGGAACAGAATACTGGGTCCTTT-3'

F: 5'-TGTAAAACGACGGCCAGTCATGGGAAACATTTTATCAGC-3'

R: 5'-CAGGAAACAGCTATGACCTGTTGATGTTTCTTGGCCTCC-3'

V7 NCMD / MCDR1 Tandem DUP 6: 99984309-100082698   98,389 bp DUP France / Italy Manes et al 2019 / Small et al F: 5'-AGGCACCTGAGGTAAGCAGA-3'

R: 5'-CCTGACCTCAGGTGATCTGC-3'

V10 PBRCA   SNP   6:100046804 c.-8107T>C NM_021620.3 T>C UK Silva et al 2019
V11 severe NCMD / PBRCA- SNP   6: 100046783 c.-8128A>C NM_021620.3 A>C Asian / Egypt Silva et al 2019  / Small et al
V12 NCMD / MCDR1 Tandem DUP 6: 99112389-99168616   56,228 bp DUP Turkey Small et al 2020 /Vance/Ozge/deBaere
V13 NCMD / MCDR1 SNP CHF? 6: 100040974   A>C   Namburi et al 2020
MCDR3 Chromosome 5
V5 NCMD / MCDR3 Tandem DUP 5: 3587901-4486027   898,126 bp DUP Denmark Small et al 2017 F: 5'-GTTTTCACGAAAGTGCAAAGG-3'

R: 5'-GGGGTGGAAGAGAAGAGAGG-3'

V8 NCMD / MCDR3 Tandem DUP 5:4391377–4436535   45,158 bp DUP UK / German Cipriani et al 2019 F:5′-TTTGCTTGATCAATTCTGCTG-3′ 

R:5′-TTCTCAGTTGGAAGAGCACAAA-3′

V9 NCMD / MCDR3 Tandem DUP 5:4396927–4440442   43,515 bp DUP UK / German Cipriani et al 2019 F: 5′-TTGTGGACTGAGCAAGCAAG-3

R:5′-GGAGCAGAAGTTAAATGTGGAGA-3′


History

North Carolina macular dystrophy (NCMD/MCDR1, OMIM 136,550) is an autosomal dominant, congenital, completely penetrant, non-progressive macular malformation first reported 50 years ago in a large family in North Carolina. This family’s retinal findings were initially described by Lefler, Wadsworth and Sidbury as “hereditary macular degeneration and amino-aciduria” and subsequently referred to as the Lefler Wadsworth Sidbury Syndrome.[1] The “aminoaciduria” component, was later found to be inconsistent making the “syndrome” a misnomer.[2][2] This same family was reported in a cross-sectional study 3 years later as “A new dominant progressive foveal dystrophy.” [2]

Twenty years later, Small encountered this same family and reevaluated and defined the disease phenotype in many of the same individuals. Only one family member lost vison over time and that appeared to be due to the development of choroidal neovascular membranes (CNVMs). This disease and this family were noted in Gass’ original Atlas of Macula Diseases as “North Carolina Macular Dystrophy” for its founder effect.[3] This has been the popular name ever since but is also inaccurate, misleading and yet another misnomer associated with this disease.[4] [5] [6] Other macular dystrophies such as “Central Areolar Pigment Epithelial Dystrophy (CAPED)” and “Autosomal Dominant Central Pigment Epithelial and Choroidal Degeneration (ADCPECD)” as described by Leveille et al. were subsequently shown by Small et al. to actually be genealogical branches of the original NCMD family.[6][7] Indeed, Leveille et al. used the presence of peripheral drusen to split ADCPECD from Lefler’s NCMD.7 Therefore, “lumping” disease phenotypes together has proven to be more accurate than “splitting.”[8][9] Although considered rare, NCMD has been reported worldwide in over 50 families by one investigator (KWS) alone.[4] [5] [6][10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] Families have been reported by Small et al and other researchers in the United States, Europe, Central America, Australia, New Zealand, Korea, Turkey and China.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]Hence, “North Carolina macular dystrophy” is a gross misnomer.

North Carolina Macular Dystrophy remains poorly understood clinically in part because of the reiterations of misinformation based on old and inaccurate data that continues to be perpetuated in current book chapters and the BSCS. [9]

Physical examination

See “DIAGNOSIS” above. In addition to the macular findings noted above, there is one family in France that additionally has “claw hand” malformations. There is also one family reported with hearing loss. Anterior segment examination is normal for age. Because the macular lesions (grade 3 colobomatous-like) are typically centered slightly temporal to the maculae, some patients has a slight exotropia appearance as they fixate with their nasal macular region. A few patients have had strabismus surgery for this without much success / improvement in visual function nor in external appearance.

Signs

See “DIAGNOSIS” above.

Symptoms

About a third of the patients are asymptomatic. A third have mild central visual impairment. Another third have mild to moderate central vision impairment. A few have severe central vision impairment typically due to CNVM.

Clinical diagnosis

See “DIAGNOSIS” above

Diagnostic procedures

Fundus exam, fundus photography, fluorescein angiography, ICG angiography, all show findings consistent with the findings noted in “DIAGNOSIS”. Additionally an active CNVM may be found.

Electroretinography (ERG): full field ERG is typically normal. This test is useful in distinguishing NCMD from other IRDs. However, there is one report by Manes et al of an abnormality with the OPs (oscillatory potentials electrooculography) consistent with Amacrine cell dysfunction which is expected as the PRDM13 gene is expressed in developing Amacrine cells. However, “normative data” of OPs is lacking in the literature and what constitutes an abnormal OP recording is not established at all. Our dataset shows no abnormality of OPs.

Electrooculogram (EOG), are typically normal although Small et al has reported several patients with a markedly reduced (abnormal) Arden ration with a normal ERG. The traditional teaching is that a normal ERG with an abnormal EOG IS consistent only with Bests Macular Dystropy (BVMD). This classic teaching is no longer true.

Color vision,: typically normal; aids in differentiating NCMD from other IRDs.

Laboratory test

DNA sequencing as noted above

Differential diagnosis

alias

  • Lefler, Wadsworth and Sidbury Syndrome,
  • Hereditary Macular Degeneration and Amino-aciduria,
  • Dominant Progressive Foveal Dystrophy,
  • Central Areolar Pigment Epithelial Dystrophy (CAPED),
  • Autosomal Dominant Central Pigment Epithelial and Choroidal Degeneration

All of these above names were assigned to this one disease in one North Carolina family

Phenocopies / differential diagnoses

  • congenital toxoplasmosis,
  • Bests vitelliform macular dystrophy (BVMD),
  • Age-related Macular Degeneration )AMD)
  • Torpedo maculopathy
  • Cone dystrophy (CORD5 CORD6)
  • “Progressive Bifocal RetinoChoroidal Degeneration” PBRCA

Management

Periodic monitoring for the development of CNVMs. When these do occur a report by our group shows that anti-VEGF injection work well (Bakall, Small et al)

General treatment

Periodic monitoring for the development of CNVMs. When these do occur a report by our group shows that anti-VEGF injection work well (Bakall, Small et al)

Medical therapy

None known currently

Medical follow up

Periodic monitoring for the development of CNVMs. When these do occur a report by our group shows that anti-VEGF injection work well (Benjamin Bakall, MD, PhD, J. Shepard Bryan III, MD, Edwin M. Stone, MD, PhD, Kent W. Small, MD. Choroidal neovascularization in North Carolina macular dystrophy responsive to anti–vascular endothelial growth factor therapy. Retin Cases Brief Rep. 2018 Oct 31. doi: 10.1097/ICB.0000000000000838. PubMed PMID: 30383557)

Surgery

Prior to the development of intravitreal anti-VEGF injections, submacular surgery has been performed on 2 patients that I am aware with typical submacular surgery results

Surgical follow up

Prior to the development of intravitreal anti-VEGF injections, submacular surgery has been performed on 2 patients that I am aware with typical submacular surgery results

Complications

The development of CNVMs can cause some progressive vision loss.

Prognosis

Generally the prognosis is good for maintaining useful and stable vision throughout the life of the patient. Even patients with severe appearing grade 3 colobomatous-like lesions can have 2/40 visual acuity.

Additional Resources

Kent W Small MD (kentsmall@hotmail.com) has a database of experience with over 300 affected patients over a 35 year span of time. KWS is responsible for accurately describing the phenotype, mapping the disease in the Human Genome Project and finding initial and most of the mutations. KWS is always interesting in finding new families and helping them with this disease. 310-659-2200

References

  1. Lefler WH, Wadsworth JA, Sidbury JB. Hereditary macular degeneration and amino-aciduria. Am J Ophthalmol. 1971;71:224–230.
  2. 2.0 2.1 2.2 Frank HR, Landers MB, Williams RJ, Sidbury JB. A new dominant progressive foveal dystrophy. Am J Ophthalmol. 1974;78:903–916.
  3. Agarwal A. Gass’ Atlas Of Macular Diseases. 5th ed. Edinburgh, Scotland: Elsevier Saunders; 2012.
  4. 4.0 4.1 Small KW. North Carolina macular dystrophy: revisited. Ophthalmology 96:1989,1747-1754.
  5. 5.0 5.1 Small KW, Killian J, McLean W. North Carolina's dominant progressive foveal dystrophy. How progressive is it? British Journal of Ophthalmology 75:1991,401-406
  6. 6.0 6.1 6.2 Small KW, Hermsen V, Gurney N, Fetkenhour CL, Bresnick G, Folk JC: North Carolina macular dystrophy (NCMD) and central areolar pigment epithelial dystrophy (CAPED), one family, one disease. Archives of Ophthalmology 110:1991,515-518.
  7. Leveille AS, Morse PH, Kiernan JP. Autosomal dominant central pigment epithelial and choroidal degeneration. Ophthalmology. 1982 Dec;89(12):1407-13. doi: 10.1016/s0161-6420(82)34621-7. PMID: 7162784.
  8. Traboulsi EI. To lump or to split? Ophthalmic Pediatric Genetics. 1993 Dec;14(4):141-2. doi: 10.3109/13816819309042912.
  9. 9.0 9.1 Freund KB, Sarraf D, Mieler WF, Yannuzzi LA, Shields CL. The Retinal Atlas. Philadelphia, PA: Elsevier:2017.
  10. 10.0 10.1 Rabb M, Small KW, Mullen L, Yelchits L, Udar, N. North Carolina macular dystrophy maps to the MCDR1 locus (MCDR1) phenotype in Central America. Am J Ophthalmol 125:502-508, 1998.
  11. 11.0 11.1 Small KW, Puech B, Mullen L, Yelchits L. North Carolina macular dystrophy phenotype in France maps to the MCDR1 locus. Molecular Vision 3:1, 1997.
  12. 12.0 12.1 Small KW. North Carolina macular dystrophy. Transactions of the American Ophthalmological Society XCVI: 926-961, 1998.
  13. 13.0 13.1 Voo I, Glasgow B, Flannery J, Udar U, Small KW. Clinicopathologic correlation of North Carolina macular dystrophy. Am J Ophthalmol. 2001;132(6):933-5.
  14. 14.0 14.1 Small KW, Voo I, Glasgow B, Flannery J, Udar N. Clinicopathologic correlation of North Carolina macular dystrophy. Trans Am Oph Soc 99: 233-238, 2001
  15. 15.0 15.1 Kiernan DF, Shah RS, Hariprasad SM, Grassi MA, Small KW, Kiernan JP, Mieler WF. Thirty Year Follow-up of an African-American Family with North Carolina Macular Dystrophy (MCDR1). Ophthalmology 2011;118:1435–1443.
  16. 16.0 16.1 Small KW, Puech B, Mullen L, Yelchits S. North Carolina macular dystrophy phenotype in France maps to the MCDR1 locus. Mol Vis. 1997;3:1.
  17. 17.0 17.1 Small KW, Garcia CA, Gallardo G, et al. North Carolina macular dystrophy (MCDR1) in Texas. Retina. 1998;18:448e452.
  18. 18.0 18.1 Rabb MF, Mullen L, Yelchits S, et al. A North Carolina macular dystrophy phenotype in a Belizean family maps to the MCDR1 locus. Am J Ophthalmol. 1998;125:502e508.
  19. 19.0 19.1 Small K, Small L, Tran E, Rao R, Shaya F. Multimodal Imaging and Functional Testing in a North Carolina Macular Disease Family: Toxoplasmosis, Fovea Plana, and Torpedo Maculopathy Are Phenocopies. Ophthalmology Retina, Volume 3, Issue 7, 607-614.
  20. 20.0 20.1 Small KW, Vincent A, Knapper CL, Shaya F. Congenital toxoplasmosis as one phenocopy of North Carolina Macular Dystrophy (NCMD/MCDR1). American Journal of Ophthalmology Case Reports, Volume 15, 2019, 100521. https://doi.org/10.1016/j.ajoc.2019.100521.
  21. 21.0 21.1 Small KW, Agemy S, Shaya FS. Terminology of MCDR1: What’s in a name? JAMA Ophthalmol. 2016;134:355e356.
  22. 22.0 22.1 Benjamin Bakall, MD, PhD, J. Shepard Bryan III, MD, Edwin M. Stone, MD, PhD, Kent W. Small, MD. Choroidal neovascularization in North Carolina macular dystrophy responsive to anti–vascular endothelial growth factor therapy. Retin Cases Brief Rep. 2018 Oct 31. doi: 10.1097/ICB.0000000000000838. PubMed PMID: 30383557
  23. 23.0 23.1 Small KW, Weber JL, Roses AD, Pericak-Vance M. North Carolina macular dystrophy maps to chromosome 6. Genomics 13:1992,681-685.
  24. 24.0 24.1 Small KW, Weber J, Pericak-Vance MA. MCDR1 (North Carolina macular dystrophy) map to 6q14-q16. Ophthalmic Pediatrics and Genetics 14:143-150, 1993.
  25. 25.0 25.1 Small KW, Weber JL, Pericak-Vance MA, Vance J, Hung W, Roses AD. Exclusion map of North Carolina macular dystrophy using RFLPs and microsatellites. Genomics 11:1991,763-766.
  26. 26.0 26.1 Small KW, Udar N, Yelchits S, et al. North Carolina macular dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis. Mol Vis. 1999.
  27. 27.0 27.1 Small KW, DeLuca AP, Whitmore SS, et al. North Carolina macular dystrophy is caused by dysregulation of the retinal transcription factor PRDM13. Ophthalmology. 2016;123:9e18.
  28. 28.0 28.1 Pauleikhoff D, Sauer CG, Müller CR, et al. Clinical and genetic evidence for autosomal dominant North Carolina macular dystrophy in a German family. Am J Ophthalmol.1997;124:412e415.
  29. 29.0 29.1 Rohrschneider K, Blankenagel A, Kruse FE, et al. Macular function testing in a German pedigree with North Carolina macular dystrophy. Retina. 1998;18:453e459.
  30. 30.0 30.1 Reichel MB, Kelsell RE, Fan J, et al. Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q. Br J Ophthalmol. 1998;82:1162e1168.
  31. 31.0 31.1 Rosenberg T, Roos B, Johnsen T, et al. Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy. Mol Vis. 2010;16:2659e2668.
  32. 32.0 32.1 Kim SJ, Woo SJ, Yu HG. A Korean family with an early-onset autosomal dominant macular dystrophy resembling North Carolina macular dystrophy. Korean J Ophthalmol. 2006;20: 220e224.
  33. 33.0 33.1 Small KW, Van de Sompele S, Nuytemans K, et al. A novel duplication involving PRDM13 in a Turkish family supports its role in North Carolina macular dystrophy (NCMD/MCDR1). Mol Vis. 2021;27:518-527.
  34. 34.0 34.1 Seiple W, Szlyk JP, Paliga J, Rabb MF. Perifoveal Function in Patients with North Carolina Macular Dystrophy: The Importance of Accounting for Fixation Locus. Invest. Ophthalmol. Vis. Sci. 2006;47(4):1703-1709. doi: 10.1167/iovs.05-0659.
  35. 35.0 35.1 Manes G, Joly T, Smirnov S, et al. A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in Drosophila eye reproduces the human phenotype. Hum Mol Genet. 2017;26:4367e4374.
  36. 36.0 36.1 Bowne SJ, Sullivan LS, Wheaton DK, et al. North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. Mol Vis. 2016;22:1239e1247.
  1. Green DJ, Lenassi E, Manning CS, McGaughey D, Sharma V, Black GC, Ellingford JM, Sergouniotis PI. North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants. Invest Ophthalmol Vis Sci. 2021 Jun 1;62(7):16. doi: 10.1167/iovs.62.7.16.
  2. Kent W. Small, Lee M. Jampol, Benjamin Bakall, Leslie Small, Robert Wiggins, Steven Agemy, Nitin Udar, Jessica Avetisjan, Andrea Vincent & Fadi S. Shaya (2021) Best Vitelliform Macular Dystrophy (BVMD) is a phenocopy of North Carolina Macular Dystrophy (NCMD/MCDR1), Ophthalmic Genetics, DOI: 10.1080/13816810.2021.2010771
  3. Watanabe S, Sanuki R, Sugita Y, et al. Prdm13 regulates subtype specification of retinal amacrine interneurons and modulates visual sensitivity. J Neurosci. 2015;35:8004e8020.
  4. Cipriani V, Silva RS, Arno G, et al. Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus. Sci Rep. 2017;7(1):7512. Published 2017 Aug 8. doi:10.1038/s41598-017-06387-6.
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