North Carolina Macular Dystrophy

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Review:
Assigned status Up to Date
 by Sun Young (Sunny) Lee, MD, PhD on June 18, 2022.


Disease

North Carolina Macular Dystrophy (NCMD)

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

Etiology

Inherited, autosomal dominant

Figure 1. Retinal images from the left eye of an individual who demonstrated typical findings and evolution of NCMD over three decades of follow up. A, B, color and red-free fundus photographs, respectively, at age 6 years, when the patient’s visual acuity was 20/50 in each eye. C, D, Fluorescein angiography at age 6 years did not show active neovascularization. E, At age 8 years, this individual demonstrated a central fibrotic scar, which progressively worsened through age 10 years (F), which then relatively stabilized between 11 years (G) through 33 years (H). At 33 years, visual acuity was 20/60-1 in the right eye and 20/70-1 in the left eye. I, OCT of the left eye, which demonstrates severe outer retinal and retinal pigment epithelial degeneration involving the fovea. [1]

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 choroidal neovascular membrane (CNVM) formation.

History

NCMD 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.[2][3] The “aminoaciduria” component, was later found to be inconsistent making the “syndrome” a misnomer.[3] This same family was reported in a cross-sectional study 3 years later as “a new dominant progressive foveal dystrophy.” [3]

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 vision over time, which appeared to be due to the development of CNVM. This disease and this family were noted in Gass’ original Atlas of Macula Diseases as “North Carolina Macular Dystrophy” for its founder effect.[4] This has been the popular name ever since but is also inaccurate and yet another misnomer associated with this disease.[5] [6] [7] 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.[7][8] Indeed, Leveille et al. used the presence of peripheral drusen to split ADCPECD from Lefler’s NCMD.[8] Therefore, “lumping” disease phenotypes together has proven to be more accurate than “splitting.”[9][10] Although considered rare, NCMD has been reported worldwide in over 50 families.[5] [6] [7][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] [37][38] Affected families have been reported in the United States, Europe, Central America, Australia, New Zealand, Korea, Turkey and China.[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] [37] Hence, “North Carolina macular dystrophy” is a gross misnomer.

Pathophysiology

NCMD is a congenital developmental abnormality of the macula. Most affected individuals carry a mutation in noncoding DNA found on the MCDR1 locus of Chromosome 6. The implicated variants alter a DNase1 hypersensitivity binding site upstream of the PRDM13 gene, which is proposed to dysregulate the PRDM13 gene through altered chromatin assembly. [39] The PRDM13 gene product is a transcription factor expressed in developing neural retina, particularly in amacrine cells.[40] The MCDR3 locus on chromosome 5 has also separately been implicated in causing NCMD. At this locus in diseased individuals, Cirpriani et al have reported discovery of a duplicated region containing the IRX1 gene, whose product is also a developmental transcription factor not exclusive to the nervous system. [39] Although detailed mechanisms of macular degeneration as a result of these mutations remain unclear, one theory is that these mutations alter chromatin folding causing dysfunctional structural variants.

Diagnosis

Clinical Diagnosis

There is a great deal of variable expressivity in the appearance of affected 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 bow back into the choroid and sclera (grade 3), often with surrounding subretinal fibrosis (most likely from CNVM). Figure 1 demonstrates the appearance of typical macular lesions from an affected individual over three decades of follow up. [41]

Visual acuity is generally better than would be expected given the appearance of the lesions but has been reported to range from 20/20 to worse than 20/400. The visual acuity generally stabilizes throughout the patient’s lifetime unless the patient develops a CNVM in the area of fixation (typically slightly nasal to the fovea). Color vision is typically normal, which aids in differentiating NCMD from other inherited retinal disorders.

Figure 2. Gene variants on the MCDR1 locus (chromosome 6) that cause NCMD. Chromosomal segment marked with asterisk represents a genetic recombinant found in an unaffected individual. Variants V1, V2, and V3 fall within a DNase hypersensitivity site (red) upstream of the PRMD13 gene (green).[1] bp = base pairs

Other Exam

Because the macular lesions (grade 3 colobomatous-like) are typically centered slightly temporal to the macula, some patients may have the appearance of strabismus as they adjust fixation. Some affected families have shown “claw hand” malformations or hearing loss. Examining other family members can reveal the variable expressivity of involved mutations and can greatly facilitate diagnosis.

Molecular Diagnosis

Known causative mutations of NCMD have been discovered in the MCDR1 locus on chromosome 6 (Figure 2) and the MCDR3 locus on chromosome 5. Clinical diagnosis can be confirmed with DNA sequencing for known mutations (see table below). It must be emphasized that failing to detect a known mutation does not exclude a diagnosis of NCMD. Of note, commercial labs offering genetic testing for inherited retinal disorders currently only detect mutations on the MCDR1 chromosome 6 locus and not on the MCDR3 chromosome 5 locus, which are more prevalent in the European population.  Clinical judgment should determine whether further specialized genetic testing, such as whole genome or exome sequencing should be pursued.

Variant Number phenotype Type of Variant Chromosomal Position (Hg19)   Nucleotide Change Geographic location Found by:   PCR sequencing primer sequences
           
  MCDR1   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′

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[36]  of an abnormality with the oscillatory potentials (OPs) electrooculography consistent with amacrine cell dysfunction.  However, “normative data” of OPs is lacking in the literature and what constitutes an abnormal OP recording is not well-established.

Electrooculogram (EOG) recordings, are typically normal although Small et al has reported several patients with an abnormally reduced Arden ratio with a normal ERG. The traditional teaching is that a normal ERG with an abnormal EOG suggests the diagnosis of Best Vitelliform Macular Dystrophy (BVMD).  This classic teaching does not account for the same finding in some patients with NCMD.

Differential diagnosis

  • Congenital toxoplasmosis
  • Best vitelliform macular dystrophy (BVMD)[42]
  • Age-related macular degeneration (AMD)
  • Torpedo maculopathy
  • Cone dystrophy (CORD5 CORD6)
  • Progressive Bifocal RetinoChoroidal Degeneration (PBRCA)

General treatment

Periodic monitoring for the development of CNVMs.  Studies have demonstrated that anti-VEGF injections work well to address complications from CNVM in NCMD.[43]

Medical therapy

Anti-VEGF injections to manage CNVM in affected patients.

Surgery

Prior to the development of intravitreal anti-VEGF injections, submacular surgery was rarely performed. For patients with macular lesions affecting fixation with resultant appearance of strabismus, strabismus surgery has not been reported to have much success in improving visual function or appearance.

Complications

The development of CNVMs can cause progressive vision loss.

Prognosis

Prognosis is generally good for maintaining useful and stable vision throughout the life of the patient.  Even patients with severe appearing grade 3 colobomatous-like lesions can maintain 20/40 visual acuity.

References

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  2. Lefler WH, Wadsworth JA, Sidbury JB. Hereditary macular degeneration and amino-aciduria. Am J Ophthalmol. 1971;71:224–230.
  3. 3.0 3.1 3.2 Frank HR, Landers MB, Williams RJ, Sidbury JB. A new dominant progressive foveal dystrophy. Am J Ophthalmol. 1974;78:903–916.
  4. Agarwal A. Gass’ Atlas Of Macular Diseases. 5th ed. Edinburgh, Scotland: Elsevier Saunders; 2012.
  5. 5.0 5.1 Small KW. North Carolina macular dystrophy: revisited. Ophthalmology 96:1989,1747-1754.
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  7. 7.0 7.1 7.2 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.
  8. 8.0 8.1 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.
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  36. 36.0 36.1 36.2 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.
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  39. 39.0 39.1 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.
  40. Watanabe S, Sanuki R, Sugita Y, Imai W, Yamazaki R, Kozuka T, Ohsuga M, Furukawa T. Prdm13 regulates subtype specification of retinal amacrine interneurons and modulates visual sensitivity. J Neurosci. 2015 May 20;35(20):8004-20. doi: 10.1523/JNEUROSCI.0089-15.2015. PMID: 25995483; PMCID: PMC6795186.
  41. Small KW, DeLuca AP, Whitmore SS, Rosenberg T, Silva-Garcia R, Udar N, Puech B, Garcia CA, Rice TA, Fishman GA, Héon E, Folk JC, Streb LM, Haas CM, Wiley LA, Scheetz TE, Fingert JH, Mullins RF, Tucker BA, Stone EM. North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13. Ophthalmology 123:9-18, 2016
  42. Small KW, Jampol LM, Bakall B, Small L, Wiggins R, Agemy S, Udar N, Avetisjan J, Vincent A, Shaya FS. Best Vitelliform Macular Dystrophy (BVMD) is a phenocopy of North Carolina Macular Dystrophy (NCMD/MCDR1). Ophthalmic Genet. 2021 Dec 13:1-11. doi: 10.1080/13816810.2021.2010771. Epub ahead of print. PMID: 34895015.
  43. Bakall B, Bryan JS 3rd, Stone EM, Small KW. CHOROIDAL NEOVASCULARIZATION IN NORTH CAROLINA MACULAR DYSTROPHY RESPONSIVE TO ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. Retin Cases Brief Rep. 2021 Sep 1;15(5):509-513. doi: 10.1097/ICB.0000000000000838. PMID: 30383557.
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