North Carolina Macular Dystrophy: A Developmental Maculopathy

  • Post author:Haseeb N. Akhtar, Ayesha Salejee, Hassan A. Mirza
  • DOIDOI:10.48089/jfo7688281
  • Reader Impact Rating Impact Rating: 8.26 / 10 from 42 reader votes.

Haseeb N. Akhtar,*1 Ayesha Salejee,*1 Hassan A. Mirza

*Joint First Authors

1University College London, London, UK

Introduction

North Carolina Macular Dystrophy (NCMD) is a rare autosomal dominant disorder characterised by congenital macular abnormalities. It was first described in a large cohort of patients from North Carolina, USA in the 1970s (1,2). Despite its name, NCMD has been reported globally, with considerable phenotypic variability, ranging from subtle drusen-like deposits to severe coloboma-like macular lesions (2,3). The condition is linked to non-coding variants upstream of the PRDM13 gene on chromosome 6. This variant leads to disruption of retinal development and gene expression (4,5). Early diagnosis is important to inform genetic counselling and monitoring for secondary complications, e.g. choroidal neovascularisation.

Epidemiology

There is a paucity of cases of NCMD; in one recent study, the phenotypic variability of six individuals were studied (2). There is no gender or ethnic predilection for NCMD that has been observed thus far. However, the disease does exhibit complete penetrance, albeit there is considerable phenotypic variability, even within families (6).

Pathophysiology

NCMD is caused by dysregulation of PRDM13, a transcription factor integral to retinal amacrine cell function during foetal development (4,7). Downstream of the noncoding variants in chromosome 6, there is overexpression of PRDM13 in macular tissue, leading to aberrant retinal differentiation and subretinal deposits (5,8,9). Histopathology may reveal sub-retinal pigment epithelium (RPE) deposits and loss of photoreceptors in advanced cases of NCMD (10).

Clinical Features

NCMD typically presents at birth or in early childhood, although less severe phenotypes may remain asymptomatic into adulthood (11). Visual acuity is often correlated to the degree of macular involvement, i.e. a higher degree of macular involvement will lead to a poorer visual acuity. Here are the key features that may be suggestive:

  • Macular lesions: yellow white drusen-like deposits, often arranged radially. Severe cases may present as coloboma-like excavations with RPE atrophy.
  • Peripheral retinal lesions: hyperautofluorescent lesions in the far periphery which can be detected via ophthalmic imaging (2).
  • CNV: can occur in approximately 5-10% of cases; if it does occur, it is usually in childhood (12).

Diagnosis

The key features of NCMD can be subclassified dependent on the type of multimodal imaging used. In all modalities, findings are bilaterally symmetrical. On fundus autofluorescence, there is classically hyperautofluorescence due to drusen-like deposition. On optical coherence tomography, you may expect to find confluent sub-RPE deposits, outer retinal thinning and CNV (2). ERG and EOG are usually normal. A hallmark feature, as described previously, is the presence of peripheral retinal lesions, which can be detected on widefield imaging (4). Genetic testing to find the PRDM13 variant is the gold-standard investigation to help confirm the diagnosis (4).

Management

Unfortunately, like many other causes of inherited retinal disease, there is not a cure for NCMD. However, symptomatic relief can be provided via low vision rehabilitation services and a referral should be considered at the time of molecular diagnosis and during subsequent follow-up visits. Genetic counselling is paramount, especially in view of the inheritance pattern (autosomal dominance). Furthermore, these patients should be under regular follow-up to monitor any lesions and treatment of CNVs if necessary.

Conclusion

NCMD is a developmental maculopathy with significant phenotypic heterogeneity. Noncoding variants in the PRDM13 gene on chromosome 6 form the molecular basis of genetic diagnosis of this rare but important inherited retinal disease. An array of imaging, including widefield imaging, should be considered in these subset of patients. Of course, targeting PRDM13 regulation in the future may yield therapeutic insights.

References

1.        Frank HR, Landers MB, Williams RJ, Sidbury JB. A new dominant progressive foveal dystrophy. Am J Ophthalmol [Internet]. 1974 Dec 1 [cited 2025 Feb 2];78(6):903–16. Available from: https://www.ajo.com/article/0002939474908009/fulltext

2.        Green DJ, Lenassi E, Manning CS, McGaughey D, Sharma V, Black GC, et al. North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants. Invest Ophthalmol Vis Sci [Internet]. 2021 Jun 1 [cited 2025 Feb 2];62(7):16–16. Available from: https://doi.org/10.1167/iovs.62.7.16

3.        Silva RS, Arno G, Cipriani V, Pontikos N, Defoort-Dhellemmes S, Kalhoro A, et al. Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy. Hum Mutat [Internet]. 2019 May 1 [cited 2025 Feb 2];40(5):578–87. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23715

4.        Small KW, DeLuca AP, Whitmore SS, Rosenberg T, Silva-Garcia R, Udar N, et al. North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13. Ophthalmology [Internet]. 2016 Jan 1 [cited 2025 Feb 2];123(1):9–18. Available from: https://www.aaojournal.org/article/S0161642015011537/fulltext

5.        Manes G, Joly W, Guignard T, Smirnov V, Berthemy S, Bocquet B, 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 [Internet]. 2017 Nov 15 [cited 2025 Feb 2];26(22):4367–74. Available from: https://pubmed.ncbi.nlm.nih.gov/28973654/

6.        Birtel J, Gliem M, Herrmann P, Neuhaus C, Holz FG, MacLaren RE, et al. North Carolina macular dystrophy shows a particular drusen phenotype and atrophy progression. British Journal of Ophthalmology [Internet]. 2022 Sep 1 [cited 2025 Feb 2];106(9):1269–73. Available from: https://bjo.bmj.com/content/106/9/1269

7.        Bessodes N, Parain K, Bronchain O, Bellefroid EJ, Perron M. Prdm13 forms a feedback loop with Ptf1a and is required for glycinergic amacrine cell genesis in the Xenopus Retina. Neural Dev [Internet]. 2017 Sep 1 [cited 2025 Feb 2];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/28863786/

8.        Fulco CP, Nasser J, Jones TR, Munson G, Bergman DT, Subramanian V, et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat Genet [Internet]. 2019 Dec 1 [cited 2025 Feb 2];51(12):1664–9. Available from: https://pubmed.ncbi.nlm.nih.gov/31784727/

9.        Cherry TJ, Yang MG, Harmin DA, Tao P, Timms AE, Bauwens M, et al. Epigenomic profiling and single-nucleus-RNA-seq reveal cis-regulatory elements in human retina, macula and RPE and non-coding genetic variation. bioRxiv [Internet]. 2018 Sep 8 [cited 2025 Feb 2];(September 8). Available from: https://hdl.handle.net/1854/LU-8641344

10.      Voo I, Glasgow BJ, Flannery J, Udar N, Small KW. North Carolina macular dystrophy: Clinicopathologic correlation. Am J Ophthalmol [Internet]. 2001 Dec 1 [cited 2025 Feb 2];132(6):933–5. Available from: https://www.ajo.com/article/S0002939401011849/fulltext

11.      Ellingford JM, Barton S, Bhaskar S, Williams SG, Sergouniotis PI, O’Sullivan J, et al. Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. Ophthalmology [Internet]. 2016 May 1 [cited 2025 Feb 2];123(5):1143–50. Available from: https://pubmed.ncbi.nlm.nih.gov/26872967/

12.      Small KW, Wiggins R, Udar N, Silva-Garcia R, Avetisjan J, Vincent A, et al. North Carolina Macular Dystrophy: Long-term Follow-up of the Original Family. Ophthalmol Retina [Internet]. 2022 Jun 1 [cited 2025 Feb 2];6(6):512–9. Available from: https://www.ophthalmologyretina.org/article/S2468653022000628/fulltext

Leave a Reply