North Carolina Macular Dystrophy

Key Points at a Glance

Key Points of This Disease

• North Carolina Macular Dystrophy (NCMD) is a congenital macular dysplasia with autosomal dominant inheritance.
• Non-coding DNA mutations in the MCDR1 locus on chromosome 6 are the main cause, involving dysregulation of the PRDM13 gene.
• The lesions are congenital, bilateral symmetric, and essentially non-progressive.
• Approximately one-third of patients are asymptomatic, and visual acuity is often better than expected from the severity of findings.
• Normal full-field electroretinogram and color vision are useful for differentiating from other hereditary retinal diseases.
• Progressive vision loss occurs when complicated by choroidal neovascularization (CNVM).
• There is no effective curative treatment; anti-VEGF therapy for CNVM and low vision care are the mainstays of treatment.

1. What is North Carolina Macular Dystrophy?

North Carolina Macular Dystrophy (NCMD) is one of the macular dystrophies, a group of hereditary retinochoroidal degenerative diseases that primarily affect the macula. It is a congenital, non-progressive macular dysplasia with autosomal dominant inheritance and complete penetrance.

History and Naming

It was first reported about 50 years ago in a large family from North Carolina. Initially described by Lefler, Wadsworth, and Sidbury as “hereditary macular degeneration and aminoaciduria.” However, the association with aminoaciduria was inconsistent, and the term “syndrome” proved to be a misnomer. Later, Small re-evaluated the phenotype of the same family, and in Gass’s Atlas of Macular Diseases, it was named “North Carolina Macular Dystrophy” due to the founder effect.

Epidemiology

It is considered a rare disease, but more than 50 families have been reported worldwide. Affected families have been identified in the United States, Europe, Central America, Australia, New Zealand, Korea, Turkey, and China, so the name “North Carolina” is not geographically limited.

Other Names

It is also known by the following names:

• Lefler-Wadsworth-Sidbury syndrome
• Dominant progressive foveal dystrophy
• Central areolar pigment epithelial dystrophy (CAPED)

CAPED and “autosomal dominant central pigment epithelial and choroidal degeneration (ADCPECD)” have been shown to be familial branches of the original NCMD family.

Q How rare is NCMD?

A

More than 50 families have been reported worldwide. It has been confirmed not only in the United States but also in Europe, Asia, Oceania, and other regions, and is not as localized as the name “North Carolina” suggests.

2. Main symptoms and clinical findings

Subjective symptoms

The subjective symptoms of NCMD vary greatly depending on the severity of the lesion.

• Asymptomatic: About one-third of patients have no subjective symptoms.
• Mild central visual impairment: Seen in another third.
• Mild to moderate central visual impairment: Seen in another third.
• Severe central visual impairment: Seen in a few cases, usually due to CNVM.

Visual acuity is often better than expected from the appearance of the lesion. It ranges widely from 20/20 (1.0) to less than 20/400 (0.05). Unless CNVM develops, it is generally stable throughout life. Color vision is usually normal.

Clinical findings

There is great phenotypic diversity in macular lesions. The lesions are congenital and bilaterally symmetric. They are generally classified into grades 1 to 3.

Grade 1

Central drusen: Small to medium-sized yellowish-white deposits scattered in the central area.

Visual acuity: Often remains relatively good.

Grade 2

Confluent drusen and vitelliform lesions: Drusen coalesce, presenting a vitelliform lesion in the central area.

Visual acuity: May be accompanied by mild decrease.

Grade 3

Coloboma-like lesion: Large central defect with atrophy that depresses toward the choroid or sclera. Often accompanied by subretinal fibrosis around it.

Visual acuity: Although it appears severe, some cases can maintain 20/40 (0.5) vision.

Grade 3 coloboma-like lesions are usually centered slightly temporal to the macula. Some patients may appear to have strabismus when adjusting fixation.

Why vision is preserved even in Grade 3

Coloboma-like lesions are often centered temporal to the macula, and part of the fovea may be spared. A characteristic of NCMD is the discrepancy between the apparent severity and actual visual function.

Q Is NCMD a progressive disease?

A

The macular lesions in NCMD are congenital and essentially non-progressive. Without the complication of CNVM, vision often remains stable throughout life. However, if CNVM develops, it can lead to progressive vision loss (see “Standard Treatment” section).

3. Causes and Risk Factors

NCMD is a congenital developmental abnormality of the macula caused by genetic factors.

Loci and causative genes

NCMD involves mainly two genetic loci.

• MCDR1 locus (chromosome 6): Found in most affected individuals. It is caused by a non-coding DNA mutation in a DNase I hypersensitive binding site upstream of the PRDM13 gene, thought to lead to dysregulation of PRDM13 through changes in chromatin structure.
• MCDR3 locus (chromosome 5): Involves a duplicated region containing the IRX1 gene.

The PRDM13 gene product is a transcription factor expressed in the developing neural retina (particularly amacrine cells). The IRX1 gene product is also a transcription factor involved in development, but is not limited to the nervous system.

Inheritance pattern

Autosomal dominant inheritance with complete penetrance. However, there is significant variable expressivity, with different severities from grade 1 to grade 3 even within the same family.

About genetic counseling

Since NCMD is autosomal dominant, children of an affected individual have a 50% chance of inheriting the mutation. Family testing may reveal mild cases and can provide diagnostic clues. Please consult a specialized facility for genetic counseling.

4. Diagnosis and testing methods

Clinical diagnosis

Diagnosis is made clinically based on characteristic bilateral symmetric congenital macular lesions and family history. Examining other family members may reveal phenotypic variability and facilitate diagnosis.

For diagnosis of macular dystrophy, visual acuity, visual field testing, fundus examination, fluorescein angiography, fundus autofluorescence, OCT, as well as electrophysiological tests (ERG, EOG) are useful.

Fundus examination and imaging

• Fundus examination and fundus photography: Confirm grade 1 to 3 macular lesions.
• Fluorescein angiography (FA): Shows hyperfluorescence due to window defects in the lesion. Can assess the presence of active CNVM.
• Indocyanine green angiography (ICG): Useful for detecting CNVM.
• Optical coherence tomography (OCT): Evaluates degeneration and atrophy of the outer retina and retinal pigment epithelium (RPE). Grade 3 shows severe degeneration involving the fovea.

Electrophysiological testing

Test	Findings in NCMD	Differential significance
Full-field electroretinogram	Usually normal	Useful for differentiating from other IRDs
EOG	Usually normal	Useful for differentiating from Best disease

A normal full-field electroretinogram is an important finding for distinguishing NCMD from other inherited retinal diseases such as cone dystrophy and Stargardt disease.

The EOG is usually normal, but cases with a normal electroretinogram and abnormally reduced Arden ratio have been reported. Although a normal electroretinogram with abnormal EOG is considered characteristic of Best disease, it should be noted that similar findings can also be seen in some cases of NCMD.

Molecular Diagnosis

Clinical diagnosis can be confirmed by DNA sequencing of the MCDR1 locus (chromosome 6) and the MCDR3 locus (chromosome 5). However, NCMD cannot be ruled out even if no known mutations are detected. Many private testing laboratories for inherited retinal diseases only detect the MCDR1 locus and not the MCDR3 locus.

Differential Diagnosis

• Best vitelliform macular dystrophy (Best disease): Abnormal EOG (reduced Arden ratio) is found in nearly 100% of Best disease cases. It is usually normal in NCMD.
• Congenital toxoplasmosis: Often unilateral, with different morphology of chorioretinal scars.
• Age-related macular degeneration (AMD): Onset in older age, whereas NCMD is congenital.
• Torpedo maculopathy: Oval hypopigmented lesion in the macula.
• Cone dystrophy: Reduced cone responses on electroretinography. In NCMD, the electroretinogram is normal.

Q How to differentiate NCMD from Best disease?

A

In Best disease, the Arden ratio on EOG is abnormally reduced in nearly 100% of cases. In NCMD, the EOG is usually normal. Best disease is also characterized by a yellow, vitelliform elevated lesion in the macula, with findings changing as the disease progresses. NCMD is essentially non-progressive, and full-field electroretinography is normal, which is useful for differentiation.

5. Standard Treatment

Currently, there is no curative treatment for NCMD. Management focuses on symptomatic treatment for CNVM complications and low vision care.

Observation

Regular monitoring for the development of CNVM is important. Periodic evaluation with OCT and FA should be performed.

Treatment for Choroidal Neovascularization (CNVM)

When CNVM is present, intravitreal injection of anti-VEGF agents is effective. For foveal CNV, intravitreal administration of VEGF inhibitors is performed.

Low Vision Care

For cases with progressive vision loss, support using refractive correction and low vision aids (such as magnifiers and magnifying reading devices) is provided. Cataract surgery may also be considered depending on the eye condition.

Early detection of CNVM is important

The main cause of progressive vision loss in NCMD is the complication of CNVM. If metamorphopsia or sudden vision loss is noticed, prompt ophthalmological consultation is necessary. Regular eye examinations to detect CNVM early and initiate treatment are key to maintaining vision.

6. Pathophysiology and Detailed Pathogenesis

NCMD is a congenital developmental abnormality of the macula, and the essence of the pathology is impairment of neural retinal development due to genetic mutations.

MCDR1 Locus and PRDM13

Most affected individuals have mutations in the MCDR1 locus on chromosome 6. The mutations are located in a DNase I hypersensitive binding site (non-coding DNA) upstream of the PRDM13 gene. It is proposed that these mutations alter chromatin structure and impair transcriptional regulation of the PRDM13 gene.

The PRDM13 gene product is a transcription factor expressed in the developing neural retina, particularly in amacrine cells. Abnormalities in oscillatory potentials consistent with amacrine cell dysfunction have been reported, but the definition of the normal range is not well established.

MCDR3 Locus and IRX1

The MCDR3 locus on chromosome 5 has also been implicated as another cause. A duplicated region containing the IRX1 gene has been found; this gene product is a transcription factor involved in development, but not limited to the nervous system.

Pathogenesis of Macular Degeneration

It has been suggested that these mutations alter chromatin folding and cause structural variants, but the detailed mechanism leading to macular degeneration remains unknown.

Q Is it possible that the causative gene for NCMD is not found in some cases?

A

NCMD cannot be ruled out even if known mutations (MCDR1 and MCDR3 loci) are not detected. Commercial genetic testing often targets only the MCDR1 locus, and MCDR3 or unknown mutations may not be detected. Diagnosis is made by combining clinical findings and family history.

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8. References

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(1):9-18. PMID: 26507665
2. 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. PMID: 28790370
3. Khurana RN, Sun X, Pearson E, et al. A reappraisal of the clinical spectrum of North Carolina macular dystrophy. Ophthalmology. 2009;116(10):1976-1983. PMID: 19616854
4. Green DJ, Lenassi E, Manning CS, et al. North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants. Invest Ophthalmol Vis Sci. 2021;62(7):16. PMID: 34125159
5. Birtel J, Gliem M, Herrmann P, et al. North Carolina macular dystrophy shows a particular drusen phenotype and atrophy progression. Br J Ophthalmol. 2022;106(9):1269-1273. PMID: 33785507
6. Diaz A, Hartung KJ, Small K. North Carolina Macular Dystrophy. Adv Exp Med Biol. 2025. PMID: 40736823