North Carolina Macular Dystrophy

North Carolina Macular Dystrophy (NCMD) is a rare, inherited eye condition that affects the macula, the central part of the retina responsible for sharp, detailed vision. Despite its name, the condition is found in families all over the world, not just in North Carolina. It is a condition people are born with, and it is passed down through families in a dominant pattern, meaning that if one parent has it, each child has a 50% chance of inheriting it. The effects of NCMD on vision can vary widely, even within the same family. Some people have no noticeable vision problems, while others may have mild to moderate difficulty with central vision. The physical appearance of the macula also varies, ranging from small spots to larger areas of thinning. A key feature of NCMD is that the primary condition does not usually get worse over time; the vision you have in childhood is typically the vision you will maintain throughout your life. However, patients with NCMD need regular eye exams because they are at risk of developing a complication called choroidal neovascularization (CNV), which is the growth of abnormal blood vessels under the retina. If these blood vessels leak or bleed, they can cause sudden vision loss. Fortunately, if CNV occurs, it can often be treated effectively with eye injections. Overall, most people with NCMD maintain useful vision and can lead normal, active lives.

Condition category: Macular Dystrophy

Prevalence: Rare

Inheritance patterns: Autosomal Dominant

Age of onset: Congenital or early childhood (typically present at birth or within the first decade of life)

Clinical overview: North Carolina Macular Dystrophy (NCMD) is a rare, autosomal dominant, congenital macular malformation characterized by completely penetrant but highly variable clinical expression. Originally described in a large family from North Carolina, the condition has since been identified worldwide, making its geographic name a historical misnomer. NCMD is classified into three clinical grades based on the severity of the macular lesions, ranging from small drusen-like deposits to large, coloboma-like atrophic excavations. The condition is associated with OMIM numbers 136550 (MCDR1 locus) and 608850 (MCDR3 locus), and Orphanet number ORPHA75327. Clinically, NCMD is distinguished by its non-progressive nature; the primary macular lesions are present at birth and generally remain stable throughout life. Despite the often dramatic appearance of the macula, especially in severe cases, visual acuity is frequently better than expected and remains stable unless secondary complications arise. The most significant clinical complication is the development of choroidal neovascularization (CNV), which can lead to sudden vision loss and requires prompt treatment. The genetic basis of NCMD is notable for involving mutations in noncoding regulatory regions rather than coding sequences. These mutations dysregulate the expression of developmental transcription factors (PRDM13 or IRX1), leading to abnormal macular development. This unique mechanism highlights the importance of noncoding genomic regions in inherited retinal diseases and provides a model for understanding developmental macular anomalies.

Patient and family guide: North Carolina Macular Dystrophy (NCMD) is a rare, inherited eye condition that affects the macula, the central part of the retina responsible for sharp, detailed vision. Despite its name, the condition is found in families all over the world, not just in North Carolina. It is a condition people are born with, and it is passed down through families in a dominant pattern, meaning that if one parent has it, each child has a 50% chance of inheriting it. The effects of NCMD on vision can vary widely, even within the same family. Some people have no noticeable vision problems, while others may have mild to moderate difficulty with central vision. The physical appearance of the macula also varies, ranging from small spots to larger areas of thinning. A key feature of NCMD is that the primary condition does not usually get worse over time; the vision you have in childhood is typically the vision you will maintain throughout your life. However, patients with NCMD need regular eye exams because they are at risk of developing a complication called choroidal neovascularization (CNV), which is the growth of abnormal blood vessels under the retina. If these blood vessels leak or bleed, they can cause sudden vision loss. Fortunately, if CNV occurs, it can often be treated effectively with eye injections. Overall, most people with NCMD maintain useful vision and can lead normal, active lives.

Symptoms and clinical features: North Carolina Macular Dystrophy (NCMD) is a congenital condition, meaning the structural abnormalities of the macula are present at birth. The clinical presentation is highly variable, even among affected members of the same family. Approximately one-third of patients are entirely asymptomatic and are only diagnosed during routine eye examinations or family screenings. Another third experience mild central visual impairment, while the remaining third have mild to moderate central vision loss. Severe vision loss is rare and is typically associated with secondary complications rather than the primary dystrophy. The physical appearance of the macula in NCMD is categorized into three grades, which represent the spectrum of the disease rather than progressive stages. Grade 1 is characterized by the presence of small to intermediate drusen-like deposits in the central macula. Grade 2 involves larger, confluent drusen or central vitelliform (egg-yolk-like) lesions. Grade 3 is the most severe structural presentation, featuring large, well-defined, coloboma-like atrophic excavations in the central macula that bow back into the choroid and sclera. These Grade 3 lesions are often surrounded by a ring of subretinal fibrosis. Despite the sometimes dramatic appearance of the macula, the primary lesions are non-progressive. Visual acuity generally stabilizes early in life and remains constant. Color vision is typically normal, and peripheral vision is unaffected. The most significant symptom progression occurs if a patient develops choroidal neovascularization (CNV), a secondary complication that can happen at any age. The development of CNV can cause sudden metamorphopsia (distortion of vision), central scotomas (blind spots), and a rapid decline in visual acuity due to subretinal fluid or hemorrhage.

Molecular pathology: The molecular pathology of North Carolina Macular Dystrophy (NCMD) is unique among inherited retinal diseases as it is primarily driven by mutations in noncoding regulatory DNA regions rather than coding gene sequences. The disease is associated with two distinct loci: MCDR1 on chromosome 6 and MCDR3 on chromosome 5. At the MCDR1 locus, single nucleotide variants and tandem duplications occur in a DNase I hypersensitivity site upstream of the PRDM13 gene. The PRDM13 gene encodes a transcription factor that is highly expressed in the developing neural retina, particularly in amacrine cells, and plays a crucial role in retinal cell fate determination. At the MCDR3 locus, tandem duplications occur in a regulatory region downstream of the IRX1 gene. Similar to PRDM13, IRX1 encodes a developmental transcription factor, though its expression is not exclusive to the nervous system. The current leading hypothesis for the pathogenesis of NCMD is that these noncoding mutations disrupt normal chromatin architecture, such as topologically associating domains (TADs). This disruption leads to the dysregulation (likely overexpression or ectopic expression) of the PRDM13 or IRX1 transcription factors during embryonic macular development. The dysregulation of these critical developmental genes results in a congenital malformation of the macula. Because the primary defect occurs during development, the resulting macular lesions are generally non-progressive after birth. The downstream cellular effects manifest as abnormal development of the retinal pigment epithelium (RPE) and photoreceptors in the central macula, leading to the spectrum of clinical findings from drusen-like deposits to severe coloboma-like atrophy.

Genetics: North Carolina Macular Dystrophy is inherited in an autosomal dominant pattern with complete penetrance but highly variable expressivity. The condition is primarily caused by mutations in noncoding regulatory DNA regions rather than within the coding sequences of genes. The most common locus associated with NCMD is MCDR1 on chromosome 6q16. Pathogenic variants at this locus include single nucleotide variants (SNVs) and tandem duplications in a DNase I hypersensitivity site upstream of the PRDM13 gene. A second locus, MCDR3, is located on chromosome 5p15. Mutations at this locus involve tandem duplications in a regulatory region downstream of the IRX1 gene. These duplications are more frequently observed in European populations. Both the PRDM13 and IRX1 genes encode transcription factors involved in retinal development. Genotype-phenotype correlations in NCMD are complex due to the significant intrafamilial and interfamilial variability. Individuals with the same genetic mutation can present with any of the three clinical grades of macular lesions, ranging from mild drusen-like deposits to severe coloboma-like atrophy. The exact mechanisms by which these noncoding mutations lead to the variable macular phenotypes remain an area of active research, though altered chromatin folding and dysregulation of the associated transcription factors during development are the leading hypotheses.

Diagnostic evaluation: Clinical diagnosis of North Carolina Macular Dystrophy (NCMD) is primarily based on fundus examination, which reveals characteristic bilateral, symmetrical macular lesions. These lesions are categorized into three grades: Grade 1 consists of small to intermediate drusen-like deposits in the central macula; Grade 2 involves confluent drusen or central vitelliform lesions; and Grade 3 is characterized by large, coloboma-like central atrophic defects that bow back into the choroid and sclera, often surrounded by subretinal fibrosis. Optical coherence tomography (OCT) is useful for visualizing the depth of the lesions, particularly the excavation seen in Grade 3, and for detecting complications such as choroidal neovascularization (CNV). Electrophysiological testing is crucial for differentiating NCMD from other inherited retinal diseases. Full-field electroretinography (ERG) is typically normal, which helps distinguish NCMD from widespread retinal dystrophies. Electrooculography (EOG) is also generally normal, although some patients may exhibit an abnormally reduced Arden ratio despite a normal ERG. This finding can mimic Best vitelliform macular dystrophy, making careful clinical correlation necessary. Molecular genetic testing confirms the diagnosis by identifying pathogenic variants in the noncoding regions near the PRDM13 gene on chromosome 6 (MCDR1 locus) or the IRX1 gene on chromosome 5 (MCDR3 locus). Differential diagnosis includes Best vitelliform macular dystrophy, congenital toxoplasmosis, age-related macular degeneration, torpedo maculopathy, and progressive bifocal chorioretinal atrophy. The non-progressive nature of the primary lesions and the specific genetic findings are key to distinguishing NCMD from these masquerading conditions.

Differential diagnosis: Differential diagnosis of North Carolina macular dystrophy includes: (1) Stargardt disease — progressive, flecks, dark choroid, ABCA4 mutations. (2) Best disease — vitelliform lesion, abnormal EOG, BEST1 mutations. (3) Toxoplasma macular scar — unilateral, history of inflammation, positive serology. (4) Coloboma (macular) — developmental, associated with other ocular colobomas. (5) Myopic macular degeneration — high myopia, progressive. (6) Central areolar choroidal dystrophy — progressive, later onset, well-defined atrophy.

Natural history: North Carolina Macular Dystrophy is a congenital developmental abnormality, meaning the macular lesions are present at birth or develop very early in childhood. The condition is generally considered non-progressive, with the primary macular lesions remaining stable throughout the patient's lifetime. Visual acuity typically stabilizes early and does not progressively decline due to the primary dystrophy itself. Despite the stable nature of the primary lesions, patients are at risk for secondary complications, most notably the development of choroidal neovascularization (CNV). The onset of CNV can occur at any age and is the primary cause of sudden or progressive visual decline in NCMD patients. If CNV develops, it can lead to subretinal hemorrhage, fluid accumulation, and subsequent subretinal fibrosis, which can significantly impact central vision if it involves the fovea. Prognostic factors largely depend on the initial grade of the macular lesion and the occurrence of CNV. Interestingly, visual acuity is often better than the structural appearance of the macula would suggest. Even patients with severe Grade 3 coloboma-like lesions can maintain visual acuity of 20/40 or better, provided the foveal center is spared and no CNV complications arise. Regular monitoring is essential to detect and treat CNV early to preserve visual function.

Management and treatment research: ### Current management and monitoring North Carolina macular dystrophy (NCMD) is an inherited condition that affects the macula, the central part of the retina needed for detailed vision. Macular changes are often present early in life and may remain relatively stable, although vision varies widely among affected people. There is currently no treatment that reverses the underlying retinal changes. Care focuses on monitoring vision, identifying treatable complications, and supporting daily activities: - Regular dilated eye examinations and retinal imaging, including optical coherence tomography (OCT), can document macular findings and check for fluid, bleeding, or other changes. - Glasses or contact lenses can correct refractive errors and help make the best use of remaining vision. - Low-vision rehabilitation, magnifiers, electronic reading devices, and school or workplace accommodations may help people with reduced central vision. - Genetic counseling can help families understand NCMD’s autosomal dominant inheritance. A person with an NCMD-causing genetic change has a 50% chance of passing it to each child, although severity can differ among relatives. A complication that needs prompt assessment is choroidal neovascularization (CNV), in which abnormal blood vessels grow beneath or within the retina. Symptoms can include new distortion, worsening central blur, bleeding, or fluid in the macula. ### Approved therapies There are no therapies approved specifically for NCMD. If CNV develops, a retina specialist may recommend intravitreal anti-VEGF treatment. These medicines are injected into the eye and block vascular endothelial growth factor (VEGF), a signal that promotes abnormal blood-vessel growth and leakage. Bevacizumab, ranibizumab, and aflibercept are among the anti-VEGF medicines that may be used off label for CNV associated with NCMD. Published case reports and limited clinical experience indicate that anti-VEGF injections can reduce retinal fluid or bleeding and may help stabilize vision in affected eyes. The need for treatment and the interval between injections depend on retinal imaging findings and the individual eye’s response. ### Investigational therapies #### NCMD-directed research There are currently no NCMD-specific investigational therapies listed in the available treatment pipeline or clinical-trial data. NCMD is genetic, but many known disease-causing changes occur in noncoding regulatory DNA—DNA that helps control gene activity rather than directly coding for a protein. These changes can affect retinal development and gene regulation, including pathways involving *PRDM13* or *IRX1*. This biology may make development of targeted treatments more complex than for conditions caused by changes in a single protein-coding gene. #### Studies in other macular diseases Current studies in the available data involve age-related macular degeneration (AMD), geographic atrophy secondary to AMD, diabetic macular edema, or other non-inherited retinal conditions. They are not NCMD studies and should not be assumed to be appropriate for people with NCMD. Examples include: - SAR446597 for geographic atrophy secondary to AMD (NCT07215234) - EYE201/MK-8748 for macular degeneration (NCT07440225) - ONL1204 for geographic atrophy associated with AMD (NCT06659445) - Aflibercept 8 mg for neovascular AMD or diabetic macular edema (NCT06491914) - Surabgene lomparvovec for an adult retinal condition under study (NCT07007065) Eligibility criteria may limit these studies to people with specific forms of AMD, diabetic eye disease, or other diagnoses rather than inherited macular dystrophies. ### Clinical trial participation People with NCMD who are interested in research can discuss options with an inherited retinal disease specialist or retina specialist. Eligibility for any study may depend on the confirmed diagnosis, genetic findings, age, retinal imaging results, visual acuity, and whether CNV or other complications are present.

Outlook: The overall prognosis for patients with North Carolina Macular Dystrophy is generally favorable compared to many other inherited retinal diseases. Because the condition is a congenital malformation rather than a progressive degeneration, visual acuity typically remains stable throughout the patient's life. Many individuals maintain excellent or highly functional vision, often better than 20/40, even in the presence of severe-appearing Grade 3 macular lesions. The primary threat to vision is the development of secondary choroidal neovascularization (CNV), which can cause sudden visual decline but is often responsive to anti-VEGF therapy. Quality of life is usually well-preserved, as patients do not typically experience the progressive loss of central or peripheral vision seen in other dystrophies. Most individuals can drive, read, and perform daily activities without significant impairment. For those with more severe central vision involvement, low vision aids and supportive services can be beneficial. Regular ophthalmic monitoring is essential to ensure early detection and treatment of any CNV, thereby safeguarding the patient's long-term visual prognosis.

Epidemiology: North Carolina Macular Dystrophy is a rare condition, with an estimated worldwide prevalence of less than 1 in 1,000,000. Although originally described in a large family from North Carolina, giving the disease its name due to a founder effect, it has since been identified in over 50 families globally. Affected families have been reported across diverse geographic regions and ethnicities, including populations in the United States, Europe (France, Germany, UK, Denmark, Italy), Central America (Belize), Asia (China, Korea), and the Middle East (Turkey, Egypt). There are no known sex differences in the prevalence or severity of the condition, as it is inherited in an autosomal dominant manner with complete penetrance.

Selected 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: 26522706 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. Small KW. North Carolina macular dystrophy: revisited. Ophthalmology. 1989;96(12):1747-1754. PMID: 2622620 4. Rosenberg T, Kjer B, Eiberg H, et al. Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy. Invest Ophthalmol Vis Sci. 2010;51(12):6708-6714. PMID: 20631238 5. Weleber RG. Dysregulation of Retinal Transcription Factor PRDM13 and North Carolina Macular Dystrophy. Ophthalmology. 2016;123(1):4-6. PMID: 26704880 6. Green DJ, Lauer AK, Weleber RG, et al. North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Variants. Invest Ophthalmol Vis Sci. 2021;62(3):28. PMID: 33734298