North Carolina Macular Dystrophy

Autosomal dominant congenital macular malformation, fully penetrant and as a rule non-progressive, caused by non-coding variants and duplications that dysregulate the retinal transcription factor PRDM13 (MCDR1 locus, 6q16.2) or by duplications downstream of IRX1 (MCDR3 locus, 5p15.33), with the allelic forms progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypoplasia.

Literature and regulatory information updated: 6 November 2026.

0. Reference Summary Table

1. Introduction

1.1. Original description and successive names

In 1971, Lefler, Wadsworth and Sidbury described a North Carolina family with four generations affected by a dominant macular degeneration, which they entitled "hereditary macular degeneration and aminoaciduria" [1]. Onset was at the end of the first decade and colour vision was preserved, which, for the authors, separated the disease from Stargardt disease; in a random urine sample, 11 of 17 affected individuals had generalised aminoaciduria and 2 had increased glycine, without it being clarified whether relatives without maculopathy also had it [2]. In 1974, Frank and colleagues restudied the same kindred under the name dominant progressive foveal dystrophy: onset occurred before the first year of life, the end stage was reached by early adolescence, foveal changes always preceded the loss of acuity and the aminoaciduria was unrelated to the macular disease [2, 19]. The name "North Carolina macular dystrophy" (NCMD) was introduced by Gass in 1987 and fixed the geographical name of the founder kindred [2].

The adjective "progressive" was abandoned in the following decade. On re-examining 22 affected members of the original kindred and comparing the fundus with old photographs, Small found evidence of progression in only 1, described severe lesions with a staphylomatous or excavated rather than flat and atrophic appearance, and identified drusen in the retinal periphery, contradicting the initial description of a normal periphery [26]. Of 34 at-risk relatives, 17 were affected and, of the 15 followed for at least 10 years, only 1 showed objective deterioration, in one eye only [27]. With the study extended to 68 affected individuals, progression remained exceptional (2 cases) and median acuity was between 20/40 and 20/50, with many mildly affected asymptomatic carriers at 20/20 [2].

In 1992, the genealogy of the kindred, by then with more than 2000 members, was traced back to three Irish brothers who settled in North Carolina around 1790 [28]. Two families published as distinct entities, the central areolar pigment epithelial dystrophy (CAPED) of Fetkenhour and the central pigment epithelial and choroidal degeneration of Hermsen and Judisch, descended from the same brothers; the work, entitled "one family, one disease", simplified the nosology and added choroidal neovascular membranes to the phenotype [28]. A 2025 review places the brothers' emigration in the 1830s, which diverges from the 1992 primary genealogical reconstruction [11, 28]. A six-generation North Carolina family with CAPED of onset between 32 and 53 years, with progressive visual loss over 3 to 10 years and a variable electroretinogram, was later incorporated into the original kindred [2, 29].

1.2. Mapping and locus heterogeneity

Using microsatellite markers, Small and colleagues linked the disease to chromosome 6q13-q21 in 1992 (lod 13.10 with marker MFD97) and, with 247 individuals from the kindred (96 affected), refined the locus, designated MCDR1, to 6q14-q16.2 with a lod of 23 [12, 30]. Families from France, Belize (Mayan ancestry), Texas, the United Kingdom and Germany were linked to the same region; the Texan family shared the haplotype of the original kindred, whereas the French and Belizean families had different haplotypes, indicating independent mutations [31–35]. In 13 families of various origins, 232 individuals examined and 117 affected, multipoint analysis placed the gene in a 1.1 cM interval between D6S249 and D6S1671, with a maximum lod of 40.03 and no genetic heterogeneity; five North American families shared the same ancestral haplotype, and the disease was recognised as present worldwide and not the result of a single founder [36, 37].

In 2003, a four-generation British family with an early-onset dominant macular dystrophy resembling NCMD was linked to 5p15.33-p13.1 (lod 3.61), and the locus was named MCDR3 [38]. A Danish family with ten affected members and a typical phenotype, in which the 6q locus had been excluded, confirmed linkage to 5p and reduced the critical interval to 12.75 Mb [4, 39]. Retinal macular dystrophy type 2 (MCDR2, gene PROM1), type 4 (MCDR4, CLEC3B) and type 5 (MCDR5, CDHR1) complete the OMIM series of retinal macular dystrophies, but they are disorders of coding genes with a different mechanism [2].

Progressive bifocal chorioretinal atrophy was described in 1968 in a Scottish family by Douglas, Waheed and Wyse [40]. In 1995, Kelsell and colleagues linked it to 6q14-q16.2 (lod 11.8 between D6S249 and D6S283), overlapping MCDR1, and anticipated that the phenotypic differences would imply distinct mutational mechanisms [41].

1.3. Molecular discovery

For two decades, sequencing of the coding regions of the MCDR1 interval found no mutations; the interval was narrowed to 1.8 Mb in six families and the eleven annotated genes were screened without result [42]. In 2016, Small and colleagues used whole-genome sequencing in 141 members of 12 families and found, in a DNase I hypersensitivity site upstream of PRDM13 and CCNC, three non-coding SNVs (V1, V2 and V3), a 123 kb duplication containing the whole of PRDM13 (V4) and, in the 5p-linked family, a 900 kb duplication that included IRX1 (V5); all five variants segregated with the disease in 102 affected individuals and were absent in 39 unaffected relatives and 261 controls [43]. In the same year another tandem duplication of PRDM13 was described in a family that exome sequencing and custom capture of the interval had not solved [44]. In 2017, overlapping 43 and 45 kb duplications downstream of IRX1 clarified the basis of MCDR3 [9], and in 2019 genome sequencing identified in PBCRA two SNVs in the same regulatory site, about 7.8 kb upstream of the PRDM13 transcription start [13].

In 2022, a multi-omic analysis of the human retina showed that the SNVs occupy two hotspots that act as active cis-regulatory elements during maculogenesis, and the authors classified NCMD as a retinal "enhanceropathy", that is, a disease caused by alteration of a transcriptional enhancer [10]. In the same year, an Egyptian family with a variant in the PBCRA hotspot and a phenotype intermediate between PBCRA and NCMD led to the proposal of the name congenital posterior polar chorioretinal hypoplasia [6].

1.4. Definition of the entities covered in this article

NCMD (MCDR1) is defined as a congenital, autosomal dominant, fully penetrant and non-progressive macular malformation caused by SNVs in DHS6S1 or by duplications that include PRDM13 [2, 45]. MCDR3 corresponds to the same phenotype caused by duplications of the IRX1_cCRE10 element at 5p15; Orphanet groups both under ORPHA:75327 [3, 4]. PBCRA is an autosomal dominant congenital chorioretinal dystrophy with two foci of atrophy, macular and nasal to the optic disc, slow progression, nystagmus, myopia and diffuse retinal dysfunction [5, 17]. CPPCRH designates a severe phenotype with extensive chorioretinal absence centred on the macula, posterior bulging of the choroid and sclera and cone and rod dysfunction, without bifocality or progression [6]. The recessive neurological disorders due to loss of function of PRDM13 share the gene, but not the mechanism or the target organ, and are covered only as allelic disorders and in the differential diagnosis [8, 14].

2. Molecular Genetics and Pathophysiology

2.1. The PRDM13 gene and the protein

PRDM13 (6q16.2; GRCh38 6:99,606,833–99,615,562) has four exons and encodes a 707-amino-acid protein of the PRDM family, with an N-terminal PR domain, a zinc finger, a long spacer region and a cluster of three C-terminal zinc fingers; the MANE Select reference transcript is NM_021620.4 (ENST00000369215.5) [8, 14]. The protein has histone methyltransferase activity, with trimethylation of lysines 9 and 27 of histone H3 in overexpression systems [14]. In the neural tube, PRDM13 is induced by the factor PTF1A, in complex with RBPJ, and represses the glutamatergic specifiers TLX1 and TLX3, including through interaction with ASCL1, favouring the PAX2-positive GABAergic lineage [14]. Expression persists in adulthood in a limited number of neuronal types, in particular in the dorsomedial hypothalamus and in retinal amacrine cells [46].

In the retina, PRDM13 specifies amacrine cell subtypes and their synaptic connections [11, 21]. In retinal organoids derived from induced pluripotent stem cells, PRDM13 expression falls as cells pass from the pluripotent state to mature retinal neurons (days 0, 30, 60 and 100 of differentiation), and PRDM13 is the only gene in the MCDR1 interval expressed only in the neural retina [14, 43]. Single-nucleus sequencing data from the human embryonic retina show peak PRDM13 expression between days 67 and 80, when amacrine cells emerge and begin to establish synapses with ganglion cells, and there is no expression in adult tissues outside these neurons [10, 11, 21]. CCNC, transcribed in the opposite direction from the same region, encodes cyclin C, a ubiquitous cell-cycle regulator [7, 11].

IRX1 (5p15.33; NM_024337.4) belongs to the Iroquois family of homeobox transcription factors, involved in embryonic patterning; in the human fetal retina it is preferentially expressed in the macula and, according to single-nucleus data, mainly in ganglion cells [8–10].

2.2. Mechanism: an enhanceropathy of macular development

The defect in NCMD is cis-regulatory: the coding sequence of PRDM13 is intact and the variants alter the amount or timing of gene expression in the developing central retina [8, 10]. The region upstream of PRDM13 contains two mutational hotspots: hotspot-1 corresponds to the candidate cis-regulatory element PRDM13_cCRE3 (chr6:99,592,841–99,593,364, GRCh38), overlapping DHS6S1, and hotspot-2 to PRDM13_cCRE5 (chr6:99,598,651–99,599,224), where the PBCRA variants and those of the Korean families lie [10, 47]. By chromosome conformation capture (UMI-4C) in adult retina, 18 candidate cis-regulatory elements were identified at the PRDM13 and IRX1 loci; PRDM13_cCRE1 interacts with the PRDM13 promoter, has in vivo activity in the eye and brain of Xenopus and is active at the time when central retinal progenitors exit the cell cycle, behaving as a PRDM13 enhancer [10]. Both hotspots are active around day 103 of embryonic development, a critical period of maculogenesis characterised by proliferation and differentiation of retinal progenitors [10].

Luciferase assays in ARPE-19 cells showed that variants V1, V2, V3, V12 and V16 significantly increase reporter activity relative to the wild-type sequence, whereas other variants of the same set reduce it; duplication of the IRX1_cCRE10 element reduced the reporter to about half relative to the single copy (p<0.001) [4, 10]. The prevailing hypothesis is one of aberrantly high or insufficiently switched-off PRDM13 expression during retinal differentiation [10, 11]. This hypothesis is consistent with animal models: in Drosophila, overexpression of the PRDM13 orthologue (CG13296) causes severe loss of the eye-antennal imaginal disc, whereas silencing of either gene or overexpression of the CCNC orthologue has no effect [48]; in a mouse model of temporally inducible PRDM13 expression, excess PRDM13 reduced photoreceptor function and survival, altered markers of amacrine subpopulations and dysregulated genes of development, phototransduction and photoreceptor health, including downregulation of Prdm1 and Nr2e3, and suppression of the excess halted the degeneration and restored part of the function [49]. None of these models has a macula, and the link between amacrine specification and the macular malformation remains to be clarified [21].

For MCDR3, the minimal region shared by the pathogenic duplications is about 39 kb, in a gene desert 800 kb downstream of IRX1 and 693.9 kb upstream of ADAMTS16, and contains DNase I hypersensitivity sites active in a restricted window of retinal development [9]. Only one of the three published MCDR3 duplications covers the coding region of IRX1, and there are benign duplications in the DGV database that include the whole of IRX1; therefore, the mechanism is not IRX1 dosage itself, but regulatory [4, 10]. The shared duplicated region contains an ultraconserved non-coding element (UCNE) active between days 74 and 103 of development [10]. Breakpoint analyses suggest non-homologous end-joining or replicative mechanisms for the duplications at both loci [10, 50].

The final target tissue includes the choroid and the retinal pigment epithelium (RPE). Histopathology of the enucleated eye of a 72-year-old woman with the MCDR1 haplotype showed a well-demarcated macular lesion with focal absence of photoreceptors and RPE, attenuation of Bruch's membrane and choriocapillaris atrophy, with lipofuscin in the adjacent RPE [2, 51]. In a Chinese family, RPE and choroidal atrophy in grade 3 lesions exceeded that of the neurosensory retina, suggesting a role of these layers in the formation of the "caldera" [52]. Multimodal imaging of a family with all three grades showed malformation of all layers of the retina and choroid, with preserved retinal vasculature on optical coherence tomography angiography [53].

2.3. Variant spectrum and nomenclature

NCMD variants are intergenic and have no c. or p. notation; they are described by genomic coordinates, and the literature uses either GRCh37/hg19 or GRCh38/hg38, and a V1–V20 numbering assigned in order of publication. The GRCh38 coordinates below were confirmed in ClinVar for the registered variants [54].

The MCDR1 duplications published up to 2025 are compiled in the following table, with the GRCh37 coordinates from the review by Spedicati and colleagues [11].

In MCDR3, the following have been described: a 900 kb duplication containing the whole of IRX1 (Danish family, V5), a 43 kb duplication (chr5:4,396,927–4,440,442, GRCh37) shared by 25 affected individuals from 9 British families with a common ancestral haplotype, and a 45 kb duplication (chr5:4,391,377–4,436,535) in a Latvian family; the last two were not found in 16 controls, in 650 patients with other retinal dystrophies or in the public structural variant database [4, 9, 43].

The V10/V11 numbering is not consistent between articles (the 2025 review assigns V10 to the variant chr6:100,046,783A>C and V11 to 100,046,804T>C, whereas the Korean publication places its variants "10 to 22 bp downstream of V10" with a different reference), so that, in practice, variants should be identified by coordinates and the reference genome version [11, 47]. The same coordinate can appear with two different substitutions (V1 G>T and V16 G>C), which led to the proposal that position g.99593030 is a mutational hotspot [55].

2.4. Founder variants and haplotypes

V1 is present in the original kindred and in the Texan family, which share a haplotype, and in an African American family followed for 30 years that has the same haplotype as the founder kindred [24, 33, 43]. Five North American families share an ancestral haplotype at MCDR1 [37]. The 43 kb MCDR3 duplication is shared by nine British families with evidence of a common ancestral haplotype [9]. The families from France, Belize, Korea and Mexico result from independent mutational events [31, 32, 47, 55]. In the recessive forms, the 13 bp PRDM13 deletion found in Malta (c.398-3_407del, NM_021620.4) was detected in the heterozygous state in 1 of 42 Maltese controls and is associated with a shared haplotype, consistent with a local founder effect [14, 15].

2.5. Penetrance, expressivity and genotype–phenotype correlation

Penetrance is complete in the families studied: all carriers examined have some macular change, however minimal [10, 12, 45]. Expressivity is highly variable within the same family, from asymptomatic foveal drusen to coloboma-like excavations, and severity correlates neither with age nor with generation [21, 56, 59]. In the review of 32 MCDR1 families, the two small duplications involving only PRDM13 (V14, 56.2 kb, and V19, about 148 kb) were associated with severe phenotypes and no intrafamilial variability, whereas duplications involving PRDM13 and CCNC and the SNVs showed marked variability; the authors put forward the hypothesis, to be confirmed in larger cohorts and with functional studies, that smaller duplications disturb the temporal regulation of PRDM13 more [11]. The two Korean families show that nearby variants in the same hotspot can produce different grades (grade 2 in one family and grade 1 in all affected members of the other) [47].

Modifiers have been proposed without proof. In a Georgian Jewish family, a six-nucleotide deletion in CFH (c.2247_2252del, p.(Leu750_Lys751del)) was present in 5 of the 6 affected individuals and absent in the oldest, who had the mildest phenotype, consistent with dry age-related macular degeneration; the authors suggest a modifying effect that does not by itself explain the variability of the disease [56]. In a Chinese family with a PRDM13 duplication, the affected individuals were also heterozygous for ABCA4 variants [52].

2.6. Allelic forms of the same regulatory element

Variants in hotspot-2 are associated with a more severe spectrum. In PBCRA, the variant chr6:100,046,804T>C arose independently in a Scottish and a French family, and chr6:100,046,783A>C, 21 bp away, arose de novo in a mother with a mild NCMD phenotype and was transmitted to a son with a PBCRA phenotype; the mother was mosaic, with a read ratio of 78%/22% (reference/alternative) versus 58%/42% in the son [7, 13]. The same variant chr6:100,046,783A>C was found in five adults of an Egyptian family with the CPPCRH phenotype [6]. These data indicate that the position and allelic dose of the variant within the same element modulate the extent of the malformation, from NCMD to PBCRA [6, 13, 46].

2.7. Recessive allelic disorders of PRDM13

Biallelic loss of function of PRDM13 does not cause maculopathy, but disorders of the hindbrain and hypothalamus. In two Maltese siblings and an unrelated Maltese man, homozygosity for c.398-3_407del (NM_021620.4), which spans the intron 3/exon 4 junction and is predicted to alter splicing with loss of the four zinc fingers, causes intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty due to congenital hypogonadotropic hypogonadism (OMIM 619761); mutant mice have fewer kisspeptin neurons in the arcuate nucleus, fewer PAX2+ progenitors in the cerebellar ventricular zone, ectopic Tlx3 expression, cerebellar hypoplasia and delayed puberty [14, 15]. In pontocerebellar hypoplasia type 17 (OMIM 619909), eight affected individuals from four families had homozygous variants: the three frameshift variants (c.839del p.(Ala280GlyfsTer21), c.844del p.(Val282SerfsTer19) and c.800del p.(Gly267AspfsTer34), NM_021620.3) were associated with death in the first days or months or with termination of pregnancy, whereas the missense p.His619Leu was associated with a milder phenotype in siblings alive at 4.5 years and 11 months; neuropathology showed hypoplasia of the inferior olives, dysplasia of the dentate nucleus and a sparse Purkinje layer [14, 16]. The heterozygous parents in these families were described as unaffected and the sources do not report a macular phenotype in carriers [14].

3. Clinical Spectrum and Manifestations by System

3.1. Overview

NCMD is an exclusively ocular disease; the sources describe no systemic manifestations, and the aminoaciduria in the 1971 description proved to be independent of the maculopathy [2, 19]. The lesions are present from birth or from the first months, reach their definitive appearance in childhood and, barring complications, remain stable throughout life [19, 20, 27]. Visual acuity (VA) ranges from 20/20 to 20/400, with a median of 20/60 in a synthesis of the MCDR1 families; colour vision is normal and so is the full-field electroretinogram [2]. Both eyes are as a rule affected symmetrically [10].

3.2. Fundus grading

The three-grade classification of Gass and Small is the one used in all series [2, 10, 45].

The grade 3 excavation is neither a staphyloma nor a true coloboma: ultrasonography and spectral-domain OCT show a deep chorioretinal excavation that spares the sclera, for which the term macular "caldera" was proposed [62]. In a North American family with 12 eyes examined, 10 had grade 3; the size and depth of the caldera did not depend on age (the youngest individual had the largest lesion) and the distance between the disc and the nasal rim was similar in all, suggesting mainly temporal expansion [2, 44]. In the Mexican family with the V19 duplication, all seven affected individuals had symmetrical, excavated colobomatous lesions, and OCT showed lacunae and loss of the inner retinal layers [18].

3.3. The disproportion between appearance and function

Acuity is consistently better than the fundus appearance would predict [2, 24]. In a British family, patients with large lesions had good acuity with fixation at the edge of the lesion, at about 5° of eccentricity [34]. On microperimetry, function is absent in the area of the grade 3 lesion, which corresponds to the absence of photoreceptors on OCT, but preserved in the adjacent photoreceptors [24]. In five patients, the areas of best sensitivity lay in the nasal macula, acuity in the better eye ranged from −0.10 logMAR (about 20/16) to 0.50 logMAR (about 20/63) with no change during follow-up, and all had local deficits on the multifocal electroretinogram (mfERG); the authors interpreted the findings as early development of fixation displaced towards the optic nerve side [64]. Psychophysical loss extends beyond the visible lesions and mfERG implicit times are delayed throughout the central retina, whereas amplitude is reduced only in the lesion, indicating a diffuse effect on the middle and outer retina [65]. Congenital onset allows specialisation of the eccentric retina and explains the good acuity in eyes with extensive lesions [34].

3.4. Drusen and peripheral deposits

Peripheral drusen, absent from the original description, were documented in the founder kindred in 1989 [26]. On re-examination of 27 members of the original kindred 30 to 50 years after the first assessment, 14 (51%) had peripheral drusen, with no correlation with macular severity [20]. In three families with the V2 variant, all six affected individuals had yellow-white dots in the far temporal periphery, often in a radial arrangement, hyperautofluorescent and easily visible on widefield imaging [21]. In a German and British series of 21 individuals from six families with the same variant, all had small drusen-like deposits, clustered in the macula or around atrophic or fibrotic changes, hyperautofluorescent, with mild irregularities on OCT and frequent in the radial temporal periphery; the authors stress that they differ from the drusen of age-related macular degeneration [60]. In the Danish MCDR3 family, the bright elements showed no accumulation of material between the RPE and Bruch's membrane and appeared to lie in the outermost layers of the retina [39].

3.5. Choroidal neovascularisation and other complications

Choroidal neovascularisation (CNV) is the main cause of acquired visual loss [20, 45]. In the original kindred, among 17 individuals (34 eyes) re-examined after 30 years, 4 eyes (12%) worsened with fibrosis attributed to neovascular membranes; grade 2 patients appeared to be at higher risk [20]. In the African American family followed between 1979–1982 and 2005–2009, 2 members developed CNV treated with laser and 1 had a vitreous haemorrhage requiring 25-gauge pars plana vitrectomy [24]. CNV has been described at 3 years [66] and at 6 years, bilateral, in a child with grade 3 [21]; in a Baltimore family with nine affected among 13 examined, drusen, macular staphyloma, CNV, RPE tear and geographic atrophy occurred [62]; in a German family there was CNV in one patient and geographic atrophy in the oldest members [35]. In grade 3 lesions, CNV and fibrosis typically form at the temporal edge of the "coloboma" and may not affect acuity, whereas patients with moderate to severe loss are, as a rule, those who have had CNV, often in one eye only [45]. The French PNDS classifies neovessels in NCMD as rare, in contrast with Sorsby fundus dystrophy, in which they are very frequent [22].

Amblyopia and exotropia in one eye at 7 years [24], slow growth of pre-existing atrophy over 14 years and bilateral chorioretinal atrophy in two patients [60], and a case of secondary multiple evanescent white dot syndrome in a 43-year-old man after a respiratory infection, which regressed within 11 weeks after a short course of oral corticosteroids [67], have been described.

3.6. Electrophysiology

The full-field electroretinogram is normal in NCMD and the electro-oculogram (EOG) is usually normal [2, 11]. There are exceptions: two patients with NCMD had an abnormal EOG with a normal electroretinogram, a combination considered characteristic of Best disease [61]; in a Chinese family the EOG had a reduced Arden ratio with a normal electroretinogram [58]; in a French family, oscillatory potentials OP3 and OP4 had reduced amplitudes and increased latencies [2, 48]; and the Italian grade 3 proband had asymmetrical rod-cone dysfunction [11]. The mfERG shows local deficits and diffuse delays [64, 65].

3.7. Variability and distribution of grades within families

In the five-generation British family, of the 13 patients examined 8 had grade 1 (peripheral drusen-like deposits and normal acuity), 1 had grade 2 (20/40 in one eye) and 4 had grade 3 with acuities of 20/30 to 20/200 [2, 34]. In two French families, grades 1 and 2 had 20/20 and grade 3 had 20/20 to 20/60 [2, 48]. In the Turkish family, the proband with grade 3 lesions had five of six children affected with similar malformations [50]. In a Mexican family, the proband had symmetrical vitelliform-like lesions resembling Best disease, her two children had large macular colobomas and her 80-year-old mother had only grade 1 lesions [55]. In three English families with V2, acuity ranged from 0.0 to 1.6 logMAR [21].

3.8. MCDR3

The MCDR3 phenotype overlaps MCDR1 [4]. The original British family had early-onset changes confined to the macula, from mild RPE pigmentary changes to atrophy, characteristic drusen-like deposits and subretinal neovascular membrane as a complication [38]. In the Danish family, the 13-year-old proband presented with photophobia, had slightly constricted kinetic fields, normal colour vision and electroretinogram and oval macular lesions of granular depigmentation; three asymptomatic siblings had the same lesions and a paternal uncle, with subnormal vision detected at 7 years and "toxoplasmosis-like" macular scars, reported at 33 years words that disappeared while reading [4, 39]. In a three-generation Latvian family (8 affected), acuity was reduced in the 6 examined, colour vision was normal and there was no progression [59]. MCDR3 has been described with more frequent colour vision defects and progression, but the published families show broad overlap [4]. Two families with a developmental macular disorder resembling NCMD and digit anomalies showed suggestive linkage to 5p15.32, overlapping MCDR3, with no causal variant identified by exome sequencing [68].

3.9. Progressive bifocal chorioretinal atrophy and posterior polar hypoplasia

In the large Scottish family, 15 of 31 living affected individuals were examined between 4 days and 63 years of age: acuity ranged from 20/120 to counting fingers, with no correlation with the extent of atrophy; all had coarse horizontal nystagmus, most were myopic, and there were photopsia and retinal detachment in 2 of the 15 patients [5, 69]. In stage 1 there is a large punched-out macular chorioretinal atrophy, visible at 4 days of life, with vertically oval optic discs and white deposits and RPE hyperpigmentation outside the macula; in stage 2 the macular lesion extends beyond the arcades and the nasal foci of atrophy coalesce into a confluent white lesion; in stage 3 both advance towards the disc, leaving a narrow vertical bridge of retina across the disc [5, 17]. The photopic and scotopic electroretinogram is markedly reduced, the EOG shows no light rise and colour sensitivity is reduced on all three axes [5]. In the French family, patients had visual impairment, photophobia and nystagmus at birth, and a second atrophic focus appeared at the end of the second decade; the son in the mother–son family had a retinal detachment at 3 years requiring surgery [5, 13]. In the Egyptian CPPCRH family, five adults had acuity of 20/200 to 20/400, extensive chorioretinal absence or thinning beyond the maculae with posterior bulging of the choroid and sclera, cystoid oedema in two and macular detachment in one, and reduced cone and rod responses on the electroretinogram [6].

3.10. Natural history and treated disease

The natural history is that of a stable malformation: without CNV, there was no significant change in acuity over 30 years in the African American family [24] and patients in the original kindred retained vision and fundus appearance throughout life, except for eyes with CNV [20]. In a follow-up of 11 patients, the phenotype remained stable in 9; in one there was growth of the atrophy over 14 years and in another a unilateral decline in acuity due to macular neovascularisation [60]. There are no series of treated patients that would allow the course with and without treatment to be compared; the available treatment data are individual reports.

4. Clinical Recognition and Red Flags

4.1. When to suspect

NCMD should be considered in the presence of congenital or early-childhood bilateral macular lesions, more severe in appearance than the visual function, with normal colour vision and electroretinogram and a dominant family history [2, 3]. The French PNDS lists as signs in favour of hereditary maculopathy a non-correctable reduction in central acuity, bilateral and symmetrical (except in the vitelliform forms), central scotoma and dyschromatopsia proportional to the loss of acuity; marked photophobia at presentation points to cone dystrophy, and reduction of the peripheral field or night blindness point to a mixed dystrophy [22]. The absence of a family history does not exclude the diagnosis, and in an isolated case drug causes (synthetic antimalarials, antiretrovirals), recreational drugs (poppers), laser injuries, diabetes, vascular occlusions and inflammatory diseases, including toxoplasmosis, should be ruled out [22].

Three clinical contexts deserve attention. The first is the child or adult with a diagnosis of bilateral congenital toxoplasmosis: grade 3 lesions and toxoplasmosis scars are indistinguishable on examination and on OCT, several members of the original kindred were labelled as toxoplasmosis, and a 7-year-old Australian boy with that diagnosis had the V2 variant [57, 70]. The second is the asymptomatic adult with "early-onset drusen": the three mildest cases in an English series were so labelled before genetic testing [21]. The third is the vitelliform-appearing macular lesion with an abnormal EOG, which may be NCMD and not Best disease [55, 61]. The presence of radial yellow-white dots in the temporal periphery on widefield imaging, although not pathognomonic, justifies requesting targeted testing [21]. Examination of relatives is decisive, because variability can only be appreciated when several members are examined [53, 71].

4.2. Urgent signs

A recent decrease in acuity, metamorphopsia or the appearance of macular haemorrhage or fluid in a patient with NCMD indicate CNV until proven otherwise and require prompt retinal assessment, because anti-VEGF therapy is effective only in the active phase [20, 22]. In the young child, who does not report symptoms, surveillance should be active, since CNV has been described at 3 and 6 years [21, 66]. Strabismus or asymmetry of acuity in an affected child suggests amblyopia [24]. In PBCRA, symptoms of retinal detachment are a surgical emergency, including at preschool age [13, 69].

4.3. Screening

There is no newborn screening. The relevant screening is ophthalmological examination of at-risk relatives, together with testing for the familial variant according to the rules for testing minors [11, 22].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Criteria

No formal diagnostic criteria have been published by a society. In the practice of the published series, the clinical diagnosis rests on four elements: congenital bilateral macular lesions of grade 1 to 3; disproportion between appearance and acuity; normal colour vision and full-field electroretinogram; and autosomal dominant transmission with variable expressivity in the family [2, 10, 39]. Absence of progression during follow-up is itself a diagnostic element [8, 18]. The diagnosis is confirmed by identification of a known variant or of a new variant that segregates with the disease at the MCDR1 or MCDR3 locus [10, 11].

5.2. Ophthalmological assessment

The PNDS recommends measuring distance and near acuity, the visual field (central abnormalities with preserved peripheral field), fundus examination and multimodal imaging; fundus autofluorescence is indispensable and has replaced fluorescein angiography, which is not indicated in hereditary dystrophies; the full-field electroretinogram according to the International Society for Clinical Electrophysiology of Vision (ISCEV) is indispensable in any maculopathy to assess severity and to separate maculopathies from cone dystrophies and mixed dystrophies; the EOG is performed if the electroretinogram is normal in a disease with deposits or if toxicity is suspected [22]. In the young child, rapid macular and, if possible, temporal OCT scans should be favoured, to detect an incipient mixed dystrophy, together with the electroretinogram; in the older child and the adult, the work-up includes acuity, visual field, colour fundus photographs, multimodal imaging with macular and temporal scans and OCT assessment of the ganglion cell fibres, macular and widefield autofluorescence, electroretinogram and, where appropriate, EOG [22].

In NCMD, widefield imaging shows the radial peripheral deposits [21, 60]; OCT distinguishes NCMD deposits from typical drusen and characterises the caldera [21, 62]; OCT angiography assesses CNV and shows the preserved retinal vasculature [21, 53]; microperimetry and mfERG document eccentric function [24, 64]. A normal electroretinogram separates NCMD from PBCRA and CPPCRH, in which cone and rod responses are reduced [5, 6]. Fluorescein angiography remains useful when CNV or inflammatory disease is suspected, as in the case of secondary evanescent white dots [23, 67].

5.3. Genetic testing

For maculopathies in general, the PNDS recommends written consent, sequencing of a next-generation sequencing (NGS) panel with exon copy-number analysis (208-gene retinal dystrophy panel), classification of variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and, when the panel is negative, a more extensive analysis by whole-genome sequencing to study non-coding sequences; under the France Médecine Génomique 2025 Plan (PFMG2025), maculopathies became a pre-indication for genome sequencing, which may be offered first-line, preferably as a trio [22].

For NCMD, this pathway has a specific limitation: the disease is not detected by exome sequencing or by panels restricted to coding regions, because the variants are intergenic or duplications [8, 10]. In family RFS355, exome sequencing and custom capture of the interval revealed no coding variants and the duplication was found only by copy-number analysis of the capture data [44]. When suspicion is clinical, the published strategy consists of Sanger sequencing of the two hotspots (which contain V1–V3, V12 and the hotspot-2 variants), junction PCR for the duplications already known, quantitative PCR of the copy number of PRDM13, IRX1 and the shared MCDR3 region, and genome sequencing in unsolved cases [10]. Long-read sequencing delineates the duplication breakpoints and was used in the Chinese and Italian families; single nucleotide polymorphism (SNP) arrays and comparative genomic hybridisation (CGH) arrays detect the larger duplications [11, 18, 58].

The yield depends on the population tested. In 23 unrelated index cases with a clinical diagnosis of NCMD, targeted testing plus genome sequencing in 9 solved only 3 (13%), and genome sequencing found no likely pathogenic variants in 290 retinal disease genes in the remainder; the authors attribute the low yield to incomplete knowledge of regulatory elements, to the existence of phenocopies (toxoplasmosis, BEST1 and PRPH2 maculopathies) and to complex structural variants that quantitative PCR and short-read genome sequencing do not detect [10]. In 18 British and other families with a typical phenotype, 13 were solved (10 with MCDR3 duplications and 3 with V2) [9]. Oxford Desk Reference puts the probability of a genetic diagnosis in retinal dystrophies in general with a good phenotype and family history at about 55%, and the PNDS reports positive results in more than half of maculopathies, in 62% of Stargardt cases and in 30% of non-Stargardt recessive maculopathies; these figures do not apply to NCMD, whose detection requires targeted methods [22, 71].

5.4. Limitations of testing and interpretation

A negative exome or coding panel does not exclude NCMD [8]. A negative targeted test does not exclude the disease either, because there are unsolved typical families at both loci [9, 10]. Non-coding variants and structural variants in regulatory regions are often classified as variants of uncertain significance (VUS), because of the difficulty in predicting their biological consequences, and functional confirmation of a new variant is performed only in research, with luciferase assays and enhancer assays in Xenopus [8, 10, 11]. In ClinVar, V1, V2 and the PBCRA variant chr6:100,046,804T>C are classified as pathogenic, V12 as pathogenic/likely pathogenic, chr6:100,046,783A>C as likely pathogenic and V3 with conflicting classifications [54]. Prediction tools give discordant results for variants such as V15, because they are trained mainly on coding variants [10]. Family segregation, together with ophthalmological examination of relatives, is the main clinical argument for new variants [11]. Marked intrafamilial variability may wrongly suggest a dual diagnosis, which should be excluded by integrating the techniques [11]. Low-fraction mosaicism, documented in PBCRA, may go unnoticed or be interpreted as heterozygosity with low-depth techniques [13].

The report should state the reference genome and coordinates (for example, NC_000006.12:g.99593111G>C for V2), zygosity, the breakpoints and gene content of duplications (PRDM13, CCNC, DHS), the ACMG/AMP class and the method used, including coverage of non-coding regions [11, 22, 54].

5.5. Practical algorithm

5.6. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible only when the familial variant has been identified [71]. The PNDS regards them as "very strictly regulated" possibilities, with many restrictions and with the limitations of knowledge of rare variants, to be discussed at a genetics clinic [22]. In a disease that is as a rule stable and with good central acuity, the decision requires careful counselling; the sources publish no experience of prenatal diagnosis in NCMD.

6. Differential Diagnosis

6.1. Principles

The differential diagnosis operates on three levels: the acquired phenocopies of grade 3 lesions (above all congenital toxoplasmosis), the other dominant hereditary maculopathies with drusen or vitelliform lesions, and the allelic forms and those of other loci with a similar phenotype [10, 22, 70]. Stability, a normal electroretinogram and a dominant family history with different grades in relatives are the features that point most towards NCMD [2, 53].

6.2. Comparative table

6.3. Main differential diagnoses

Congenital toxoplasmosis is the most important phenocopy, because grade 3 and the toxoplasmic scar can be identical on examination and on OCT; a bilateral symmetrical lesion, the absence of active satellite lesions, negative serology and the presence of relatives with grade 1 or 2 favour NCMD, and the authors who described the overlap recommend re-examining bilateral cases of "congenital toxoplasmosis" together with relatives and genetic testing [57, 70]. In one family, a diagnosis of toxoplasmosis was assigned in childhood to an uncle affected by MCDR3 [39].

Best disease is the second differential: some raised grade 2 lesions have a pseudovitelliform appearance on OCT, a patient with Best disease had a small choroidal excavation resembling grade 3, and two patients with NCMD had an abnormal EOG with a normal electroretinogram; testing of BEST1 and the hotspots separates the two entities [55, 61]. NCMD drusen are distinguished from those of age-related macular degeneration by age, by their radial peripheral distribution and by their appearance on OCT [21, 60].

PBCRA and CPPCRH share the locus but are distinguished by their consistent severity, by diffuse retinal dysfunction on the electroretinogram and, in PBCRA, by the second nasal focus, nystagmus and progression; hyperpigmentation and mottling of the RPE nasal to the disc in infants allow PBCRA to be distinguished from other macular atrophies of childhood [5, 6, 69]. Cone dystrophies are distinguished by early photophobia, by more severe dyschromatopsia for the same level of acuity and by a reduced photopic electroretinogram [22].

Syndromic forms with maculopathy (Bardet-Biedl, neuronal ceroid lipofuscinosis type 3, spinocerebellar ataxia type 7, maternally inherited diabetes and deafness) are excluded by history and general examination, and an NCMD-like maculopathy with progressive deafness corresponds to a distinct entity not linked to MCDR1 [22, 71, 75]. The recessive disorders of PRDM13 do not enter the ophthalmological differential, but should be remembered when interpreting exome reports with coding PRDM13 variants, which have a different clinical significance [8, 14].

7. Treatment and Risk Management Strategies

7.1. Objectives and evidence base

There is no treatment that alters the macular malformation. The French PNDS sets as objectives the management of low vision, the treatment of complications, general recommendations for protecting the macula and global care of the patient and family, and states that there is no validated pharmacological treatment for hereditary maculopathies [22]. The evidence specific to NCMD is limited to case reports and small series of CNV treatment; there are no trials, consensus statements or treatment cohorts [8]. GeneGuidance classifies the level of evidence for anti-VEGF therapy in NCMD as case report [8].

7.2. Choroidal neovascularisation

7.2.1. Indication and timing

The PNDS recommends discussing intravitreal anti-VEGF injections in the active phase of CNV and considers them not indicated and ineffective in the fibrotic phase [22]. The authors of the follow-up of the original kindred conclude that intravitreal therapy may benefit patients with CNV if given in time, which reinforces the importance of early diagnosis [20]. In grade 3 lesions in which CNV forms at the temporal edge without threatening the nasal fixation locus, the visual impact may be small, which should weigh in the decision [45].

7.2.2. Treatment reports

These reports do not allow efficacy to be estimated: they are isolated cases, with no comparison group, with different drugs and regimens, and the paediatric case shows that the response can be incomplete [21, 23]. Extrapolation from the MINERVA trial, which included CNV of rare causes that were neither myopic nor related to age-related macular degeneration, is the closest rational basis for the use of ranibizumab, but NCMD is not among the aetiologies described in that trial [80].

7.2.3. Drugs, doses and dosing

There is no guideline dose specific to NCMD; the PNDS gives no drug or dose [22]. The reference doses are therefore those of the labels for CNV, with use in NCMD declared as extrapolation.

The European ranibizumab label requires the injection to be withheld in the event of a loss of acuity of 30 letters or more, intraocular pressure of 30 mmHg or more, retinal break, subretinal haemorrhage involving the centre of the fovea or occupying 50% or more of the lesion, or intraocular surgery performed or planned within the preceding or following 28 days; it should not be given with other anti-VEGF agents; it is contraindicated in hypersensitivity, in active or suspected ocular or periocular infection and in active severe intraocular inflammation [80]. Injection-related reactions include endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and traumatic cataract, and there are transient increases in intraocular pressure within 60 minutes and sustained increases; the patient should be monitored during the following week and instructed to report pain, redness, blurred vision or photophobia [80]. Vitritis, vitreous detachment, retinal haemorrhage, eye pain, floaters, conjunctival haemorrhage and increased intraocular pressure are very common, and endophthalmitis, hypopyon and hyphaema uncommon [80]. The risk of RPE tear increases with large or high RPE detachments, which matters in raised grade 2 lesions [62, 80].

7.2.4. Comparative regulatory status

Marketing authorisation is not equivalent to commercial availability or reimbursement. The main divergence between jurisdictions is the extension of the European ranibizumab indication to all causes of CNV, supported by the MINERVA trial, which does not exist in the US label [80, 81].

7.2.5. Trial supporting the extrapolation

The trial is small per subgroup, the primary endpoint is early, the control group switched to active treatment at month 2 and it did not include patients with NCMD; transposition to this disease is an extrapolation based on the pathophysiological similarity of CNV, without direct comparison [80]. There are no negative, suspended or withdrawn trials specific to NCMD [85].

7.3. General measures and prevention

For maculopathies, the PNDS recommends a varied and balanced diet, rich in fruit, vegetables and antioxidants, fish three times a week, not smoking and regular physical activity, even if moderate (about one hour a day) [22]. The specific measures for Stargardt disease (avoiding vitamin A supplements, mandatory filters, avoiding contact sports because of the risk of haemorrhage) are aimed at ABCA4 disease and do not apply directly to NCMD; the sources describe no drugs to be avoided in NCMD [22]. Self-monitoring of each eye separately and prompt consultation in the event of loss of acuity or metamorphopsia follow from the fact that anti-VEGF therapy is useful only in the active phase [20, 22].

7.4. Visual rehabilitation, amblyopia and educational support

The best optical correction should be prescribed for all patients [22]. In children, asymmetry and strabismus require amblyopia treatment, which was the cause of unilateral loss of acuity at 7 years in a family with NCMD [24]. The PNDS recommends early rehabilitation and readaptation by low-vision teams (low-vision orthoptist, specialised optician, occupational therapist, orientation and mobility instructor), optical aids (magnifying lenses, magnifiers, telescopes), non-optical aids (large-print books, talking clocks) and electronic aids (reading systems, mini-cameras mounted on spectacles, character and voice recognition), tinted filters in the event of photophobia, and therapeutic education focused on the use of eccentric fixation; Braille and schooling in specialised establishments are rarely needed [22]. Early development of functional eccentric fixation is the explanation proposed for the good acuity of many eyes with extensive lesions [34, 64].

A child with non-syndromic maculopathy should attend mainstream education with adaptations: a seat facing the board, adequate lighting, a computer with magnification and audio, a tablet to photograph the board, course materials in digital format, a school support assistant if necessary and extra time in tests and examinations, with an individualised support plan when warranted [22]. In adults, the French PNDS considers that driving is no longer permitted with acuity below 5/10 and/or central scotoma, and recommends vocational reorientation with the occupational physician and global rehabilitation in specialised centres; fitness-to-drive criteria are national and should be applied according to the legislation of each country [22]. Psychological support should be offered, because the phase of visual loss or the disclosure of the diagnosis may be associated with anxiety and depression, and physiotherapy may help with postural musculoskeletal pain [22].

7.5. Investigational treatments and developments in the last 12 months

There is no clinical trial registered on ClinicalTrials.gov directed at NCMD or PRDM13 (search of 6 November 2026); patients can be included in registries and natural history studies of inherited retinal dystrophies, such as the Foundation Fighting Blindness registry (NCT02435940, 20,000 planned participants, recruiting) and a natural history study started in July 2025 (NCT07085533, 200 participants, recruiting) [85]. There is no gene therapy, antisense oligonucleotide or gene editing in clinical development for NCMD in the sources consulted. A targeted intervention would have to correct excess expression of a transcription factor during a window of fetal development, which makes the already established malformation poorly accessible to postnatal therapies; the 2025 mouse model, in which suppression of excess PRDM13 halted photoreceptor degeneration, is a preclinical finding that has not been tested in patients [10, 49].

The developments of the last 12 months are preclinical or descriptive: the mouse model of excess PRDM13 (August 2025, preclinical) [49]; the first Italian family, with a 98 kb duplication of PRDM13 and CCNC solved by long-read sequencing, and a review of 32 MCDR1 families with the hypothesis of a correlation between duplication size and variability (August 2025, family series and review, followed by a critical letter and the authors' reply in 2026) [11]; a review of the role of PRDM13 in retinal development (2026) [46]; and a 2026 letter on torpedo maculopathy and choroidal cavitation and excavation as diagnoses to be separated from NCMD [73]. There were no specific regulatory decisions.

7.6. Special populations and situations

In children, surveillance for CNV and amblyopia is the priority, and ranibizumab has no established paediatric dosing outside retinopathy of prematurity [21, 24, 80]. In pregnancy, the European ranibizumab label states that it should not be used unless the expected benefit outweighs the fetal risk, because its mechanism of action makes it potentially teratogenic, recommends effective contraception and an interval of at least 3 months between the last dose and conception, and advises against breastfeeding [80]. The sources describe no perioperative or anaesthetic risks specific to NCMD. Transition to adult services should be organised at the end of adolescence so as not to interrupt follow-up [22]. In the recessive neurological forms of PRDM13, care is multidisciplinary supportive care, with treatment of scoliosis and pubertal induction in hypogonadotropic hypogonadism, and palliative care in pontocerebellar hypoplasia type 17 [8].

7.7. Guideline recommendations and divergences

The HAS PNDS is the only guideline that mentions NCMD; it does so within a list of "other hereditary maculopathies" and in an appended table [22]. There are three divergences between the guideline and the specific literature. First, the PNDS classifies neovessels in NCMD as rare, but in the original kindred CNV was the cause of all the loss of acuity observed over 30 to 50 years (12% of eyes), occurred in children aged 3 and 6 years and is recognised as a treatable complication [20–22, 66]. Second, the PNDS recommends NGS panels and, if negative, genome sequencing, without pointing out that the coding panel does not detect NCMD; the literature indicates targeted testing of the hotspots and copy number, or genome sequencing, as first line when the phenotype suggests the disease [8, 10, 22]. Third, the general recommendation that fluorescein angiography is not indicated in hereditary dystrophies applies to diagnosis; when CNV or superimposed inflammation is suspected, the NCMD series used fluorescein angiography and OCT angiography [21–23]. There are no North American, ERN-EYE or other society guidelines specific to NCMD in the sources consulted.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

NCMD, MCDR3, PBCRA and CPPCRH are transmitted in an autosomal dominant manner; each child of a carrier has a 50% probability of inheriting the variant, in each pregnancy [2, 22]. Unlike other dominant maculopathies in which the PNDS draws attention to asymptomatic carriers, penetrance in NCMD is complete: anyone who inherits the variant has some macular change, although grade 1 may go unnoticed without a targeted examination [10, 21, 22]. The parent's grade does not predict the child's grade, because intrafamilial variability is the rule, especially in families with SNVs, and severity correlates neither with age nor with generation [11, 56, 59]. In the 2025 review, the two families with small duplications involving only PRDM13 had homogeneous severity, which the authors present as an observation to be confirmed and not as a basis for individual prediction [11].

For the parents of an apparently isolated case, targeted ophthalmological examination (including widefield imaging and autofluorescence) is essential before concluding that a variant is de novo, because a parent with grade 1 may be asymptomatic [11, 21]. In PBCRA, a de novo variant was documented in a mosaic mother with a mild NCMD phenotype who transmitted it to a son with a severe phenotype; in a mosaic parent, the risk to offspring may be lower than 50%, and the phenotype of the heterozygous child may be more severe than that of the parent [13]. The sources describe no isolated germline mosaicism in NCMD.

In the recessive disorders of PRDM13 (OMIM 619761 and 619909), the risk to the siblings of an affected individual is 25%; carrier testing of the partner is relevant in populations with a founder variant, such as the Maltese deletion [15, 16].

8.2. Cascade testing and testing of minors

Once the familial variant has been identified, testing of at-risk relatives should be combined with ophthalmological examination, to correlate genotype and phenotype and to exclude dual diagnoses [11]. The PNDS establishes that genetic testing requires written consent, that a minor is tested only with the agreement of the parents or guardian and only if they have clinical signs, and that, in a dominant disease, an unaffected minor should not be tested to establish their status; it also recommends discussing with the parents the psychological impact of systematic clinical examination of siblings [22]. In NCMD, in which the lesions are present from birth, fundus examination of the child usually establishes whether they are affected, and surveillance for CNV and amblyopia justifies ophthalmological examination of a carrier's children even without molecular testing [19, 21, 24].

8.3. Prenatal and preimplantation diagnosis

With the familial variant identified, prenatal diagnosis and preimplantation genetic testing are technically possible; the PNDS regards them as very strictly regulated possibilities with restrictions, to be discussed with the geneticist or genetic counsellor in the context of a parental project [22, 71]. Counselling should explain that the disease is as a rule stable, that acuity is often useful and that the grade in the fetus cannot be predicted [2, 11].

8.4. Content of the consultation

The PNDS provides for a dedicated disclosure consultation, with an explanation of the disease and its course, of the therapies available or not, of follow-up and the team, of genetic counselling and recurrence risks, and an introduction to patient associations [22]. In NCMD, the central message is that of a stable congenital malformation with a risk of treatable neovascular complication [20, 45].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There is no population-based prevalence study of NCMD in the sources consulted. Orphanet assigns the class <1/1,000,000, estimated from the published families [3]. The family count is the available measure: at least 30 genetically confirmed pedigrees by 2024 and 32 families with variants at the MCDR1 locus by 2025, to which at least 10 MCDR3 families are added [9, 11, 18]. These figures count published families and not patients in the population. Underdiagnosis is likely, because grade 1 cases are often asymptomatic and grade 3 cases are confused with congenital toxoplasmosis, and the authors who studied this overlap consider the disease more frequent than recognised [21, 70]. In a national Israeli study of 9396 patients with 67 inherited retinal disease phenotypes (data from May 2023), the prevalence of all inherited retinal diseases was 1:1043; the specific NCMD value was not included in the accessible part of the article [86]. The PNDS estimates that genetic maculopathies account for about 15% of retinal dystrophies in a French reference centre [22].

9.2. Geographical distribution and founders

The geographical name is historical: the disease has been described in Europe, the Americas, Asia, the Middle East, Africa and Oceania [11, 21].

In Portugal, the national IRD-PT registry included 1369 patients from 1125 families, with a genetic diagnosis in 72.3% of families and 136 genes, ABCA4 (13.0%), EYS (10.0%) and USH2A (6.9%) being the most frequent; NCMD and PRDM13 are not mentioned in the text of the article, which may reflect the absence of cases, lack of detection by the usual methods or merely the way the data are presented [87]. The sources consulted contain no data from Brazil. The absence of data in these sources does not demonstrate that there are no patients in these countries.

9.3. Special populations

Young children are the group in which CNV and amblyopia have the greatest potential impact and in which symptoms are not reported [21, 24, 66]. In adults over 50 years, NCMD with drusen and atrophy may be confused with age-related macular degeneration, and age at onset, symmetry and family history help to separate them [22, 60, 62].

9.4. Reference networks and patient associations

In Europe, the reference network is ERN-EYE [25]. In France, the PNDS refers to the SENSGENE rare sensory diseases network (https://www.sensgene.com/) and to the REFERET (Quinze-Vingts, Paris), MAOLYA (Montpellier), CARGO (Strasbourg) and OPHTARA (Necker, Paris) reference centres, and lists associations such as Retina France (http://www.retina.fr/), the Fédération des Aveugles de France and the Association Valentin Haüy [22]. In the United Kingdom, Oxford Desk Reference lists the Royal National Institute of Blind People, the Macular Society (https://www.macularsociety.org/), RP Fighting Blindness UK, Fight for Sight and SENSE [71]. Internationally, Retina International (https://www.retina-international.org/) and the Foundation Fighting Blindness (https://www.fightingblindness.org/), which maintains a patient registry (NCT02435940), are resources for patients with retinal dystrophies [85, 88, 89].

10. Illustrative Clinical Case

In 2021, Green and colleagues described three British families with six patients heterozygous for the V2 variant (chr6:100,040,987G>C in GRCh37; NC_000006.12:g.99593111G>C in GRCh38), upstream of PRDM13 [21, 54]. The most severely affected patient belonged to family 75898: a boy first seen at 3 years and last examined at 7, with acuity of 0.5 logMAR in the right eye and 1.6 logMAR in the left eye [21]. He had bilateral coloboma-like macular lesions, with subfoveal scarring and fluid due to CNV, and subtle peripheral drusenoid lesions [21]. CNV was diagnosed in both maculae at 6 years; the right eye had an active lesion on OCT angiography and intravitreal bevacizumab was started, but, after four injections, subretinal fluid persisted [21]. Figure 2 of the article, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC8212441/figure/fig2/, shows in this child a coloboma-like macular excavation with extensive central subretinal fibrosis and residual pockets of intraretinal fluid despite the four injections [21].

The child's mother was first seen at 4 years and, at the last examination, at 36, had 0.5 logMAR in both eyes, coloboma-like macular lesions with associated drusenoid lesions and some foveal sparing, and peripheral drusenoid lesions; the grandmother, also first seen at 4 years and re-examined at 58, had 1.5 logMAR in both eyes and similar lesions [21]. In the other two families, a 37-year-old woman and two brothers aged 50 and 52 had acuity of 0.0 logMAR with macular and peripheral drusenoid lesions; all three were asymptomatic and had been diagnosed as adults as having early-onset drusen, until OCT showed lesions different from typical drusen and genetic testing revealed the congenital nature [21]. Figure 3, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC8212441/figure/fig3/, shows on widefield imaging and autofluorescence, at 6, 36 and 48 years, yellow-white dots in a radial arrangement in the far temporal periphery, hyperautofluorescent, present in all participants despite the macular variability; this finding prompted targeted genetic testing in one of the probands [21]. Families 75898 and 89794 shared the same haplotype around the variant [21].

The case brings together the central elements of the disease: the same variant produces, across three generations, everything from asymptomatic lesions with normal acuity to macular excavations; the assessment of the mildly affected adults as "early drusen" illustrates underdiagnosis; and the most severe visual loss in the family did not result from the malformation itself, but from bilateral CNV in a 6-year-old child, which responded incompletely to anti-VEGF therapy [21]. The intravitreal bevacizumab used is off-label, and the number of injections and the response in this case do not constitute a reference regimen; the authors recommend surveillance for CNV above all in young children and cite another report in which bevacizumab in a treat-and-extend regimen improved acuity in an adult [21, 23].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The visual prognosis is determined by the initial grade and by the occurrence of CNV. Without CNV, acuity remains stable for decades: in the African American family followed for 30 years, members without CNV had no significant change, and in the original kindred patients retained stable vision and fundus appearance throughout life [20, 24]. Acquired loss is concentrated in eyes with CNV (4 of 34 eyes, 12%, over 30 to 50 years of follow-up of the original kindred), with a higher risk in grade 2 [20]; CNV can occur from preschool age [21, 66]. A minority show slow growth of pre-existing atrophy [60]. Amblyopia is a preventable cause of unilateral loss in childhood [24]. The prognosis of PBCRA is different: the atrophy progresses slowly, acuity is low from childhood and retinal detachment is a recognised complication [5, 69]. In CPPCRH, adult acuity was between 20/200 and 20/400 [6]. Life expectancy is not affected by NCMD; the recessive forms of PRDM13 have their own vital prognosis, severe in pontocerebellar hypoplasia type 17 [16].

11.2. Follow-up

The PNDS recommends a systematic annual ophthalmological examination by the patient's ophthalmologist and an assessment at the reference or competence centre every two to three years, shortening the interval if acuity falls or new difficulties arise and lengthening it when acuity stabilises [22]. The consultation includes visual field, multimodal imaging with autofluorescence and spectral-domain OCT (SD-OCT), adjustment of the optical correction, screening for complications (macular oedema, neovessels), assessment of fitness to drive (acuity and binocular visual field) and for the workplace, and may include psychology and genetics consultations [22]. The objectives of follow-up include coordinating care, informing the patient of advances in knowledge and organising transition to adult services at the end of adolescence [22].

12. Summary and Concluding Remarks

North Carolina macular dystrophy is a congenital, autosomal dominant and fully penetrant macular malformation, described in 1971 in a kindred of Irish ancestry and now documented in families on several continents. The geographical name and the former qualifier "progressive" result from the history of its description: the disease is present from birth and, without complications, remains stable throughout life.

The molecular basis is cis-regulatory. At the MCDR1 locus, non-coding SNVs in two hotspots upstream of PRDM13 and tandem duplications that include PRDM13 alter the expression of a retinal transcription factor during maculogenesis; at the MCDR3 locus, duplications of a regulatory element in a gene desert downstream of IRX1 produce the same phenotype. Variants in the second hotspot of the same element cause the more severe forms with diffuse retinal dysfunction, progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypoplasia, and biallelic loss of function of PRDM13 causes neurological disorders without maculopathy.

Clinically, the disease is recognised by the disproportion between macular lesions ranging from central drusen to coloboma-like excavations and an often useful acuity, by normal colour vision and electroretinogram, by radial peripheral drusen and by the variability of grade among relatives. Congenital toxoplasmosis, Best disease, early-onset drusen and other dominant maculopathies are the diagnoses with which it is confused. Examination of relatives is decisive, and genetic testing requires an explicit request for analysis of the non-coding regions and copy number, or genome sequencing, because exome sequencing and coding panels do not detect the disease and because some typical families still have no variant identified.

There is no treatment for the malformation. The main cause of acquired visual loss is choroidal neovascularisation, which can occur from preschool age and is treated with intravitreal anti-VEGF therapy in the active phase, with evidence limited to case reports and extrapolated from trials in CNV of other causes; in the European Union, ranibizumab is indicated for CNV of any cause in adults, whereas bevacizumab and paediatric use are off-label. Low-vision rehabilitation, optical correction, amblyopia treatment and educational and occupational adaptations complete the care. Annual ophthalmological follow-up with multimodal imaging, with periodic assessment at a reference centre, allows CNV to be detected in time. Genetic counselling starts from a 50% risk per pregnancy, complete penetrance and an unpredictable grade in the offspring, with the possibility of parental mosaicism in the forms at the same locus.

13. References

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3. Orphanet. North Carolina macular dystrophy (ORPHA:75327) [Internet]. Paris: INSERM; 2026 [cited 2026-11-06]. Available from: https://www.orpha.net/en/disease/detail/75327
4. Online Mendelian Inheritance in Man. #608850 Macular dystrophy, retinal, 3; MCDR3 [Internet]. Baltimore: Johns Hopkins University; updated 2023-10-31 [cited 2026-11-06]. Available from: https://www.omim.org/entry/608850
5. Online Mendelian Inheritance in Man. #600790 Chorioretinal atrophy, progressive bifocal; PBCRA [Internet]. Baltimore: Johns Hopkins University; updated 2021-01-22 [cited 2026-11-06]. Available from: https://www.omim.org/entry/600790
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