The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

General clinical manifestations

P1 is the proband, a boy who was noted to have a mottled macular pigment 10 days after birth, during new-born eye screening. P2 is a 16-year-old female, P1’s elder sister, who experienced poor vision since childhood. She had attended our hospital for an ophthalmological evaluation 6 years earlier but was not diagnosed with NCMD at that time. The visual acuity (VA) of P2 was 20/100 OD and 20/125 OS, and the intraocular pressure (IOP) was 18 mmHg OD and 16 mmHg OS. Exotropia was 10 degrees in the left eye, and the anterior segments of both eyes were normal. P3 is a 40-year-old man, the father of the proband; he had experienced poor vision since childhood but was not diagnosed or treated. He experienced no obvious change in vision. The VA of P3 was 20/63 OD and 20/50 OS, IOP was 16 mmHg OD and 19 mmHg OS, and both anterior segments were normal. P4 is a 68-year-old man, the grandfather of P1, who had experienced poor vision since childhood without diagnosis or treatment. The VA of P4 was 20/63 OD and 20/50 OS, IOP was 15 mmHg OD and 11 mmHg OS, and both anterior segments were normal. P5 is an 8-year-old girl, another elder sister of P1. The VA of P5 was 20/20 OD and 20/50 OS, and both anterior segments and ocular fundus were normal.

Genetic analysis

According to previous studies, MCDR1 can be caused by dysregulation of the retinal transcription factor PRDM13 [6]. High-throughput sequencing showed that the PRDM13 gene (containing 4 exons) may have manifested full gene duplication in P1-4, among which the duplication of exons 1–3 was confirmed by quantitative real-time polymerase chain reaction (qPCR, Fig. 1b-d). In addition, Sanger sequencing identified heterozygous mutations in the ABCA4 gene in P1-4 (mutation information: c.4103G > A, chr1-94,497,359, p.R1368H, Fig. 2a-d). This mutation is seen in many retinal degenerative diseases, such as Stargardt disease-1 (STGD1), and shows STGD1-like features. MCDR2 combined with a heterozygous ABCA4 mutation has been previously reported by Lee W et al., but the patients reported here did not exhibit distinct STGD1-like features (Fig. 4a-c) [10]. This may be because STGD1 is an autosomal recessive disease, and the patients in this study had heterozygous mutations.

Fig. 2figure 2

a-d show the heterozygous mutations in the ABCA4 gene (mutation information: c.4103G > A, chr1-94,497,359, p. R1368H) of P1-4, respectively, which were confirmed by Sanger sequencing

Multi-imaging

Part of the fundus image data for P2 was obtained in October 2012. All other image data were collected in January 2019. Fundus photographs revealed orange‒yellow, confluent, drusen-like lesions in the fovea region of P1’s eyes, while the eyes of P2-4 presented with macular caldera and visible sclera. Thus, P1 had grade 2 lesions, and P2-4 had grade 3 lesions (Fig. 3a, b, d, e) [7]. At the same time, typical greyish-white, accumulated subretinal tissue was found at the edge of the macular atrophy in P2-4. Pigmentation could be identified in the lesions, and drusen-like, yellow‒white dot deposits were seen around the macular atrophy (Fig. 3b, d, e). A comparison of the fundus imaging data of P2 obtained in 2012 with those obtained in 2019 revealed that the fundus lesions of P2 had not changed in 6 years (Fig. 3b, c). Furthermore, the fundus photographs of both eyes of P5 showed no abnormal manifestations (Fig. 3f). In addition, the FAF of P2-4 showed the absence of fluorescence in macular lesions, indicating the absence of retinal pigment epithelium (RPE). The edge of the lesions and the yellow‒white dot deposits exhibited high fluorescence (Fig. 4a-c). A fundus fluorescein angiography (FFA) examination of P1 showed sheet transparent fluorescence in the macular region of both eyes. On the other hand, P2 exhibited oval retinal defects in both eyes at the early stage, with fluorescence of the choroidal vessels, high fluorescence at the edge of the lesions, dot-like high fluorescence around the lesions, and fluorescence staining in the macular region at the late stage (Fig. 4d-f).

Fig. 3figure 3

a, b, d, e sequentially show the fundus photographs of P1-4; (c) c is the fundus photograph of P2 taken in October 2012, 6 years before b; (f) the left eye of P5 was normal

Fig. 4figure 4

a-c shows the fundus autofluorescence of P2-4 in turn; d shows the early fundus fluorescein angiography (FFA) stage of P1; (e, f) are the early and late FFA stages of P2, respectively

Optical coherence tomography (OCT) of P1 revealed an abnormal RPE layer in the macular region of both eyes, although the neurosensory retina was relatively normal (Fig. 5a). P2-4 had macular caldera lesions, while OCT revealed complete atrophy of the choroidal structure. Only a few large choroid blood vessels attached to the sclera and/or hyperreflective substances beneath the neurosensory retina were retained. The broken ends of the RPE and subretinal hyperreflective tissues represented in the fundus photography could be seen at the edge of the lesion. We also observed nonreflective cavities underneath the neurosensory retina (Fig. 5b-d) [11]. By careful observation of the OCT in P2-4, we were able to detect RPE and choroid atrophy at the edge of grade 3 lesions, while the neurosensory retinal layer remained relatively intact. The RPE and choroid in the lesions were completely atrophied, and the neurosensory retina was also atrophied and thinned, but some areas remained covered. Atrophy appeared in a pattern of concentric circles, so the area of RPE and choroid atrophy was larger than that of the neurosensory retina. This feature has also been shown in OCT in previous studies but has not been described in detail (Fig. 6a-c) [7, 12]. In addition, OCT in the right eye of P4 was associated with macular hole changes (Fig. 6d), and OCT in P5 showed no abnormal changes.

Fig. 5figure 5

a Optical coherence tomography (OCT) of P1’s left eye showed an abnormal retinal pigment epithelium (RPE) layer in the macula (arrow); (b) OCT of P2’s left eye revealed choroid macrovessels (arrow) and subretinal hyperreflective tissues at the edge of the lesion (arrowhead); (c) OCT of P3’s left eye showed nonreflective cavities (arrow); (d) OCT of P3’s left eye showed hyperreflective substances under the neurosensory retina (arrow)

Fig. 6figure 6

a P4’s right eye. Choroid atrophy was observed at the edge of the lesion, and the neurosensory retina and RPE were preserved (arrowhead). b P4’s left eye. RPE atrophy was observed at the edge of the lesion, and the neurosensory retina and choroid were preserved (arrow). c P2’s left eye. The remaining covering of the neurosensory retinal layer in the lesion can be observed. d P4’s right eye. Note the macular hole changes (arrow)

Electrophysiology of vision

Full-field ERG in P2-4 appeared normal but showed reduced mfERG amplitude within the lesion area and delayed mfERG implicit time in the macular area. The VEP data in P2-4 were normal (Table 1).

Table 1 Case presentationsSummary of clinical findings

In the cases reviewed in this study, P2-4 had relatively good VA despite severe fundus changes. The fundus changes in P1 were consistent with the grade 2 fundus lesions of NCMD, and the fundus changes in P2-4 were consistent with grade 3 (Fig. 3a, b, d, e) [7]. The fundus lesions of P2 did not change over a 6-year period, as reflected in fundus contrast (Fig. 3b, c). In addition, the inheritance pattern of this family was autosomal dominant (Fig. 1a) [2], and genetic analysis showed that there was whole gene duplication of the PRDM13 gene in P1-4 (Fig. 1b-d) [6]. Therefore, we believe that the diagnosis of MCDR1 in this Chinese family is correct. We summarized parts of the clinical manifestations of the patients in this study in Table 1 for ease of understanding.

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