PMC9556980_01
Examination results of the proband. (A,B) Color of the optic disc was slightly pale in both eyes, and the retinal blood vessels were stretched to the temporal side, which was obvious in the left. (C,D) OCT showed that the inner and outer layers of the central fovea in the right eye were normal but diminished foveal contour with persistent inner foveal retinal layers in both eyes and no foveal depression on the left. The thickness of the superior retinal nerve fiber layer (RNFL), inferior RNFL, and average RNFL was within the normal range. The thickness of the superior ganglion cell complex (GCC), inferior GCC, and average GCC was within the normal range. (E,F) Peripheral retinal blood vessels were flat and numerous with avascular areas in both eyes. The peripheral retina of the left eye was accompanied by mild stretch proliferation and pigmentation changes.
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F1
A mild stretch proliferation and pigmentation changes were observed in the peripheral retina of the left eye (Figure 1A-B, E-F). Optical coherence tomography (OCT) revealed a diminished foveal contour, with persistent inner foveal retinal layers in both eyes, and no foveal depression on the left eye (Figures 1C,D).
FFA of the proband showed a large avascular zone in the bilateral temporal peripheral retina, blood vessels in the peripheral retinal were flat and numerous, and the optic disc showed high fluorescence in the late stage of angiography (A,B). The temporal peripheral retina of the left eye showed patchy high fluorescence with fluorescein staining, but no obvious leakage (B).
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F2
Fundus fluorescein angiography (FFA) revealed a large avascular zone in the bilateral temporal peripheral retina, high fluorescence in the optic disc in the late stage of angiography, and patchy high fluorescence with fluorescein staining in the temporal peripheral retina of the left eye (Figure 2).
P-VEP and F-VEP of the proband. The latency of the waveform recorded by P-VEP in both eyes was delayed at high SF, which was obvious in the right eye, and the amplitude decreased at high SF, mild in the left eye, and obvious in the right eye (A). The amplitude of the waveform recorded by F-VEP was similar in both eyes (B).
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F3
The latency of the waveform recorded by the pattern VEP (P-VEP) was delayed and decreased at a high spatial frequency (SF) in both eyes, especially in the right, and there was no significant decrease in the flash VEP (F-VEP) (Figure 3).
Examination results of the proband's father. The boundary of the optic disc in the right eye was unclear, and the color was slightly pale (A). The retinal blood vessels were pulled to the temporal side on the right and slightly on the left (B). OCT showed persistent inner foveal retinal layers and diminished foveal contour with IS/OS thinned and discontinuous in the right (C). The structures of the central fovea of the left eye were normal (D). The peripheral retinal blood vessels were flat and numerous in both eyes, accompanied by fiber proliferation and traction, presented as 'sickle fold' in the right (E). The peripheral retinal vessels are straight and numerous, accompanied by avascular areas that showed 'inverted V' (F).
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F4
The optic disc of the left eye was normal, and the peripheral retinal vessels were straight and numerous, accompanied by avascular areas (Figure 4A, B, E, F). OCT revealed persistent inner foveal retinal layers and diminished foveal contour with IS/OS thinning and discontinuity in the right eye and normal structures of the central fovea in the left eye (Figures 4C,D).
FFA of proband's father showed a large avascular zone in the bilateral temporal peripheral retina, and blood vessels in the peripheral retinal were flat and numerous (A,B). The temporal peripheral retina showed patchy high fluorescence with fluorescein leakage, which is obvious in the right (B).
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F5
FFA revealed a large bilateral avascular zone and patchy high fluorescence with obvious fluorescein leakage in the late stage in the right temporal peripheral retina (Figure 5).
Examination results of the proband's mother. (A,B) Arc spot of myopia in temporal optic discs. (C,D) OCT showed that the inner and outer layers of central fovea were normal in both eyes. Optic nerve head analysis was normal. The thickness of inferior RNFL was normal, superior RNFL, and average RNFL was borderline in the right. The thickness of superior RNFL was normal, inferior RNFL, and average RNFL was borderline on the left. The thickness of superior GCC and average GCC was within normal range, and inferior GCC decreased. The focal loss volume (FLV) was within the normal range, and global loss volume was outside the normal range in both eyes.
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F6
OCT revealed no abnormality in the bilateral central foveae but was thin in the bilateral inferior ganglion cell complex layers (Figure 6).
P-VEP and F-VEP of proband's mother. The latency of the waveform recorded by P-VEP was delayed and decreased slightly at high SF in both eyes (A). The amplitude of the waveform recorded by F-VEP was normal in both eyes (B).
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F7
VEP results were within the normal range (Figure 7).
Examination results of the proband's fraternal twin brother were normal (A,B). The thickness of the superior retinal nerve fiber layer (RNFL), inferior RNFL, and average RNFL was within the normal range. The thickness of the superior ganglion cell complex (GCC), inferior GCC, and average GCC was within the normal range (C,D).
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F8
Slit-lamp biomicroscopy and OCT results were normal in both eyes (Figure 8).
Pedigrees of families. The II-1 proband is marked with an arrow and has two missense heterozygous mutations, LRP5 (c.2551C > T, p.His851Tyr) and OPA1 (c.565G > A, p.Glu189Lys). Pedigree verification analysis shows that the proband's father has a heterozygous mutation of LRP5 (c.2551C > T, p.His851Tyr) (I-1), the proband's mother has a heterozygous mutation of OPA1(c.565G > A, p.Glu189Lys) (I-2), and the proband's fraternal twin brother has no mutation (II-2).
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F9
The inheritance mode of this family was autosomal-dominant; the pedigree of the family is presented in Figure 9.
Identification of one heterozygous LRP5 mutation in the family members. (A) DNA sequence chromatograms of the unaffected and affected family members. One heterozygous LRP5 mutation c.4294C > T (p.H1432Y) in exon 20 was identified in the cases of the proband and his father. (B) Multiple-sequence alignment of the LRP5 proteins from different species. The red triangle indicates the location of the mutation. The His 1432 residue is highly conserved across species. (C) Polymorphism Phenotyping predicted that the amino acid substitution H1432Y in the protein LRP5 is probably damaging.
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F10
Functional prediction revealed that the mutation was likely pathogenic (Figure 10; Table 1).
Pedigrees of the families. The proband (II-1) and his mother (I-2) have heterozygous mutation of OPA1 (c.565G > A, p.Glu189Lys). The proband's fraternal twin brother (II-2) has no mutation.
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F11