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.2019 May 1;60(6):2347-2356.
doi: 10.1167/iovs.19-26993.

Characteristic Ocular Features in Cases of Autosomal Recessive PROM1 Cone-Rod Dystrophy

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Characteristic Ocular Features in Cases of Autosomal Recessive PROM1 Cone-Rod Dystrophy

Frederick T Collison et al. Invest Ophthalmol Vis Sci..

Abstract

Purpose: To define characteristic ocular features in a group of patients with autosomal recessive (AR) PROM1 cone-rod dystrophy (CRD).

Methods: Three males and one female from three unrelated families were first seen at the ages of 15 to 22 years and diagnosed with CRD. Clinical testing available for review included full-field electroretinogram (ERG) in three patients, as well as near-infrared autofluorescence (NIR-AF), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography in all four patients. Whole exome sequencing (WES) was performed on all cases, and whole genome sequencing (WGS) was performed in two families.

Results: WES found compound heterozygous PROM1 variants in one isolated male, plus heterozygous variants in the remaining patients. WGS uncovered deleterious PROM1 variants in these two families. ERG showed markedly reduced cone-isolated amplitudes and variably reduced rod-isolated amplitudes. The dark-adapted combined rod and cone responses demonstrated notably reduced a-wave amplitudes and moderately reduced b-waves, and the resultant waveform resembled the normal rod-isolated response. On fundus examination, oval-shaped macular lesions were observed, as were several small, circular hypoautofluorescent lesions within the posterior pole on NIR-AF. Three patients showed extramacular circular atrophic lesions.

Conclusions: The autofluorescence changes, peripheral retinal abnormalities, and ERG findings have not been emphasized in previous reports of AR PROM1, but they became a recognizable phenotype in this cohort of patients. A similar constellation of findings may be observed in CRD due to CDHR1, a functionally related gene. The pattern of abnormalities reported herein may help to focus genetic screening in patients with these findings.

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Figures

Figure 1
Figure 1
Pedigrees of the three families that participated in the study, with family A in (A), family B in (B), and family C in (C). In each of the three families, the unaffected parents were demonstrated to carry one of the two variants carried by their respective affected child/children. Segregation of variants with disease is further reinforced in each family by inclusion of one unaffected sibling, none of whom carried two disease-associated variants.
Figure 2
Figure 2
Color fundus photographs of the macula of the right eye in AR PROM1 patients 1 (A), 2 (B), 3 (C), and 4 (D), taken at ages 24, 27, 22, and 29 years, respectively. Each case showed mild vascular attenuation, peripapillary atrophy, and hypopigmentation to varying degrees in the fovea. A horizontally oval margin of either hyperpigmentation or relative sparing of macular pigment was most evident in patients 1 and 2, and a few drusenoid deposits were most evident in the macula of patient 1.
Figure 3
Figure 3
Montage retinal color photographs of patients 1 (A, right eye), 2 (B, right eye) and 3 (C, left eye), are shown at ages 26, 29, and 26, respectively. Each of these three cases demonstrated circular atrophic and hyperpigmented lesions in the mid- to far periphery. Hyperpigmentation was observed at the borders of many of the atrophic lesions (one example in each panel marked by a white arrow). Note expansion of the central atrophic lesion in patient 2, relative to the color fundus image from 2 years prior in Figure 2B.
Figure 4
Figure 4
NIR-AF in the right eye in AR PROM1 patients 1 (A), 2 (B), 3 (C), and 4 (D), taken at ages 22, 32, 28, and 29 years, respectively. Oval hypo-AF foveal lesions were evident in patients 1, 2, and 3. Small foci of hypo-AF of varying distributions throughout the macula were seen in each case. Relative to the other cases, patient 2 demonstrated confluence or enlargement of many of the hypo-AF foci, which cover not only the macula, but also the near-periphery.
Figure 5
Figure 5
Multimodal imaging of AR PROM1 patient 1. A vertical SD-OCT b-scan obtained at age 22 is shown in (A), with the corresponding IR-SLO image shown in (B). SW-AF (C) and NIR-AF (D) are overall similar, but locally more extensive changes are observable with the NIR-AF. The SW-AF shows very little focal hyperautofluorescence. The en face image in (E) is a mean intensity projection covering an area of 20° by 20°, at a distance of 24 μm anterior to Bruch's membrane, with a thickness of 10 μm. This depth location, at the anterior aspect of the retinal pigment epithelium, is demarcated by a red band on a horizontal SD-OCT b-scan in (F). The en face image (E) showed hyporeflective foci, which largely corresponded to the patterns of hypoautofluorescence in (C) and (D).
Figure 6
Figure 6
Full-field ERGs of AR PROM1 patient 2 (age 15) and patient 4 (age 21). The top panel shows the dark-adapted responses, with the rod-isolated blue stimulus above and the combined response stimulus below. The bottom panel shows light-adapted responses, with the 32-Hz stimulus above, and the single-flash white stimulus below. Gray areas represent normative ranges for a- and b-wave amplitudes and implicit times. A control subject ERG is shown in black, whereas the two AR PROM1 patients are shown in red (patient 2) and blue (patient 4).
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