Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.
Purpose Mutations in six genes have been associated with achromatopsia (ACHM): CNGA3 , CNGB3 , PDE6H , PDE6C , GNAT2 , and ATF6. ATF6 is the most recent gene to be identified, though thorough phenotyping of this genetic subtype is lacking. Here, we sought to test the hypothesis that ATF6 -associated ACHM is a structurally distinct form of congenital ACHM. Methods Seven genetically confirmed subjects from five nonconsanguineous families were recruited. Foveal hypoplasia and the integrity of the ellipsoid zone (EZ) band (a.k.a., IS/OS) were graded from optical coherence tomography (OCT) images. Images of the photoreceptor mosaic were acquired using confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Parafoveal cone and rod density values were calculated and compared to published normative data as well as data from two subjects harboring CNGA3 or CNGB3 mutations who were recruited for comparative purposes. Additionally, nonconfocal dark-field AOSLO images of the retinal pigment epithelium were obtained, with quantitative analysis performed in one subject with ATF6 -ACHM. Results Foveal hypoplasia was observed in all subjects with ATF6 mutations. Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects with ATF6 using OCT. There was no evidence of remnant foveal cone structure using confocal AOSLO, although sporadic cone-like structures were seen in nonconfocal split-detection AOSLO. There was a lack of cone structure in the parafovea, in direct contrast to previous reports. Conclusions Our data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6- ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3 - or CNGB3 -ACHM.
ncontinentia pigmenti (IP), or Bloch-Sulzberger syndrome, is a rare X-linked dominant disorder mainly seen in females because a single allele in male embryos is usually fatal. 1,2 Incontinentia pigmenti usually presents with a characteristic skin rash that leaves hypopigmented patches on the trunk and limbs. 3 The most serious events involve the retina and central nervous system (CNS) in 18% to 30%. [2][3][4][5] Loss-offunction mutations in IKBKG/NEMO impair nuclear factorkappa B (NF-κB) signaling and are responsible for most cases of IP. 6,7 Although NF-κB signaling is ubiquitous, effects from the IKBKG/NEMO mutation do not manifest in all tissues.Vision loss has been associated with vascular occlusions, secondary extraretinal neovascularization (NV), tractional retinal detachments, 2,5,8 and foveal hypoplasia. 8 Herein, we report findings from spectral-domain optical coherence tomography (SD-OCT) in children with IP examined before age 5 years. Poor visual behavior corresponded with inner retinal structural abnormalities.IMPORTANCE This report presents evidence from spectral-domain optical coherence tomography and fluorescein angiography of inner foveal structural abnormalities associated with vision loss in incontinentia pigmenti (IP).OBSERVATIONS Two children had reduced visual behavior in association with abnormalities of the inner foveal layers on spectral-domain optical coherence tomography. Fluorescein angiography showed filling defects in retinal and choroidal circulations and irregularities of the foveal avascular zones. The foveal to parafoveal ratios were greater than 0.57 in 6 eyes of 3 patients who had extraretinal neovascularization and/or peripheral avascular retina on fluorescein angiography and were treated with laser. Of these, 3 eyes of 2 patients had irregularities in foveal avascular zones and poor vision.CONCLUSIONS AND RELEVANCE Besides traction retinal detachment, vision loss in IP can occur with abnormalities of the inner foveal structure seen on spectral-domain optical coherence tomography, consistent with prior descriptions of foveal hypoplasia. The evolution of abnormalities in the neural and vascular retina suggests a vascular cause of the foveal structural changes. More study is needed to determine any potential benefit of the foveal to parafoveal ratio in children with IP. Even with marked foveal structural abnormalities, vision can be preserved in some patients with IP with vigilant surveillance in the early years of life.
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