TY - JOUR
T1 - Fundus albipunctatus associated with compound heterozygous mutations in RPE65
AU - Schatz, Patrik
AU - Preising, Markus
AU - Lorenz, Birgit
AU - Sander, Birgit
AU - Larsen, Michael
AU - Rosenberg, Thomas
N1 - Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PY - 2011/5
Y1 - 2011/5
N2 - Purpose To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations. Design Observational study. Participants Four family members. Methods Clinical examinations included full-field electroretinogram (ffERG) after standard (30-minute) and prolonged (17-hour) dark adaptation, multifocal electroretinogram (mfERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF). Molecular genetic testing included sequencing of RDH5 and RLBP1 and screening for known autosomal-recessive retinitis pigmentosa mutations by a commercially available microarray technique. RPE65 sequencing was performed after the identification of a known heterozygous splice-site mutation by array screening. Main Outcome Measures We recorded ffERG and mfERG amplitudes, OCT characteristics, the FAF intensity index, and the outcomes of DNA sequencing regarding RPE65 mutations. Results Uniform, yellow-white dots typical of fundus albipunctatus were demonstrated in the proband. These dots corresponded with discrete, hyperreflective formations extending from the Bruch's membrane and retinal pigment epithelium (RPE) into the level of the external limiting membrane, thus spanning along the entire RPE and photoreceptor outer and inner segments. A reduced thickness of the central retina and the RPEouter segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERGincluding prolonged dark adaptationdemonstrated a barely recordable rod response after standard dark adaptation and normalization (increase by more than 700%) of the response after prolonged dark adaptation. The cone 30-Hz flicker response was reduced after standard dark adaptation and increased by >50% after prolonged dark adaptation. In addition, mfERG demonstrated reduced central and peripheral responses. Molecular genetic analysis demonstrated compound heterozygous mutations (IVS1+5G>A and c.344T>C) in RPE65. No mutations were found in RDH5 or RLBP1. No significant abnormalities of retinal structure or function were detected in the parents and sister carrying single heterozygous mutations in RPE65. Conclusions This is the first reported association between compound heterozygous RPE65 mutations and fundus albipunctatus, indicative of a mutation-specific phenotypic effect in this gene. This finding, together with the reduced FAF, supports that disruption of retinoid recycling in the RPE is essential for the development of fundus albipunctatus. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
AB - Purpose To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations. Design Observational study. Participants Four family members. Methods Clinical examinations included full-field electroretinogram (ffERG) after standard (30-minute) and prolonged (17-hour) dark adaptation, multifocal electroretinogram (mfERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF). Molecular genetic testing included sequencing of RDH5 and RLBP1 and screening for known autosomal-recessive retinitis pigmentosa mutations by a commercially available microarray technique. RPE65 sequencing was performed after the identification of a known heterozygous splice-site mutation by array screening. Main Outcome Measures We recorded ffERG and mfERG amplitudes, OCT characteristics, the FAF intensity index, and the outcomes of DNA sequencing regarding RPE65 mutations. Results Uniform, yellow-white dots typical of fundus albipunctatus were demonstrated in the proband. These dots corresponded with discrete, hyperreflective formations extending from the Bruch's membrane and retinal pigment epithelium (RPE) into the level of the external limiting membrane, thus spanning along the entire RPE and photoreceptor outer and inner segments. A reduced thickness of the central retina and the RPEouter segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERGincluding prolonged dark adaptationdemonstrated a barely recordable rod response after standard dark adaptation and normalization (increase by more than 700%) of the response after prolonged dark adaptation. The cone 30-Hz flicker response was reduced after standard dark adaptation and increased by >50% after prolonged dark adaptation. In addition, mfERG demonstrated reduced central and peripheral responses. Molecular genetic analysis demonstrated compound heterozygous mutations (IVS1+5G>A and c.344T>C) in RPE65. No mutations were found in RDH5 or RLBP1. No significant abnormalities of retinal structure or function were detected in the parents and sister carrying single heterozygous mutations in RPE65. Conclusions This is the first reported association between compound heterozygous RPE65 mutations and fundus albipunctatus, indicative of a mutation-specific phenotypic effect in this gene. This finding, together with the reduced FAF, supports that disruption of retinoid recycling in the RPE is essential for the development of fundus albipunctatus. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
U2 - http://dx.doi.org/10.1016/j.ophtha.2010.09.005
DO - http://dx.doi.org/10.1016/j.ophtha.2010.09.005
M3 - Journal article
SN - 0161-6420
VL - 118
SP - 888
EP - 894
JO - Ophthalmology
JF - Ophthalmology
IS - 5
ER -