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Fundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65.

Schatz, Patrik LU ; Preising, Markus; Lorenz, Birgit; Sander, Birgit; Larsen, Michael and Rosenberg, Thomas (2011) In Ophthalmology 118. p.888-894
Abstract
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... (More)
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 RPE-outer segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERG-including prolonged dark adaptation-demonstrated 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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Ophthalmology
volume
118
pages
888 - 894
publisher
Elsevier
external identifiers
  • wos:000290090300015
  • pmid:21211845
  • scopus:79955574258
ISSN
1549-4713
DOI
10.1016/j.ophtha.2010.09.005
language
English
LU publication?
yes
id
9c3ed17a-cda0-443e-b1c4-e0940e9c2062 (old id 1777729)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21211845?dopt=Abstract
date added to LUP
2011-02-01 11:03:43
date last changed
2017-04-23 03:11:39
@article{9c3ed17a-cda0-443e-b1c4-e0940e9c2062,
  abstract     = {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 RPE-outer segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERG-including prolonged dark adaptation-demonstrated 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.},
  author       = {Schatz, Patrik and Preising, Markus and Lorenz, Birgit and Sander, Birgit and Larsen, Michael and Rosenberg, Thomas},
  issn         = {1549-4713},
  language     = {eng},
  pages        = {888--894},
  publisher    = {Elsevier},
  series       = {Ophthalmology},
  title        = {Fundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65.},
  url          = {http://dx.doi.org/10.1016/j.ophtha.2010.09.005},
  volume       = {118},
  year         = {2011},
}