Fundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65

doi:10.1016/j.ophtha.2010.09.005

Ophthalmology

Volume 118, Issue 5, May 2011, Pages 888-894

https://doi.org/10.1016/j.ophtha.2010.09.005 Get rights and content

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.

Section snippets

Methods

The study included an 18-year-old woman with night blindness since childhood, her only sibling, a 20-year-old sister, and their 2 parents (Fig 1). All the subjects were healthy and did not take any medication. There was no parental consanguinity or family history of retinal disease. Informed consent was obtained. The study was performed in accordance with institutional guidelines and the Declaration of Helsinki. Ethics committee approval was obtained.

Standard clinical examination included

Results

No subjective complaints were reported by single heterozygotes, whereas the patient with fundus albipunctatus (patient 2:2) reported night blindness since childhood (Fig 2). No significant abnormalities of retinal structure or function were recorded in the remaining family members (single heterozygotes), who all had normal fundi and normal Humphrey 30-2 perimetry. None of the family members had any significant media opacities. The following presentation refers to the findings in patient 2:2

Discussion

This is, to the best of our knowledge, the first report of fundus albipunctatus associated with compound heterozygous mutations in RPE65. The proband presented the characteristic whitish punctate lesions that were localized by OCT in the outer retina at a unique depth, namely in the photoreceptor inner and outer segment and RPE layers where the lesions were interspersed between normal-appearing stretches of outer retina. We have previously reported this in patients with fundus albipunctatus

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: Manuscript no. 2010-659.

: Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

: Supported by grants from the Dag Lenards fond, the Swedish Society of Medicine, Cronqvists stiftelse (or Cronqvists foundation) and Stiftelsen för Synskadade i fd Malmöhus län, Stiftelsen Kronprinsessan Margaretas Arbetsnämnd för synskadade, the Velux Foundation, the John and Birthe Meyer Foundation, the Øjenforeningen Værn om Synet, the Danish Research Council, the Deutsche Forschungsgemeinschaft (grant LO 457/5-1,2) and the Juvenile Diabetes Research Foundation (grant no. 8-2002-130).

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Original articleFundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Methods

Results

Discussion

J Biol Chem

J Biol Chem

Mol Ther

Ophthalmology

Exp Eye Res

Curr Biol

J Biol Chem

Evaluation of macular structure and function by OCT and electrophysiology in patients with vitelliform macular dystrophy due to mutations in BEST1

Invest Ophthalmol Vis Sci

Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents

Annu Rev Pharmacol Toxicol

Current drug patenting for retinal diseases: beyond VEGF inhibitors

Drugs

Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases

Invest Ophthalmol Vis Sci

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Proc Natl Acad Sci U S A

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus

Nat Genet

Localizations of visual cycle components in retinal pigment epithelium

Mol Vis

Lack of autofluorescence of the fundus in fundus albipunctatus associated with mutations in RDH5

Retina

Original article
Fundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65