Author Affiliations: Molecular Genetics, Institute of Ophthalmology (Drs Dev Borman, Davidson, and Webster and Prof Moore), and Institute of Child Health (Dr Thompson), University College London, Moorfields Eye Hospital (Drs Dev Borman, Robson, and Webster and Profs Holder and Moore), and Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children (Dr Thompson and Prof Moore), London, and School of Biomedicine, University of Manchester (Drs Davidson and Manson) and National Genetics Reference Laboratory (Mr O'Sullivan) and Genetic Medicine, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust (Prof Black), St. Mary's Hospital, Manchester, England; and Centre for Medical Genetics (Dr De Baere and Prof Leroy) and Department of Ophthalmology (Prof Leroy), Ghent University and Ghent University Hospital, Ghent, Belgium.
Autosomal recessive bestrophinopathy (ARB) is a recently described disorder caused by biallelic mutations in BEST1.1 To date, 12 molecularly confirmed individuals (7 families) have been reported,1- 3 mostly diagnosed in adulthood. Another family reported with atypical Best disease and compound heterozygous BEST1 mutations is likely to have ARB.4 The phenotype is associated with central visual loss, hypermetropia, irregularity of the retinal pigment epithelium (RPE), and deep, scattered, white subretinal deposits that characteristically hyperfluoresce on fundus autofluorescence imaging.1 Spectral-domain optical coherence tomography from one patient showed RPE deposits, photoreceptor detachment, elongated and thickened photoreceptor outer segments (OSs), and preserved inner retinal layers.2 The electrooculogram (EOG) light rise is severely reduced.1,2 Affected adults have an abnormal full-field electroretinogram (ffERG) and the pattern ERG is usually subnormal, reflecting macular involvement.1 Pediatric data are sparse; however, one reported child (aged 11 years) had a reduced EOG light rise, abnormal ffERGs, and reduced multifocal ERGs.2
Six patients from 5 nonconsanguineous white European families participated in this study. Table 1 describes the clinical features. Subjects 5 and 6 are brothers.
All patients had bilateral maculopathy with subretinal yellow deposits (Figure 1 and Figure 2). In subject 1, these had a classic Best disease appearance; however, the lesions extended to the inferior vascular arcades and contained bilateral parafoveal cicatricial components. The right eye developed a subretinal neovascular membrane by age 7.5 years. Subject 2 had subtle multifocal yellow deposits, macular edema, and confluent yellow subretinal change along and beyond the temporal vascular arcades. Subretinal deposits in subjects 3 to 6 were more prominent, appearing as multifocal, round, yellow lesions surrounding a macular neurosensory retinal detachment. Similar additional areas of 2 to 3 disc diameters were present above the optic discs. Subject 3 had further deposits below the discs, of approximately 1 disc diameter. Subject 5 had bilateral foveal fibrosis secondary to subretinal neovascular membranes. In all patients, fundus autofluorescence imaging displayed marked hyperautofluorescence corresponding to the yellow lesions. In subject 2, this identified additional peripapillary hyperfluorescent deposits not seen on funduscopy. The fundi of all available parents (9 of 10) were normal.
Figure 1. Fundus, autofluorescence, and spectral-domain optical coherence tomography images of childhood-onset autosomal recessive bestrophinopathy for subjects 1 to 3. For each subject, images A, B, and E represent the right eye, and images C, D, and F represent the left eye. Fundus photographs (A and C), fundus autofluorescence images (B and D), and spectral-domain optical coherence tomography images (E and F) are shown. Ages at image acquisition: subject 1, 5.5 years; subject 2, 20 years; and subject 3, 12.5 years.
Figure 2. Fundus, autofluorescence, and spectral-domain optical coherence tomography images of childhood-onset autosomal recessive bestrophinopathy for subjects 4 to 6. For each subject, images A, B, and E represent the right eye, and images C, D, and F represent the left eye. Fundus photographs (A and C), fundus autofluorescence images (B and D), and spectral-domain optical coherence tomography images (E and F) are shown. Ages at image acquisition: subject 4, 5.5 years; subject 5, 19.5 years; and subject 6, 12.75 years.
Spectral-domain optical coherence tomography revealed subretinal macular hyporeflectivity in all subjects (Figures 1 and Figure 2). Discrete hyperreflective dome-shaped subretinal elevations were seen in all patients except subject 2. The photoreceptor OS layer was more clearly visible and inner retinal layers remained intact in subjects 1, 3, 4, and 6 (aged 5.5-13 years). In subjects 2, 3, 5, and 6, the photoreceptor OS layer had stalactite-like extensions into the subretinal space. Multifocal intraretinal hyporeflectivity was seen in subjects 2 (aged 15.5 years, throughout the macula) and 5 (aged 19.5 years, in the subfoveal region).
The EOG light rise was undetectable in all patients old enough to comply with testing (Table 1). Nine of 10 available parents had normal EOG light rises (range, 185%-300%; median 208.5%), including the parents of subject 4. The ERG findings are summarized in Table 1.
All subjects, except subject 4, harbored compound heterozygous mutations in BEST1 (Table 2). Screening of DNA from the unaffected parents of subjects 1, 2, 3, 5, and 6 demonstrates that, in each instance, the heterozygous BEST1 mutations identified in the children were present in trans, one being inherited from each parent on separate alleles. DNA was unavailable from subject 4. However, both of his unaffected parents carried heterozygous BEST1 missense mutations. This study identified 6 novel BEST1 mutations.
Patients in this series were first seen by 10 years of age. Visual loss was mild and longitudinal data suggested little change in visual acuity unless subretinal neovascular membranes developed.
Subretinal hyperautofluorescent, yellow deposits with subretinal fluid, evident in all patients, showed similarity with adult ARB cases.1,2,4 However, the fundi were more variable in this pediatric cohort, ranging from a classic Best disease appearance (subject 1) to a variable multifocal pattern (subjects 2-6). Extramacular hyperautofluorescent deposits were often seen.
Intact inner retinal structures were observed on spectral-domain optical coherence tomography imaging in the younger patients (aged 5.5-13 years). In the oldest patients (aged 19.5-20 years), intraretinal hyporeflectivity was presumed to represent intraretinal cysts. Through comparison of these images with time-domain optical coherence tomography images from adults, we propose that the natural history of ARB comprises the development of intraretinal cysts with age.1,4 Subretinal macular hyporeflectivity was presumed to represent subretinal fluid, with detachment of the neurosensory retina. Stalactite-like extensions into the subretinal space may represent an unmasking of tight interdigitations that normally exist between the photoreceptor OSs and apical microvilli. Alternatively, they may represent prolongations of the photoreceptor OSs that are not phagocytosed by the RPE. It is unclear whether the hyperreflective, dome-shaped subretinal elevations identified in these patients lie above, below, or within the RPE.
The absent EOG light rise in Best disease and ARB suggests that the defect localizes to the RPE. However, EOG testing may be impossible in young children. Therefore, when ascertaining the inheritance pattern, parental testing is essential; if both have normal EOGs, the condition is almost certainly recessively inherited.
Abnormal ERGs with reduced pattern ERGs have been reported in adults.1 Of the limited pediatric data published, ffERGs demonstrated reduced rod and cone b-waves.1 In this series, pattern ERGs in the younger patients were normal in all but 1 eye of 1 child (subject 1, aged 7.5 years), who had a subretinal neovascular membrane and strabismus. In the oldest patients, pattern ERGs were subnormal (subject 5) or later became subnormal (subject 2), suggesting progressive macular dysfunction. All patients tested in childhood (aged 3.5-12.5 years) had normal ffERGs. Thus, our limited longitudinal data suggest ffERG deterioration with age.
It is hypothesized that ARB represents the null bestrophin-1 phenotype in humans resulting from either null or nonfunctional missense BEST1 mutations.1 Two variants previously reported in both Best disease and ARB (p.Arg141His and p.Ala195Val) were identified in our cohort.1,5 However, the probands with Best disease previously described with these mutations have no documented family history or clinical data, leaving open the possibility that they had ARB, in which a second allele remained undiscovered.
Funduscopy, retinal imaging, and electrophysiology findings distinguish ARB from Best disease. The demonstration that the ffERG and inner retina remain preserved in childhood leads to optimism that early treatment may be effective in preventing later photoreceptor cell death.
Correspondence: Dr Dev Borman, Professorial Unit, Moorfields Eye Hospital, 162 City Rd, London EC1V 2PD, England (firstname.lastname@example.org).
Author Contributions: Dr Dev Borman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: Prof Moore is supported by an unrestricted research grant by Alcon and has been a consultant/advisor to GlaxoSmithKline.
Funding/Support: This research has received a proportion of its funding from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. Dr Davidson was supported by National Eye Research Centre studentship SCIAD 051. The groups led by Prof Black and Dr Manson are supported by the Manchester Academic Health Sciences Centre and the National Institute for Health Research Manchester Biomedical Research Centre. Dr De Baere and Prof Leroy are senior clinical investigators of the Research Foundation–Flanders and are further supported by Research Foundation–Flanders grants 3E000203, 31509107, and 31518209 (Dr De Baere) and grant OZP 3G004306 (Dr De Baere and Prof Leroy). Additional funding has been received from the organizations Fight for Sight and Foundation Fighting Blindness.
Disclaimer: The views expressed in the publication are those of the authors and not necessarily those of the Department of Health.
Additional Contributions: Kaoru Fujinami, MD, contributed substantially to the preparation of the Figures in this article. We are also grateful to Sophie Devery, MSc, and Genevieve Wright, BSc, for their involvement with the patients and their families.
Borman AD, Davidson AE, O'Sullivan J, Thompson DA, Robson AG, De Baere E, Black GCM, Webster AR, Holder GE, Leroy BP, Manson FDC, Moore AT. Childhood-Onset Autosomal Recessive Bestrophinopathy. Arch Ophthalmol. 2011;129(8):1088–1093. doi:10.1001/archophthalmol.2011.197