Autosomal dominant Best disease with an unusual electrooculographic light rise and risk of angle-closure glaucoma: a clinical and molecular genetic study

Abstract

Purpose: To describe the clinical and molecular characteristics of two families with autosomal dominant Best disease and atypical electrooculography (EOG).

Methods: Four affected individuals from two families were ascertained. Detailed ophthalmic examinations, refraction, and biometry (anterior chamber depth [ACD] and axial length [AL]), gonioscopy, optical coherence tomography of the anterior segment and retina, retinal imaging, and electrophysiological assessment were performed. Arden ratios from EOG testing were calculated by direct measurement of the light peak to dark trough amplitudes. Mutations in bestrophin 1 (BEST1) were identified by bidirectional Sanger sequencing. In family 1, segregation of BEST1 alleles was performed by assaying four microsatellite markers (D11S935, D11S4102, D11S987, and D11S4162) that flank BEST1.

Results: The proband from family 1 (three of four siblings affected with Best disease) was 42 years old with bilateral macular vitelliform lesions, advanced angle closure glaucoma (ACG), a normal electroretinogram, and no EOG light rise. Her 44-year-old brother had similar fundus appearances and an EOG light rise of 170%. Their 48-year-old sister had a normal left fundus, whereas the right fundus showed a vitelliform lesion and subretinal thickening. There was no EOG light rise detectable from either eye. Mutation analysis of BEST1 showed all affected siblings to be heterozygous for a missense mutation, c.914T>C, p.Phe305Ser. Their unaffected sister had an EOG light rise of 200%, a normal fundus appearance, and did not harbor the BEST1 mutation. Haplotype analysis of family 1 showed that the affected brother with the 170% EOG light rise had inherited the same nondiseased parental BEST1 allele as his unaffected sister. The other two affected sisters with undetectable EOG light rises shared a different nondiseased parental BEST1 allele. An unrelated 53-year-old female carrying the same c.914T>C, p.Phe305Ser mutation showed typical features of Best disease and an EOG light rise of 180%. All four siblings from family 1 had shorter axial biometry (ACD range 2.06-2.74 mm; AL range 20.46-22.60 mm) than the normal population, contributing to their risk of ACG development. Proband 2 had deeper ACDs (2.83 mm OD and 2.85 mm OS), but similar ALs (21.52 mm OD and 21.42 mm OS) compared to family 1. She had no gonioscopic evidence of angle closure.

Conclusions: A near normal EOG light rise is uncommon in molecularly confirmed Best disease, and in the present report is associated with the same mutation in two families, suggesting a specific role for this amino acid in the retinal pigment epithelium dysfunction associated with this disorder. Haplotype analysis in family 1 was consistent with an effect of the nondisease allele in mediating the presence of an EOG light rise. Clinical assessment of ACG risk is recommended for BEST1 mutation carriers and their first degree relatives.

Figure 1

Pedigree structure and haplotype analysis of family 1. The diseased allele is indicated in black, while the haplotypes carried by the unaffected parent are indicated red and yellow.

Figure 2

Fundus signs of affected siblings in family 1. Fundus photographs, autofluorescence, and posterior segment optical coherence tomography (OCT) images of family 1. A: Individual II:1 (affected sister) had a completely normal left posterior segment examination but significant retinal pigment epithelium (RPE) layer thickening on the right. B: Individual II:3 (affected brother) had disruption of the inner segment: outer segment interface. C: Individual II:4 (proband) had exudative vitelliform lesions, demonstrated in the right eye.

Figure 3

Anterior segment optical coherence tomography findings for family 1. A-D: Right eyes of individuals II:1 to II:4 respectively. E-H: Left eyes of individuals II:1 to II:4 respectively. The unaffected sister (II:2) shown in row 2 had closed angles on anterior segment (AS)-OCT. Slit openings were observed for individuals II:1 and II:3 on AS-OCT but their angles were closed on gonioscopy. The proband shown in row 4 had the shallowest anterior chamber depths. H: This shows a thickened cornea from aphakia and corneal decompensation from previous surgery in the proband.

Figure 4

Electrooculography tracings. There is inter- and intrafamilial variability in the electrooculographic (EOG) findings. Individual II:2 is the only unaffected subject, with no clinical evidence of Best disease, and clearly normal EOG light rises. Both individuals II:3 and proband 2 demonstrate near-normal EOG light rises, which is atypical for Best disease.

Figure 5

Genotype sequences for family 1. The sequence shown on the left was shared by all three affected siblings, while their unaffected sister had the wild-type sequence shown on the right.

Figure 6

Fundus signs of proband. Color photographs and posterior segment optical coherence tomography of proband 2. The color photographs show significant subretinal fluid in both eyes under the central vitelliform lesions, confirmed on optical coherence tomography.