Elsevier

Ophthalmology

Volume 117, Issue 7, July 2010, Pages 1415-1422
Ophthalmology

Original article
Course of Visual Decline in Relation to the Best1 Genotype in Vitelliform Macular Dystrophy

https://doi.org/10.1016/j.ophtha.2009.11.044Get rights and content

Purpose

To describe the disease course in patients with vitelliform macular dystrophy (VMD) with a Best1 mutation and to determine the association between Best1 genotype and visual prognosis.

Participants

Fifty-three patients with VMD with Best1 mutations from 27 Dutch families, aged 11 to 87 years.

Methods

Best-corrected visual acuity (VA), fundus appearance, and Arden ratio on the electro-oculogram (EOG) during clinical follow-up were assessed from medical records. Mutation analysis of the Best1 gene was performed on DNA samples using denaturing high-pressure liquid chromatography and direct sequencing.

Main Outcome Measures

Cumulative lifetime risk of visual decline below 0.5, 0.3, and 0.1 for the entire group and stratified for genotype.

Results

Median age of onset of visual symptoms was 33 years (range: 2–78). The cumulative risk of VA below 0.5 (20/40) was 50% at 55 years and 75% at 66 years. The cumulative risk of decline less than 0.3 (20/63) was 50% by age 66 years and 75% by age 74 years. Two patients progressed to VA less than 0.1 (20/200). Fourteen different mutations were found. Most patients (96%) had missense mutations; the Thr6Pro, Ala10Val, and Tyr227Asn mutations were most common. Visual decline was significantly faster in patients with an Ala10Val mutation than either the Thr6Pro or the Tyr227Asn mutation (P=0.001).

Conclusions

Age of onset of visual symptoms varies greatly among patients with VMD. All patients show a gradual decrease in VA, and most progress to visual impairment at a relatively late age. Our data suggest a phenotype–genotype correlation, because the Ala10Val mutation has a more rapid disease progression than other common mutations.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Study Population

Patients with a clinical and molecular diagnosis of VMD who presented to 3 specialized ophthalmogenetic clinics in the Netherlands between 2003 and 2007 were considered eligible for inclusion in the study. The clinical and molecular diagnosis included a VMD lesion in the retina (see below) and the presence of a disease-causing mutation in the Best1 gene. Exclusion criteria were uncertain with regard to the clinical diagnosis or the absence of a disease-causing mutation. Twenty-nine probands and

Clinical Characteristics at First Presentation

Demographic data of all 53 patients are presented in Table 1. The patients were genealogically linked to 27 pedigrees; 16 individuals were sporadic patients and 37 individuals had at least 1 relative with a VMD phenotype. The study population consisted of 29 male and 24 female patients.

The age at the first visit to an ophthalmologist ranged from age 2 to 78 years, with a median of 33 years. Seventeen patients had an early onset (<10 years of age), 18 patients had an onset during age 10 to 18

Discussion

We show that VMD, caused by mutations in the Best1 gene, is a disease with a variable age of onset and clinical course, ultimately leading to visual decline. Our survival analyses indicate that the variability may in part be explained by differences in genotype. Vision in the majority of patients deteriorated to such an extent that driving was prohibited at middle age and that reading was generally compromised after age 70 years. However, development of legal blindness was rare, even at higher

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    Manuscript no. 2009-709.

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

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