Best Disease (BD)

At a glance

An inherited, gradually starting, progressive, polymorphic macular dystrophy.

Synonyms

Best Vitelliform Macular Dystrophy; Best Multifocal Vitelliform Macular Dystrophy; Vitelliform Macular Dystrophy Type 2; Polymorphic Vitelline Macular Degeneration; Early Onset Vitelliform Macular Dystrophy; Juvenile Onset Vitelliform Macular Dystrophy; Adult Onset Vitelliform Macular Dystrophy.

History

Named after the German ophthalmologist Friedrich Best (1871-1965) who described the disease in eight patients in 1905.

Incidence

A prevalence estimate of BD in Denmark cited a rate of 1.5:100,000 individuals, making BD one of the most common causes of early onset macular degeneration. A previous study from northern Sweden reported a prevalence of 2:10,000; however, that estimate was based on 95 identified cases with 75 of them belonging to a single family. Several large kindreds have been reported in the literature, with one gene source being traced back to the 17th century in Sweden.

Genetic inheritance

Autosomal dominant inheritance. BD is caused by heterozygous missense mutations in the Bestrophin 1 (BEST1) gene (also known as VMD2 (Vitelliform Macular Dystrophy 2) gene) located on chromosome 11q12.3. Autosomal recessive inherited BEST1 mutations have sporadically been described and are typically associated with more severe course of the disease. Bestrophin 1 is a transmembrane protein (chloride channel) located on the basolateral side of retinal pigment epithelial (RPE) cells and the mutations seem to affect normal chloride flux and fluid transport through the RPE. It also seems to play a critical role in the regulation of Ca²⁺ signaling in the RPE cells. The characteristic variations in the electrooculogram (EOG, see below) in response to light are mediated by changes in the chloride conductance across the basolateral plasma membrane of the RPE cells. Other diseases that have recently been linked to mutations in the BEST1 gene include autosomal recessive vitelliform macular dystrophy, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, adult-onset foveomacular vitelliform dystrophy, and retinitis pigmentosa.

Pathophysiology

The disease is characterized by a gross yellow or orange discoid, subretinal lesion in the macula. Histopathologic findings on postmortem specimens as well as spectral-domain optical coherence tomography and fundus autofluorescence imaging in living patients showed excessive lipofuscin accumulation in the retinal pigment epithelial cells and the subretinal pigment epithelial cell space with subretinal fluid collections and varying degrees of photoreceptor atrophy. Here, lipofuscin is made up of an autofluorescent collection of breakdown products from parts of the photoreceptors that include oxidized proteins, lipids, and various fluorophores. The subretinal fluid collection most likely results from a failure of the retinal pigment epithelium pump function, which is supposed to keep the subretinal space free from fluids. The final stage of retinal pigment epithelial atrophy, uncommon before the age of 40 years, may result in fibrous scarring and a choroidal neovascularization membrane with further loss in ...