Late Development of Vitelliform Lesions and Flecks in a Patient With Best Disease

Abstract

To provide the clinicopathologic findings of a patient who developed the clinical characteristics of Best disease (typically considered a juvenile macular degeneration) at the age of 75 years after being documented to be ophthalmoscopically normal at the age of 51 years. Design: A member of a large family with Best disease, possessing a Y227N mutation in the VMD2 gene (the gene responsible for the disease, which encodes the bestrophin protein), developed small vitelliform lesions in both eyes at the age of 75 years and later developed yellow flecklike depositions at the level of the retinal pigment epithelium (RPE), which were also identified in fundus photographs of family members. The patient died at the age of 93 years, and the histological features of the macular lesion and peripheral flecks were examined.

Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance

“…Mutations in bestrophin-1 therefore probably result in altered RPE function, subsequently contributing to disease. This sequence of events has been demonstrated by ocular coherence tomography in BMD patients (Pianta et al, 2003), post mortem eyes of BMD patients (Bakall et al, 2007;Mullins et al, 2007;Weingeist et al, 1982) and in canine (Guziewicz et al, 2007) and murine (Zhang et al, 2010) animal models, which reveal alterations of the RPE such as hypertrophy (Bakall et al, 2007;Guziewicz et al, 2007), lipofuscin accumulation (Bakall et al, 2007;Guziewicz et al, 2007;Mullins et al, 2005;Weingeist et al, 1982) and focal loss of RPE cells (Bakall et al, 2007;Guziewicz et al, 2007;Mullins et al, 2005). Patients affected with BMD characteristically have an absent or reduced light-peak in the electro-oculogram (Arden and Constable, 2006;Boon et al, 2009;Cross and Bard, 1974;Ponjavic et al, 1999;Renner et al, 2005;Wabbels et al, 2004;Weleber, 1989).…”

“…Bestrophin-1 is strongly expressed in the retinal pigment epithelium (RPE), where it mainly localizes to the basolateral membrane (Gouras et al, 2009;Guziewicz et al, 2007;Marmorstein et al, 2000;Mullins et al, 2007;Mullins et al, 2005;Neussert et al, 2010). The RPE fulfills a multitude of functions that are essential for excitability and the structural integrity of the photoreceptors (Strauss, 2005).…”

Human Photoreceptor Outer Segments Shorten During Light Adaptation

“…The variation in the EOG in response to light is mediated by changing chloride conductance across the basolateral plasma membrane of the RPE, 23 and the attenuated response in Best disease patients is present even in the absence of visible fundus changes. 25 The normal physiological purpose of this light-mediated alteration of RPE chloride conductance is currently unknown. There is evidence that the subretinal space expands following light onset in animals, but only if the RPE is left intact; isolated retina does not show this change.…”

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

“…18 Even before the genetic studies showed an association between AMD and complement genes, evidence of complement activation in AMD was provided by the presence of complement components 3 (C3) and 5 (C5), complement factor H, and the membrane attack complex in drusen. [19][20][21][22] Genetic studies have implicated these same gene products as well as other genetic loci in the complement pathway as having a protective or risk-enhancing role for the development of AMD. [23][24][25][26] In addition, the role of complement in AMD is suggested by the appearance of macular drusen in eyes of patients with complement-mediated renal disease 27 and by the data from animal studies showing that complement activation has a role in CNV.…”