In vivo Adaptive Optics Imaging of the Cone Photoreceptor Mosaic in Autosomal Dominant Cone Rod Dystrophy (AD-CRD) in a Three-generation Family Carrying the I143NT Mutation in the Guanylate Cyclase Activator A1A (GUCA1A) Gene

Abstract

Purpose: : To identify the pattern of cone cell loss in early AD-CRD caused by a defect in GUCA1A. GUCA1A encodes a guanylate cyclase-activating protein expressed at high levels in cone outer segments and inactivated by calcium binding under scotopic conditions. The I143NT mutation alters calcium binding, resulting in persistent stimulation of guanylate cyclase in the dark. The mechanism by which this defect leads to cone cell loss remains poorly understood. To date, the only morphological data available at the cellular level has been derived from a single histopathologic specimen of a 75-year-old patient, showing complete loss of cones in the central fovea and rare cones in the periphery. In this study, we use adaptive optics imaging to evaluate the early disease changes in the cone mosaic of patients harboring the I143NT mutation.

Methods: : Molecular genetic testing was performed on ten affected members of a 3-generation family with AD-CRD. Eight affected and four unaffected members were examined using reflectance imaging in a high-resolution adaptive optics scanning laser ophthalmoscope (AOSLO). A high-resolution montage was assembled by stitching together AOSLO images obtained with a 1.5 deg field of view. Registered AOSLO images were correlated with standard clinical tests including fundus photographs and optical coherence tomography.

Results: : Molecular genetic testing revealed the I143NT mutation in GUCA1A segregating with disease. AOSLO imaging of the older patients showed severe disruption of the photoreceptor layer with few to no identifiable cones. In younger patients, AOSLO showed a spectrum of disease ranging from near-normal cone spacing to more widespread cone loss.

Conclusions: : AOSLO imaging shows phenotypic diversity in the pattern of cone cell loss, even in patients who are only mildly affected by standard clinical tests. AOSLO provides a quantitative method to identify affected regions within the retina, monitor disease progression, and follow the effects of any potential treatments.

Keywords: retinal degenerations: hereditary • imaging/image analysis: clinical • photoreceptors