Samuel G. Jacobson,1 Artur V. Cideciyan,1 Alexander Sumaroka,1 Tomas S. Aleman,1 Sharon B. Schwartz,1 Elizabeth A. M. Windsor,1 Alejandro J. Roman,1 Edwin M. Stone,2 and Ian M. MacDonald3

PURPOSE.

To characterize in detail the disease expression in choroideremia (CHM), a blinding X-linked disease of the retina caused by loss-of-function mutations in Rab Escort Protein 1 (REP-1). CHM is readily diagnosed in the clinic and by molecular testing but has lacked an animal model to test hypotheses and therapeutics. The recent report of a mouse model for CHM prompts the need for reassessment of the human disease in anticipation of treatment initiatives. METHODS. CHM hemizygotes with REP-1 mutations, spanning an age range of 7 decades, were studied with in vivo microscopy by optical coherence tomography.

RESULTS.

The disease expression was complex. Earliest stages involved a thickening of the retina that was otherwise normally laminated. Loss of photoreceptors, either independent or associated with retinal pigment epithelium (RPE) depigmentation, was followed by disorganization and further thickening of the retina with interlaminar bridges. The dysmorphic retina then slowly thinned over decades. Laminopathy occurred first in more peripheral rod-rich regions and later in the cone-rich fovea.

CONCLUSIONS.

The CHM disease sequence involves detectable retinal thickening, which may be due to Mu¨ller cell activation and hypertrophy from photoreceptor stress. Photoreceptor degeneration, RPE depigmentation, and retinal remodeling follow. The results represent in vivo evidence in humans for retinal remodeling and provide a marker for the earliest stage of this response to genetic retinal disease. For CHM and other candidate human retinopathies considered for therapy, there is now a framework for making informed decisions about timing, retinal location, and potential value of treatment. (Invest Ophthalmol Vis Sci. 2006;47:4113–4120) DOI:10.1167/iovs.06- 0424

Reema Syed,1 Sanna M. Sundquist,1 Kavitha Ratnam,1 Shiri Zayit-Soudry,1 Yuhua Zhang,2 J. Brooks Crawford,1 Ian M. MacDonald,3 Pooja Godara,4 Jungtae Rha,4 Joseph Carroll,4–6 Austin Roorda,7 Kimberly E. Stepien,4 and Jacque L. Duncan1

PURPOSE.

To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques.

METHODS.

Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced.

RESULTS.

Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79þ1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/ 63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer