In all but the initial stage of CACD, a speckled FAF pattern that was sharply demarcated from the surrounding retina, regularly oval shaped and confined to the central macular, was observed. In fact, this feature could be considered the hallmark of CACD stages 2, 3, and 4 and was the most prominent discriminating characteristic (
Fig. 3). Although speckled FAF patterns previously have been described in AMD,
33,37 the alterations were less regularly shaped, less well demarcated, and often extended beyond the macular area. In the speckled FAF area in CACD, SD-OCT revealed a corresponding disorganization of the photoreceptors and a loss of photoreceptor outer segments, illustrated by a disruption of the inner–outer photoreceptor junction accompanied by a thinning in the ONL. The predominant photoreceptor loss in CACD is a consequence of the underlying disease process. CACD is caused by a monogenetic defect in one of the two
PRPH2 genes and potential modifying environmental factors are thought to be of little relevance in this disorder.
3 The Peripherin-2 protein may function as an adhesion molecule involved in stabilization and compaction of the outer segment discs and/or in the maintenance of the curvature of the rim of the discs.
38 –40 It has been demonstrated in a mouse model that one functional
PRPH2 allele is unable to support the normal outer segment morphogenesis in cones and rods.
41 Cones with one functional
PRPH2 allele provide better sensitivity to light stimuli than those completely lacking
PRPH2. These cones, however, are not as efficient in phototransduction as cones in wild-type mice.
41 In human CACD patients, there appears to be no detectable early cone dysfunction, but, as in mice, the disturbance of outer segment morphogenesis may result in an increased phagocytosis.
42 –44 The resulting accelerated lipofuscin accumulation in the RPE may cause progressive impartment of lysosomal functions and,
42,45 over time, may contribute to RPE cell death.
46 Increased levels of RPE lipofuscin have been measured in a CACD patient carrying the p.Arg172Trp point mutation.
47,48 It is plausible that the typical speckled FAF in the posterior pole of CACD stages 2 to 4 represent simultaneous occurrence of lipofuscin accumulation and focal atrophy of the photoreceptor–RPE functional unit. A reduction in cone density within areas of speckled FAF has also been described in four patients with macular dystrophies caused by the different
PRPH2 mutations.
49 Interestingly, in CACD stages 2 and 3, a subfoveal reflectivity was often preserved, indicating that foveal cones may be less vulnerable to the effects of a
PRPH2 mutation. Highly heterogeneous FAF patterns in patients with GA in AMD have been reported previously.
49 In this study, we selected and studied those FAF patterns of AMD-associated GA that could be confused with speckled FAF pattern as observed in CACD.