Clinicopathologic studies of patients with PD have shown similar findings (14, 15, 16). A histopathological study of the postmortem eyes of a 61-year-old female revealed focal atrophy of the RPE in the foveolar area bordered by hypertrophic RPE, with fusiform collagenous plaques of eosinophilic material located between the atrophic RPE and Bruch’s membrane. The sensory retina over the abnormal RPE displayed significant atrophy of the outer nuclear layer with loss of photoreceptor inner layer and outer segments. Pigment-laden macrophages with periodic acid Schiff-positive material had migrated into the atrophic outer retina. Ultraviolet fluorescent microscopy demonstrated massive accumulation of lipofuscin within the macular RPE as well as within the macrophages in the atrophic outer retina. Scanning electron microscopy revealed a confluent area of flattened atrophic RPE cells surrounded by
taller hypertrophic RPE cells. Transmission electron microscopy demonstrated that the RPE cells contained many lipofuscin granules (14,15). In three patients with AVMD, RPE and photoreceptor cell loss were observed in the central area. A moderate number of pigment-laden macrophages were present in the subretinal space and outer retina. The RPE was distended to both sides of the central lesion with abundant lipofuscin (16).

PD is genetically heterogeneous. To date, the most common genes known to harbor mutations that can cause nonsyndromic PD include PRPH2 (Peripherin 2) (Stone, personal communication referred to in Grover et al. [17]) (18), ELOVL4 (19), and BEST1 (20) (previously known as VMD2; see also Chapter 11F). In addition, as noted above, gene mutations in DTM (myotonic dystrophy) and mtDNA 3243 may be associated with a “PD-like” phenotype.

PRPH2 encodes peripherin 2, a membrane-associated glycoprotein restricted to photoreceptor outer segment discs (21). Normal levels of this protein are required for the morphogenesis and maintenance of the photoreceptor outer segments (22). The rds mouse exhibiting the retinal degeneration slow phenotype was found to have a single spontaneous mutation (23). The phenotype in the rds mouse is characterized by abnormal development of photoreceptor outer segments in the retina followed by a slow degeneration of the rods and cones, resembling the phenotypes described in human retinal dystrophies associated with PRPH2 mutations (24). A feature seen in both humans with PRPH2 mutations and mice with the rds mutation is a loss of photoreceptor function. Ali et al. (25) demonstrated that a subretinal injection of recombinant adeno-associated virus (rAAV) encoding an rds transgene resulted in the stable generation of outer segment structures and formation of new stacks of discs, which were morphologically similar to normal outer segments, and electrophysiological tests confirmed function. rAAV-mediated gene replacement of peripherin 2 restored retinal ultrastructure and function for as long as 14 weeks in the rds mouse. In this model, however, AAV-mediated gene replacement was not sustained in the long term.

Although studies have described a common consistent phenotype caused by certain mutations in peripherin 2, such as the Arg172Tryp mutation associated with macular dystrophy (26), significant variation in phenotypic expressivity in the same family has also been described in PD associated with PRPH2 mutations (5). For example, the same mutation can cause retinitis pigmentosa, PD, and fundus flavimaculatus in a single family (5). Yang et al. (4) described three separate families, each of which had a distinct PD phenotype that differed from those of the other families, although they all had the same mutation in PRPH2 and an identical disease haplotype.

ELOVL4 is a photoreceptor-specific gene that is involved in the biosynthesis of very long chain fatty acids. It is expressed in retina and skin. Defective protein trafficking may underlie the molecular mechanism associated with degeneration of the macula (27). It is possible that some patients with multifocal PD simulating STGDFFM have mutations in this gene, as mutations in ELOVL4 have been found in patients with AD Stargardt-like disease (19,28).

The age of onset in PD is usually in late adulthood, but with a positive family history it may occur in early adulthood. The progression of visual loss is usually slow, and most patients maintain reading vision until later in life. The condition can be quite
asymmetrical. Monitoring vision, especially in drivers, is important. Regular self-monitoring with an Amsler grid should be encouraged, and patients should be advised to seek ophthalmic review if sudden onset of blurring or distortion occurs, which could indicate the development of CNV. CNV was originally thought to be rare in PD (29), but is probably not uncommon (30,31). Macular atrophy has been observed both at presentation and over time in patients with PD (32).