The majority of cases of RP are nonsyndromic (isolated); about 25% occur as part of a syndrome, the most common being Usher syndrome (RP and neurosensory hearing loss), which represents 14% of all RP cases (1). Other syndromic forms include Bardet-Biedl syndrome (RP, polydactyly, obesity, renal abnormality, and mental retardation), Refsum disease, and other disorders associated with renal, metabolic, skeletal, or neurological disease (2,3). The prevalence of isolated RP varies according to the inheritance pattern; recent estimates suggest that AD RP forms account for approximately 30%, AR RP for 20%, and X-linked for 15% of cases (4). A further 5% have been classified as early-onset forms of RP (Leber congenital amaurosis). The other 30% represent sporadic cases, which are most likely to be AR, but X-linked or de novo dominant forms might also be included in this group (4). To add to the complexity, different genes have been implicated in similar patterns of inheritance. Since the identification of the RHODOPSIN (RHO) gene as the first gene implicated in AD RP (5), more than 180 genes have been linked to the physiopathology of retinal dystrophies. The products of these genes are implicated in very diverse cellular functions, including the phototransduction cascade, retinoid cycle, photoreceptor structures,
transcription factors, outer segment renewal, splicing factors, and intracellular trafficking (3). For most of these genes, expression is restricted to the photoreceptors, especially rods, and/or the retinal pigment epithelium (RPE), but others, such as splicing factors, are more ubiquitously expressed. The mechanism by which a ubiquitously expressed gene is responsible for a restricted photoreceptor disease is not well understood, but it may relate to the uniquely high metabolic demand of the photoreceptors.

In addition, in AD RP, nonpenetrance has been described associated with certain genotypes (e.g., PRPF31 mutations [6]), which may complicate genetic counseling. Some genes are implicated in different phenotypes; for instance, RHO is the gene most commonly implicated in AD RP (20%-30% of AD RP [7]), but it can also be involved (less commonly) in AR RP and AD congenital stationary night blindness (8,9). Similarly, NR2E3, which is responsible for Enhanced S Cone syndrome (10), a recessive disorder, can be found in 1%-3% of cases of AD RP (11,12).

Because of the genetic heterogeneity of RP, the precise molecular mechanisms leading to photoreceptor cell death are still not fully understood. It is thought that photoreceptors degenerate through a common final pathway by apoptosis (13,14), which may involve calpains (15,16). Causes of apoptosis include ionic imbalance, protein aggregates, or default in photoreceptor structure (3). Explanations have also been given to the secondary cone cell death in the case of mutation in genes expressed only in rods, and evidence suggests that cones rely on rods to survive (17,18).

Fundus examination can be normal (RP sine pigmento), especially in the early stages of the disease. In the course of RP, RPE changes will appear in the midperiphery with pigment migration into the inner retinal layers as photoreceptors die. Blood vessel attenuation and pallor of the optic disc are hallmarks of advanced stages and are thought to result from the decreased metabolic demand with photoreceptor degeneration. The posterior pole is usually preserved until late in the course of the disorder. However, in about 63% of all cases of RP, foveal lesions are present, including atrophic changes (43%) and cystic changes (20%), mainly oedematous, that can be documented with fluorescein angiography (FA) or optical coherence tomography (OCT) (19, 20, 21) (see below). These macular changes will cause early loss of central vision. Premature posterior subcapsular cataract may also occur, resulting in impaired visual acuity.

ERG is essential for establishing the diagnosis of RP when there are no or only subtle abnormalities on fundus examination. In RP, the dark-adapted bright flash ERG a-wave, which predominantly reflects rod photoreceptor hyperpolarization, is abnormal with milder photopic ERG abnormalities, indicating milder cone-system involvement. The degree of macular cone system involvement varies among patients and may be assessed by pattern ERG (PERG) (22) and multifocal ERG (mfERG) (23). The PERG P50 component is a response to an alternating checkerboard stimulus that depends on the integrity of macular cones and has been used extensively as an objective index of macular function (24,25). Multifocal ERG is typically performed using a stimulus array comprised of 61 or 103 hexagonal stimulus elements centered at the fovea and usually extending over the central 55-60 degrees. The mfERG responses
are mathematically derived using a cross-correlation algorithm and allow assessment of localized cone-system function at multiple retinal locations across the posterior pole (26). Both PERG (27, 28, 29, 30, 31) and mfERG (32, 33, 34, 35) recordings have been used to objectively assess macular function in RP. The extent of macular involvement is not always related to the severity of generalized or peripheral dysfunction, and serial testing with either technique may prove to be of prognostic value for predicting functional sparing of the macula or the rate of disease progression.