Signs of the following disorders can be similar to RP. Comparisons may be useful for a differential diagnosis:

Leber’s congenital amaurosis (LCA) and early-onset RP (EORP) are special forms of RP characterized by the presence of severe symptoms from birth or shortly thereafter, respectively. This sub-group of RP forms is inherited in an autosomal recessive fashion, although also X-linked RP tends to have a significantly earlier onset than other forms of RP. When present from birth as in LCA, the visual deficit of affected children is typically recognized because of the coexistence of unsteadiness of the eyes known as nystagmus. Nystagmus is characterized by either fast-beating movements or by wandering movements of the eyeballs. The appearance of the back of the eye can be normal or near normal for several years, but testing of retinal function in response to flashes of light (the electroretinogram, or ERG) will invariably reveal the disease status in these patients. LCA patients often develop a deformation of the cornea causing high astigmatism up to a frank cone-shaped deformation of the cornea known as keratoconus. Prompt recognition of, and molecular genetic diagnostic testing for LCA is becoming increasingly important since three independent gene therapy trials have thus far demonstrated partial restoration of vision in one form of LCA linked to the RPE65 gene (see below). There are many different genes responsible for LCA and for recessive EORP. (For more information on this condition, choose “Leber congenital amaurosis” as your search term in the Rare Disease Database.)

Pericentral RP is a subtype of RP that is characterized by loss of side vision right around the center of a patient’s vision in the shape of a donut. This form of RP can be inherited in various ways (recessive, dominant, and sporadic, that is, without an uncertain mode of inheritance). Pericentral RP tends to have later onset than typical RP, causes far less loss of peripheral vision (in fact, the farthest portions of the field of vision in pericentral RP are rarely affected), it has been reported to have an overall slower progression rate than typical RP but, unlike RP, once it becomes symptomatic to patients, pericentral RP tends to encroach the center of the patients’ vision more rapidly and more severely than typical RP. As a result of this feature of the disease, patients with pericentral RP tend to experience a greater loss in visual acuity and central vision than peripheral vision, which is opposite to what seen in typical RP, and is more similar to what observed in “RP inversa”, more properly termed nowadays cone-rod dystrophy. By ERG criteria, pericentral RP tends to equally compromise rod and cone cells (the primary vision cells of the retina) or, at times, cone cells more than rod cells. The genes responsible for pericentral RP have not been identified yet, but research is ongoing to discover them.

A group of disorders that is often confused with RP is that linked to mutations, to date, to a single gene, known as NR2E3. This gene affects the development of progenitor retinal cells. Mutations in this gene lead to disorders that can present with distinct clinical pictures, known respectively as Goldmann-Favre vitreoretinal dystrophy, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration. These three conditions, all inherited as an autosomal recessive trait, share the feature of congenital night blindness and better than normal (or selectively better preserved) vision of the short wavelength-sensitive (blue, or S) cones, due to the erroneous development of rods into S-cones in the retina of affected patients. Unlike RP, these patients have slower disease progression rates, but are also prone to complications that RP patients do not typically incur, such as splitting of the retina at the macular and peripheral level (retinoschisis) and retinal detachments. The retinal changes affecting patients with this group of disorders vary in appearance from whitish flecks to coin-shaped areas of confluent pigmentation that is typically located underneath the retina and not within it as seen in RP.

Cone-rod dystrophy (CORD) is a term that identifies a group of disorders that can be inherited as autosomal recessive, autosomal dominant, X-linked recessive, or mitochondrial (maternally inherited) traits. Opposite to RP, CORD typically affects central and daytime vision much more severely than peripheral and night vision, hence the classical term “RP inversa” with which this family of conditions was also known. CORDs are, at least in part, genetically distinct from RP. However, depending on the mutations, certain genes expressed in both rods and cones can cause either RP or CORD (for example, the RDS/peripherin gene in dominant forms, the ABCA4 gene in recessive forms, and the RPGR gene in X-linked forms).

Choroideremia is a vision disorder inherited as an X-linked recessive trait characterized by extensive defects (atrophy) in the pigmented layer of cells underneath the retina, the retinal pigment epithelium, and of the capillaries of the underlying vascular layer, the choroids, called the choriocapillaris. Much like RP, the major symptoms of this disorder include a progressive loss of the peripheral field of vision and night blindness, which can start as early as during childhood and as late as young adulthood. It has been shown that, despite the extensive retinal pigment epithelium and choriocapillaris loss that can occur early on in the disease, the neuroretina above areas of atrophy of these other tissues can remain at least partially intact and, therefore, partially functioning for an extended period of time, thereby explaining why, often times, the changes seen at the back of the eye of affected males appear more severe than the actual degree of visual loss experienced by the patients. Unlike RP, patients with choroideremia do not typically develop bone spicule-like pigmentary deposits in the retina, but rather scattered patches of irregularly shaped hyperpigmentation underneath the retina. The overall prognosis of choroideremia appears to be, on average, better than that of RP and XLRP in particular, but severe vision loss has been reported in choroideremia as well.

With very few exceptions, choroideremia affects only males. Unlike females carriers of X-linked RP, who commonly experience some sign of the disease however mild or late-onset they may be, female carriers of choroideremia only sometimes have symptoms, although a few will complain about dim light or night vision late in life. Despite the relative lack of symptoms experienced by female carriers, they can usually be identified as such by characteristic pigment mottling in the retina after the pupils of the eye has been dilated.

Related Syndromes

The most common associations of RP with general health (so called “systemic”) problems causing more complex disorders known as “syndromes” are hearing loss and obesity.

Some individuals with RP can be born deaf (Usher syndrome type I or infantile-onset Refsum disease), or hearing-impaired (Usher syndrome type II), or can become hearing impaired (Usher syndrome type III or adult-onset Refsum disease). A more rare form of hearing-related syndrome that can present also with an RP-like retinopathy is Wolfram syndrome, but optic atrophy and diabetes mellitus are the most manifestations of this disorder. Hearing impairment of various degrees of severity and type can be present also in RP variants caused by changes in mitochondrial DNA. The type of deafness/hearing loss presented by patients with these conditions is termed sensorineural, that is, linked to malfunction or progressive degeneration of the hearing nerves and nervous structures, which are much like the type of visual loss that occurs at the level of the retina.

Usher syndrome is a group of inherited disorders characterized by RP and hearing impairment. Usher syndrome accounts for about 50% of all deaf-blinding disorders. The exact prevalence (frequency) of Usher syndrome in the population is not precisely known, but it has been estimated to affect 1:10,000 to 1:20,000 people. Usher syndrome is, for the most part, genetically distinct from non-syndromic forms of RP, although some cases of simple RP (that is, without hearing loss) in association to mutations in the USH2A gene have been reported. There are three major types of Usher syndrome, distinguished by the severity and the age of onset of the hearing features. Type I is characterized by congenital, non-progressive, profound hearing loss. Type II is characterized by congenital, non-progressive, mild to moderate hearing loss, whereby speech is much less affected. Type III, which is more rare, is characterized by progressive, late-onset (post-verbal) hearing loss; speech is typically not affected. Although three main types of Usher syndrome are recognized clinically, many more genes accounting for these clinical subtypes exist. To date, 10 genes have been mapped (six for Usher syndrome type I, USH1B-G, three for type II, USH2A-C, and one for type III, USH3A), eight of which cloned. The USH1A gene on chromosome 14q has been withdrawn. A type IV Usher syndrome with X-linked recessive inheritance was suspected to exist in the past, but this has now been shown to be a pseudo-Usher syndrome linked to mutations affecting the RRC1-like domain of the RPGR gene, a common cause of X-linked RP, which is also expressed in the epithelial lining of the respiratory tract and in the inner ear. This variant is also associated with recurrent upper respiratory tract infections (especially otitis and sinusitis) and immotile cilia-like symptoms.

Refsum syndrome is a slowly progressive disorder of fat (lipid) metabolism inherited as an autosomal recessive trait that is characterized by the accumulation of phytanic acid in the blood and tissues. The main features of this disorder in its more common, adult-onset form are RP, peripheral neuropathy (typically numbness and weakness), impaired ability to coordinate movement (ataxia), and late-onset, progressive hearing loss. As such, unlike Usher syndrome type I and II but similar to Usher syndrome type III, speech is typically not affected in Refsum disease. Infantile-onset forms, though, are more severe, and include other features such as congenital deafness and failure to thrive. Prompt recognition of this disorder is important because it can be either kept from worsening or reversed with a high-calorie diet devoid of foods rich in phytanic acid (such as butter and animal fat) combined with plasmapheresis. Demonstration of elevated levels of circulating phytanic acid is diagnostic. To date, there are five distinct genes that can cause Refsum disease, two causing the adult-onset form and three that cause the infantile-onset form, which are all linked to defective function of peroxisomes.

Obesity syndromes are rarer than the ones associated with hearing loss. Of them, the most common form of obesity syndrome is Bardet-Biedl syndrome (BBS). The BBS spectrum of clinical manifestations includes, in addition to RP, obesity, abnormality of the extremities such as more than the normal number of fingers and/or toes (polydactyly), fused digits (syndactyly), or shorter than normal digits (brachydactyly), and underdevelopment of the testes and small external genitalia (more apparent in males), kidney anomalies at times as severe as kidney failure, impairment of smell function (typically revealed only by formal testing), dental abnormalities, vertebral abnormalities, behavioral abnormalities, and in some cases intellectual disability. Some individuals also have asthma, diabetes, and elevated lipid profiles.

BBS is estimated to affect less than 1:100,000 people, although in populations with high degree of consanguinity (inbreeding) the incidence can be significantly higher (e.g., certain Bedouin tribes in which the first few BBS genes were mapped). Despite its rarity, BBS is markedly heterogeneous from a genetic point of view, with 17 distinct genes implicated in causing this disorder to date. Most BBS genes share a role in the function of cilia, which are present, for example, in the retina and kidneys, or that of functioning as chaperonins (e.g., BBS6, BBS10, and BBS12). BBS1 accounts for the majority of cases of BBS, followed by BBS10. The genetic overlap between BBS and other conditions has recently emerged, with mutations in CEP290 (also known as or NPHP6), which is the cause of LCA, Senior-Loken syndrome, Joubert syndrome, and Meckel syndrome type 4, being associated also with BBS (BBS14 gene). It has also been suggested that, unlike most other conditions, more than two mutations in more than one gene may be necessary to cause BBS (triallelic or polyallelic inheritance). However, this phenomenon has not been verified as necessary in all studies. Most certainly, though, the convergence of the BBS genes at certain subcellular levels, such as the cilia, creates the premises for significant epistatic effects, i.e., an increase (or decrease) in severity of the disease, caused by the main mutations (inherited in a classical Mendelian autosomal recessive mode), exerted on these mutations by mutations (or polymorphisms) in either other BBS genes or in additional ones relevant to the function of the subcellular structure in question in the case of BBS, the cilium.

Despite the similarity in symptoms between RP and BBS, BBS patients often have late-onset retinal changes, whereby the diagnosis of BBS is often delayed until an ERG is performed, showing invariably profound retinal disease. Similar to LCA, development of nystagmus and high astigmatism are also common in BBS.

Alström syndrome (ALMS) is another rare obesity syndrome inherited as an autosomal recessive trait, characterized by CORD, obesity, dilated cardiomyopathy (typically infantile in onset) and subsequent development of diabetes mellitus, sensorineural, post-verbal hearing loss, and kidney disease. Unlike RP patients and most BBS patients, but similar to LCA, ALMS patients are typically born with nystagmus. However, ALMS patients also complain primarily of light aversion and far less so of night blindness. ALMS patients do not usually have polydactyly, syndactyly, or brachydactyly as seen in BBS. The gene responsible for ALMS is ALMS1. Although distinct from the BBS genes, ALMS1 is also involved in ciliary function, explaining the similarity between BBS and ALMS and establishing an additional link between ciliary dysfunction and syndromes characterized by obesity and kidney dysfunction. Consistent with this, partial overlap in the manifestations of the two syndromes has been reported, with BBS patients with documented BBS gene mutations exhibiting ALMS-like features such as hearing loss and diabetes.

Senior-Loken syndrome (SLSN) is a variant of LCA inherited as an autosomal recessive trait in which, similar to BBS and ALMS, there is multi-cystic involvement of the kidneys that can evolve in serious damage to kidney function (nephronophthisis), which carries marked morbidity. Unlike BBS and ALMS, though, SLSN patients are not obese and do not have abnormalities of the digits. Additional features that can often be observed in SLSN patients are sensorineural hearing loss and cone-shaped deformity of long bone epiphyses. Less commonly, SLSN patients can also present with liver fibrosis, cerebellar ataxia, diabetes insipidus and, at the ocular level, with congenital cataracts and keratoconus. Although SLSN is rarer than LCA and BBS, due to the severity of the renal involvement, prompt recognition of this disorder has important diagnostic and prognostic implications.

Five distinct genes responsible for SLSN have been cloned to date, all of which are part of the family of the nephrocystins, important proteins expressed in the kidney as well as in the retina and other organs and tissues characterized by the presence of cilia. Therefore, also SLSN is a member of the emerging group of ciliopathies. As noted above in the BBS section, CEP290 (also known as NPHP6), which is responsible for a form of LCA, is also one of the genes responsible for one type of SLSN as well as BBS and other clinically distinct but clearly allelic conditions.

Lastly, a rare RP syndrome is abetalipoproteinemia, or Bassen-Kornzweig syndrome, a disorder inherited as an autosomal recessive trait characterized by the presence of misshapen red blood cells (acanthocytosis) in the circulating blood. This disorder usually begins in the first year of life and is characterized by a progressive inability to coordinate movement (ataxia), RP, the malabsorption of fat in the digestive system with fatty, greasy stools (steatorrhea) and low serum cholesterol since childhood (celiac syndrome). Serum beta lipoprotein is absent as a result of defective function in the microsomal triglyceride transfer protein, encoded for by the MTP gene. The aforementioned clinical and laboratory features allow for differentiation of this condition from Refsum disease. Despite its rarity, awareness of the characteristics abetalipoproteinemia is very important because the syndrome is responsive to vitamin A, E and K supplementation. Therefore, as in Refsum disease, early diagnosis of abetalipoproteinemia is crucial.