Retinitis pigmentosa (RP) is a group of related hereditary disorders characterized by loss of night vision followed by progressive loss of visual acuity. Characteristic clinical features include “bone spicule” pigmentary clumps initially in the midperiphery of the fundus, retinal vascular attenuation, and optic disc pallor (▶ Fig. 17.1). Other common findings are posterior subcapsular cataracts (PSC) and pigment in the anterior vitreous. Patients may also develop intraretinal cystoid spaces or cystoid macular edema (CME), epiretinal gliosis, or premature vitreous detachment. It is a progressive primary retinal degeneration involving the death of rod photoreceptors followed by loss of cone photoreceptors.
Fig. 17.1 End-stage retinitis pigmentosa, showing 360 degrees of “bone spicule” pigmentary clumping, severe vessel attenuation, pale optic disc, and macular atrophy.
The estimated prevalence of RP ranges from 1:3,000 to 1:8,000 individuals. RP can be classified as nonsyndromic (not affecting other organs or tissues) or syndromic (association with other affected organs or tissues; see text box below). Major forms of syndromic RP are Usher syndrome in which there is variable sensorineural deafness with/without vestibular abnormalities and Bardet–Biedl syndrome (BBS), which includes obesity, polydactyly, renal abnormalities, and developmental delay as well as other features.
Syndromic Retinitis Pigmentosa (OMIM)
Congenital disorders of glycosylation (212065).
Kearns–Sayre syndrome (530000).
RP-deafness syndrome (500004).
Neuropathy, ataxia, and RP (NARP; 551500).
Leigh’s syndrome (256000).
Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS; 540000).
Rhyns’s syndrome (602152).
Abetalipoproteinemia (Bassen–Kornzweig disease; 200100).
Ataxia with vitamin E deficiency (277460).
Short-rib thoracic dysplasia with or without polydactyly (266920; includes Ellis–van Creveld syndrome; Jeune syndrome; asphyxiating thoracic dystrophy; short-rib polydactyly syndrome; Mainzer–Saldino syndrome).
Senior–Løken syndrome (266900).
Epiphyseal dysplasia, microcephaly, and nystagmus (Lowry–Wood syndrome; 226960).
Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC; 612674).
Posterior column ataxia with RP (609033).
Neuronal ceroid lipofuscinoses.
Joubert syndrome (213300).
Oregon eye disease.
RP may be inherited as autosomal dominant (AD), autosomal recessive (AR), X-linked recessive, X-linked dominant, or mitochondrial. Rare digenic forms also occur. There are likely over 100 genes that can result in RP when mutated. RP simplex is a term applied when an individual is the only affected family member. Any of the inheritance patterns may apply. AD RP can be caused by mutations in RDS/PRPH2, rhodopsin, or 21 other genes currently described. Although AD RP is generally less severe with later age of onset, and X-linked recessive RP more severe with earlier onset, this is not always the case. Whereas carriers of AR RP may show mild abnormalities on electroretinogram (ERG), 50% of female carriers of X-linked RP may show ERG abnormalities, pigmentary retinopathy, and/or a tapetal reflex.
Vision loss occurs either from cataract, CME or intraretinal cystoid spaces, or the natural history of the retinal degeneration, which affects the central macula last. Approximately only 1-in-1,000 patients progress to no light perception. CME or intraretinal cystoid spaces are seen in 15 to 50% of patients with RP. The distinction between the two is made by intravenous fluorescein angiography (IVFA), but treatment with topical and/or carbonic anhydrase inhibitors may be effective for either. Nonleaking intraretinal cystoid spaces have been reported with RP due to mutations in NR2E3, XLRS, CRB1, GPR98, MAK, CNGB1, and others, which will likely be described.
Supportive treatment for RP may include vitamin A palmitate (15,000 IU per day), which remains controversial and is likely best used for certain genotypes, a correlation that is yet to be elucidated. It should not be used in children, pregnant women, or women of child-bearing age not on birth control. It should also not be used in RP due to mutations in ABCA4. A high dose of vitamin E should be avoided. Increased intake of docosahexaenoic acid and lutein–zeaxanthin, especially through dietary fatty fish, may slow progression, as well as ultraviolet A (UVA) and UVB blocking sunglasses. Although cataract surgery may be useful, patients with RP have a higher rate of postoperative CME that may be irreversible and vision compromising. Even small PSC may have a large effect on vision in patients with very constricted visual fields. Other treatments, such as intravitreal triamcinolone injection, intravitreal VEGF (vascular endothelial growth factor) inhibitors, hyperbaric oxygen, acupuncture, and light deprivation lack evidence of efficacy. The Food and Drug Administration (FDA) approved the first retinal implant, the Argus II Retinal Prosthesis System, for selected patients with advanced RP aged 25 years or older. Clinical trials are under way using neurotrophic factors, stem cells, and gene therapy. Patients should also be encouraged to seek low vision services, vocational counseling, and mobility training as indicated.
17.2 Molecular Genetics
With more than 55 genes identified, many loci within which the gene has yet to be found, and over 3,000 mutations in the genes already described, RP is clearly a genetically heterogeneous disorder. Mutations in 23 genes are known to cause AD RP, 36 genes cause AR RP, and Two genes cause X-linked RP. Although the proportion varies in different regions, approximately 40% of RP is sporadic (RP simplex) with no other affected family members. Of these cases, approximately 1 to 2% are X-linked, up to 10 to 15% AD, and the remainder AR. In places were consanguinity is more common, AR inheritance pattern can be higher (up to 40%). Digenic forms of RP are infrequent (e.g., heterozygous mutations in both ROM1 and PRPH2).
The most frequent genes associated with AD RP include RHO (up to 30%), PRPF31 (up to 10%), PRPH2 (up to 10%), and RP1 (up to 4%). Other genes may be frequent in specific populations (e.g., GUCA1B or FSCN2 in Japan). More than 100 pathogenic variants in RHO have been reported. Of the RP1 known mutations, c.2029C>T and c.2285_2289delTAAAT account for approximately half of the cases.
In patients with AR RP, the population particularly influences the estimated proportion of specific genes. For instance, USH2A (up to 15%), ABCA4 (up to 5%), PDE6A (up to 5%), or PDE6B (up to 5%) are frequently found in European families, and other genes, such as CRB1 or EYS, are more frequent in Hispano Americans.
X-linked RP is mostly caused by two genes. RPGR (also known as RP3) is associated with 70 to 90% of cases and RP2 accounts for 10 to 20%. In the case of RPGR, the identification of exon ORF15 increased the mutation detection rate. The RPGR gene has 23 exons, including the alternatively spliced exons 9a, ORF15, 15a, and 15b. Most pathogenic variants are located in ORF15, which is predominantly present in retinal transcripts.
Patients with mitochondrial DNA (deoxyribonucleic acid) mutations can get isolated RP. More commonly, affected individuals or their family members can present with other findings such as neurologic abnormalities or myopathy.
17.3 Differential Diagnosis
17.3.1 Choroideremia (OMIM 303100)
This X-linked recessive disorder can be distinguished by the early fundus appearance. The predominant finding is choroidal loss, which appears to be primary with the retina degeneration secondary. It is caused by mutations in CHM. End-stage choroideremia can be somewhat indistinguishable from end-stage RP. The symptoms experienced by affected individuals are also much like that seen with RP.
17.3.2 Gyrate Atrophy (OMIM 258870)
This is an AR disorder that is caused by mutations in OAT. It is characterized by sharply defined, scalloped defects of the retinal pigment epithelium (RPE) and choroid, which begin peripherally and progress toward the macula. Patients have elevation of plasma ornithine concentration caused by deficiency of the enzyme ornithine–ketoacid aminotransferase.
17.3.3 Cone–Rod Dystrophies
These disorders are characterized by loss of central visual acuity, photophobia, and color vision defects. In more advanced disease, the rod system becomes involved with peripheral visual loss and defective dark adaptation.
17.3.4 Leber Congenital Amaurosis
This is a group of congenital retinal dystrophies usually diagnosed in the first year of life. Most forms are AR. Although there are multiple phenotypes, the retinal appearance may be indistinguishable from classic RP.