Retinitis pigmentosa

Last update: December 4, 2018

Panel testing recommended at Breda Genetics for this condition:

Retinitis pigmentosa, classic (ABCA4, AIPL1, ARL6, BBS2, BEST1, C2ORF71, C8ORF37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, CYP4V2, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IMPDH1, IMPG2, IFT172, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF8, PRPH2, RBP3, RDH12, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF513)

or

Retinitis pigmentosa, extended (ABCA4, AGBL5, AIPL1, ARL3, ARL6, BBS2, BEST1, C2ORF71, C8ORF37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, CYP4V2, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IMPDH1, IMPG2, IFT172, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, RBP3, RDH12, REEP6, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SLC7A14, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF408, ZNF513)

Summary

Retinitis pigmentosa (usually abbreviated as RP) is caused by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina which lead to progressive visual loss. The disease begins with defective dark adaptation (“night blindness” or nyctalopia), followed by constriction of peripheral visual fields and, eventually, loss of central vision. It differs from Stargardt disease in that the hallmark of Stargardt is decreased central vision with decreased color perception, whereas side vision is usually preserved. Retinitis pigmentosa is one of the most clinically and genetically heterogeneous diseases known to date, because of its huge genotypic multiplicity and great phenotypic variability. Causative mutations can occur in one of several different genes. Retinitis pigmentosa can be seen as an isolated disease (nonsyndromic retinitis pigmentosa, discussed here) or as part of a syndrome (syndromic/systemic retinitis pigmentosa)

Detailed clinical description

The diagnosis of retinitis pigmentosa relies on electroretinogram (ERG) and visual field testing to document the loss of photoreceptor function.

The loss of rod function predominates early in the clinical course, leading to defective dark adaptation, also called “night blindness” or nyctalopia. The initial collection of the clinical history may be difficult, as symptoms of defective dark adaption are not immediately recognized by several patients. Even the subsequent stage of the “tunnel vision” (restricted mid-peripheral vision) might be unrecognized by the patients themselves. Sometimes patients are considered “clumsy” until the disease is diagnosed.

Rods, which are firstly involved in the pathogenesis, are located at the periphery of the retina. This explains why the loss of the peripheral vision is the first symptom. Cone photoreceptors, which are located in the central area of the retina, are also involved early, as demonstrated by sensitive function tests. However, the loss of central vision appears later in the course of the disease.

Changes in fundus appearance start as arteriolar narrowing, fine dust-like intraretinal pigmentation, and loss of pigment from the pigment epithelium. The loss of pigmentation progresses during the course of the disease and intraretinal clumping of melanin begins to appear, most often as coarse clumps in a “bone spicule” configuration. In the advanced stages of the disease waxy pallor of the optic nerve and moderate to severe attenuation of the retinal vessels become evident. On the optic nerve head it sometimes possible to observe drusen (hyaline bodies).

Posterior subcapsular cataracts of unknown origin are common in all forms of retinitis pigmentosa and require surgery in at least half of the patients.

Dust-like, colorless particles in the vitreous appear in most patients. These particles comprise free melanin pigment granules, pigment epithelium, uveal melanocytes, and macrophage-like cells.

Sometimes white dots appear within the pigment epithelium. This manifestation is referred to as retinitis punctata albescens.

In patients at advanced stages there’s the possibility of Coats-like disease, which is a form of exudative vasculopathy leading to telangiectatic vessels, lipid deposition in the retina, and serous retinal detachment. Coats-like disease is actually rare in retinitis pigmentosa and has been more often associated to mutations in the CRB1 gene.

Sector retinitis pigmentosa is a disease subtype with involvement limited to just a quadrant or half of the fundus, most often bilaterally and symmetrically. The disease is less severe and defective dark adaption is sometimes absent. However, true sector retinitis pigmentosa is actually rare and should not be confused with a possible sectorial onset of the disease, which later develop into the classical, widespread form. Sectorial retinitis pigmentosa is more frequently autosomal dominant (like the one caused by the common p.Pro23His pathogenic variant in the RHO gene).

Prevalence

The estimated prevalence of retinitis pigmentosa in Europe and USA is 1:3,500 to 1:4,000 individuals. In other populations the prevalence is thought to be even lower, approximating 1:2,500 (e.g. Denmark). Certain mutations are common in specific populations but not in others, as a consequence of the founder effect. For instance, the RHO mutation p.Pro23His is very frequent in the European populations but not elsewhere.

Molecular genetics

Nonsyndromic retinitis pigmentosa is one of the most genetically heterogeneous disorders known to date. Mutations in several different genes have been identified. Inheritance can be autosomal dominant, autosomal recessive or X-linked. Digenic inheritance has also been reported, but it’s very rare and thus far uniquely reported in individuals who are heterozygous for both a ROM1 and a PRPH2 pathogenic variant. Y-linked inheritance has been hypothesized in a Chinese kindred, where only males were affected. Most cases are simplex (i.e. there is only one affected individual in the family). The second most common forms are autosomal dominant. Autosomal recessive and X-linked forms come afterwards.  Some investigators have found a general correlation between age-related visual acuity and mode of inheritance, suggesting that autosomal dominant retinitis pigmentosa has the best prognosis, whereas males with X-linked forms have the worst prognosis and individuals with autosomal recessive and simplex forms are intermediate in severity.

Autosomal dominant retinitis pigmentosa has been associated with mutations in the following genes: ABCA4, AIPL1, BEST1, CA4, CRX, FSCN2, GUCA1B, IMPDH1, KLHL7, NR2E3, NRL, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, RDH12, RGR, RHO, ROM1, RP1, RP9, RPE65, SEMA4A, SNRNP200, TOPORS. An additional, unconfirmed autosomal dominant form may be caused by mutation in the ARL3 gene.

Autosomal recessive retinitis pigmentosa has been associated to mutations in the following genes: ABCA4, AGBL5, ARL6, BBS2, BEST1, C2ORF71, C8ORF37, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, DHDDS, EYS, FAM161A, HGSNAT, IDH3B, IMPG2, IFT172, KIZ, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, PDE6A, PDE6B, PDE6G, PRCD, PROM1, RBP3, RGR, RHO, RLBP1, RP1, RPE65, SAG, SEMA4A, SLC7A14, SPATA7, TTC8, TULP1, USH2A, ZNF408, ZNF513.

X-linked retinitis pigmentosa can be caused by mutations in the RPGR or RP2 gene. An unconfirmed X-linked gene is OFD1.

Digenic retinitis pigmentosa is caused by two heterozygous mutations, one in the ROM1 and the other one in the PRPH2 gene.

An instance of somatic mosacism for a RHO mutation in an unaffected individual has been reported.

Differential diagnosis

Conditions to be considered in the differential diagnosis of classic retinitis pigmentosa include the ones mentioned below. In these diseases the retinal involvement is sometimes referred to as atypical retinitis pigmentosa. The conditions are:

  • Usher syndrome type 1, type 2 and type 3, which are typically associated to hearing loss (CDH23, CIB2, CLRN1, DFNB31, GPR98, MYO7A, PCDH15, PDZD7, USH1C, USH1G, or USH2A gene mutations)
  • Gyrate atrophy of the choroid and retina (ornithine aminotransferase deficiency), which is caused by biallelic mutations in the OAT gene and include type II muscle fiber atrophy
  • Choroideremia, an X-linked disorder caused by mutation in the CHM gene
  • Cone or cone-rod dystrophy, sometimes called inverse or central retinitis pigmentosa, where loss of central visual acuity, photoaversion, and color vision defects appear before peripheral visual loss and defective dark adaptation. Con-rod dystrophies are often syndromic, see for instance: Alström syndrome (ALMS1 gene mutations), Bardet-Beidl syndrome (ALMS1, ARL6, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CCDC28B, CEP290, LZTFL1, MKKS, MKS1, SDCCAG8, TRIM32, TTC8, or WDPCP gene mutations), neuronal ceroid lipofuscinosis (CLN3, CLN5, CLN6, CLN8, CTSD, DNAJC5, MFSD8, PPT1, or TPP1 gene mutations), and the Joubert spectrum, which include Joubert syndrome and Meckel syndromes (AHI1, ARL13B, B9D1, B9D2, C5orf42, CC2D2A, CEP290, CEP41, KIF7, MKS1, NPHP1, NPHP3, OFD1, RPGRIP1L, TCTN1, TCTN2, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, or TTC21B gene mutations), Senior-Løken syndrome (NPHP1 gene mutations) and Dekaban-Arima syndrome (no gene known). Of note, mutations in the BBS2 have been reported in nonsyndromic retinitis pigmentosa too.
  • Leber congenital amaurosis (LCA), a severe dystrophy of the retina, which typically becomes evident in the first year of life (AIPL1, CABP4, CEP290, CRB1, CRX, GUCY2D, IMPDH1, IQCB1, KCNJ13 , LCA5, LRAT, NMNAT1, OTX2, RD3, RDH12, RPE65, RPGRIP1, SPATA7, or TULP1 gene mutations)
  • Congenital disorders of glycosylation (CDG) type 1a, caused by biallelic pathogenic variants in PMM2
  • Mitochondrial diseases, caused either by mitochondrial DNA (mtDNA) mutations or nuclear DNA mutations (more than 1000 nuclear genes encode for mitochondrial proteins)
  • Bassen-Kornzweig disease (abetalipoproteinemia), caused by biallelic mutation in the MTP gene and treatable by administration of vitamins A and E
  • Ataxia with vitamin E deficiency (AVED), caused by mutation in th TTPA gene and treatable by the administration of vitamin E
  • Refsum disease, caused by mutations in the PHYH or PEX7 and treatable with dietary reduction of phytanic acid.

Non-inherited retinopathies should also be taken into account (trauma, infection, autoimmune retinopathy, and drug toxicity).

Genetic testing strategy

Because of extensive genetic heterogeneity, next generation sequencing panel testing is certainly the best approach to the genetic diagnosis of any clinically confirmed affected individual. Nowadays, not more than the 50% of retinitis pigmentosa cases are attributable to identified genes, whereas the rest of molecular defects are still undetectable, especially in populations where few genetic screenings have been performed. Because of this, panel testing can be fruitfully performed based on whole exome sequencing or whole genome sequencing, which opens to the possibility to diagnosing mutations in as yet unknown genes. Whole genome based solutions also enable the screening of copy number variations (CNV, i.e. large deletions and large duplications).

Panel testing recommended at Breda Genetics for this condition:

Retinitis pigmentosa, classic (ABCA4, AIPL1, ARL6, BBS2, BEST1, C2ORF71, C8ORF37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, CYP4V2, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IMPDH1, IMPG2, IFT172, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF8, PRPH2, RBP3, RDH12, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF513)

or

Retinitis pigmentosa, extended (ABCA4, AGBL5, AIPL1, ARL3, ARL6, BBS2, BEST1, C2ORF71, C8ORF37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, CYP4V2, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IMPDH1, IMPG2, IFT172, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, RBP3, RDH12, REEP6, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SLC7A14, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF408, ZNF513)

The test is available based on clinical exome sequencing (6,000 genes), whole exome sequencing (20,000 genes) or whole genome sequencing*.

*performed by a partner facility on an Illumina X-ten system. Minimum coverage available: 30x.

References

Nonsyndromic Retinitis Pigmentosa Overview. Fahim AT, Daiger SP, Weleber RG. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2000 Aug 4 [updated 2017 Jan 19]. PMID: 20301590

Mitochondrial Disorders Overview. Chinnery PF. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2000 Jun 8 [updated 2014 Aug 14]. PMID: 20301403

PMM2-CDG (CDG-Ia). Sparks SE, Krasnewich DM. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2005 Aug 15 [updated 2015 Oct 29]. PMID: 20301289

De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. Strom SP, Clark MJ, Martinez A, Garcia S, Abelazeem AA, Matynia A, Parikh S, Sullivan LS, Bowne SJ, Daiger SP, Gorin MB. PLoS One. 2016 Mar 10;11(3):e0150944. PMID: 26964041

Genetic Analysis of the Rhodopsin Gene Identifies a Mosaic Dominant Retinitis Pigmentosa Mutation in a Healthy Individual. Beryozkin A, Levy G, Blumenfeld A, Meyer S, Namburi P, Morad Y, Gradstein L, Swaroop A, Banin E, Sharon D. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):940-7. PMID: 26962691

A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies. Sorrentino FS, Gallenga CE, Bonifazzi C, Perri P. Eye (Lond). 2016 Dec;30(12):1542-1548. PMID: 27564722

OMIM: 400004

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