Retinitis Pigmentosa

• Heterogenous group of rod-cone dystrophies
• Commonest inherited retinal disease
• Varying clinical appearances due to varying inheritance patterns

Genetics

• 20% autosomal dominant: later onset, less severe

• 20% autosomal recessive

• 8-25% X-linked recessive: most severe

• 20-25% isolated (unidentifiable inheritance pattern)

• 50% have no family history

• Over 150 gene mutations identified

  • Classic mutation: Rhodopsin Pro23His mutation

Autosomal dominant RP

• Rhodopsin gene on chromosome 3q

• Rhodopsin molecule is a seven-loop transmembrane protein in the rod outer segment with the C terminus in the cytoplasm and the N terminus in the intradiscal space

  • Mutations can affect the protein in the intradiscal, transmembrane and cytoplasmic domains
  • They affect the protein conformation and therefore function
  • The most common mutation is P23H in which the protein does not fold properly and accumulates in the rough ER

• Peripherin/RDS gene on chromosome 6p

  • Great allelic heterogeneity
  • A range of dominantly inherited retinal degenerations from ADRP, macular degeneration, mattern macular dystrophy, vitelliform macular dystrophy...

Autosomal recessive RP

• Defects in the alpha or beta subunits of rod phosphodiesterase (rod PDE)

  • Nonsense mutations

• Null mutations of the rod cGMP-gated cation channel

Aetiology

• Progressive dysfunction, cell loss and atrophy of retinal tissue

  • Photoreceptors initially: rods first
  • Subsequent atrophy of other retinal layers
  • NFL preserved until late

• Highly symmetrical

Clinical features

• Classic triad

  • Night blindness and dark adaptation difficulty
  • Visual field loss from RPE dysfunction: tunnel vision
  • ERG abnormalities: severely depressed

• Bone spicules: formed by dispersion of pigment in the RPE leading to clumping that looks like bone under the microscope

  • May occur without bone spicule formation (RP sine pigmentum)

• Other features

  • Keratoconus
  • Cataract: posterior subcapsular
  • Myopia (and myopic degeneration): especially in X-linked
  • Attenuated arterioles: early feature
  • Open angle glaucoma
  • Waxy pallor of the optic nerve
  • Disc drusen
  • Macular oedema
  • ERM
  • Coat’s-like vasculopathy

• Sectoral RP: features limited to one or two quadrants. Usually AD

• Leber’s congenital amaurosis: an age-related variant of RP

  • AR
  • Nystagmus
  • Oculodigital syndrome: may lead to enophthalmos
  • Poor pupillary light reflex
  • ‘Normal’-looking fundus
  • Extinguished ERG

Tests

• ERG: reduced scotopic rod responses early on, extinguished response later
• EOG: subnormal with absent light rise
• Colour vision: normal
• Visual fields: ring scotoma
• OCT: CMO, ERM, loss of external limiting membrane and IS/OS junction
• Genetics: especially for RPE65 gene

Syndromes (<25% of RP)

• Usher: deafness, ataxia

  • Most common form of syndromic RP
  • AR, USH2A

• Laurence-Moon-Biedl (aka Bardet-Biedl): polydactyly, adiposogenital syndrome, deafness

  • Second most common syndromic form of RP
  • AR

• Kearns-Sayre: ophthalmoplegic retinal degeneration syndrome

  • Mitochondrial DNA deletion
  • Atypical retinitis pigmentosa
  • Ptosis, deafness, CPEO
  • Ataxia, cardiac conduction defects
  • Proximal muscle weakness

• Refsum: autosomal recessive, polyneuropathy, cerebellar ataxia, deafness, anosmia, cardiomyopathy, ichthyosis.

  • AR
  • Treatable with dietary restriction of phytanic acid (resolves ichthyosis, neuropathy and ataxia, and may improve retina)

• Cockayne: dwarfism, retinal atrophy, deafness

• Hallgren: deafness, ataxia

• Friedreich ataxia: spinocerebellar ataxia, dysarthria, deafness, diabetes

• Bassen-Kornzweig: ptosis, PEO, spinocerebellar ataxia, acanthocytosis

Treatment

• Supportive, visual support, blind registration etc
• Refraction
• Cataract extraction
• CMO: topical carbonic anhydrase inhibitors
• Voretigene neparvovec (a virus-vector gene therapy): NICE approved for RPE65 cases

Treatable forms of RP

• Refsums: dietary restriction of phytanic acid
• Bassen-Kornzweig syndrome: fat-soluble vitamin supplementation (ADEK)
• Friedreich-like ataxia: vitamin E supplementation in some cases

RP masqueraders

• Rubella retinopathy (‘salt and pepper’)
• Syphilitic retinopathy
• CMV retinopathy
• Toxoplasmosis
• Cancer-associated retinopathy
• Toxicity: chlorpromazine, thioridazine, chloroquine
• Traumatic retinopathy