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Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

Abstract

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70–80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.

  • (MeSH terms): retinal diseases
  • leber congenital amaurosis
  • lca
  • early onset severe retinal dystrophy
  • eosrd
  • severe early childhood onset retinal dystrophy
  • secord
  • gene therapy
  • rtinal rod photoreceptor cells
  • retinal cone photoreceptor cells
  • review

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Footnotes

  • Contributors NK drafted the manuscript and provided critical revision. MM conceived and supervised the manuscript and provided critical revision. ATM and RGW provided critical revision of the manuscript.

  • Funding Supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology (UK), Fight For Sight (UK), Moorfields Eye Hospital Special Trustees (UK), Moorfields Eye Charity (UK), the Foundation Fighting Blindness (FFB, USA), Retinitis Pigmentosa Fighting Blindness (UK), and the Wellcome Trust (099173/Z/12/Z) (UK). Michel Michaelides is a recipient of an FFB Career Development Award.

  • Disclaimer The funding organisations had no role in the design or conduct of this research.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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