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Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration
  1. Abigail T Fahim1,
  2. Zaina Bouzia2,3,
  3. Kari H Branham1,
  4. Neruban Kumaran2,3,
  5. Mauricio E Vargas4,
  6. Kecia L Feathers1,
  7. N Dayanthi Perera1,
  8. Kelly Young1,
  9. Naheed W Khan1,
  10. John R Heckenlively1,
  11. Andrew R Webster2,3,
  12. Mark E Pennesi4,
  13. Robin R Ali1,3,
  14. Debra A Thompson1,5,
  15. Michel Michaelides2,3
  1. 1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA
  2. 2Moorfields Eye Hospital NHS Foundation Trust, London, UK
  3. 3Institute of Ophthalmology, University College London, London, UK
  4. 4Department of Ophthalmology, Oregon Health & Science University - Casey Eye Institute, Portland, Oregon, USA
  5. 5Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Abigail T Fahim, Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48109, USA; ahteich{at}med.umich.edu

Abstract

Background Defects in retinol dehydrogenase 12 (RDH12) account for 3.4%–10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration.

Methods A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.

Results 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.

Conclusions This study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

  • child health (paediatrics)
  • degeneration
  • dystrophy
  • genetics
  • retina
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Footnotes

  • Contributors AF participated in study design, subject enrolment, data collection, data analysis, manuscript preparation and editing. ZB participated in data collection and manuscript editing. KHB participated in study design, subject enrolment, manuscript preparation and editing. NK participated in data collection and manuscript editing. MEV participated in data collection and manuscript editing. KLF participated in data collection, data analysis and manuscript editing. NDP participated in data collection, data analysis and manuscript editing. KY participated in subject enrolment, data collection and manuscript editing. NWK participated in data collection and manuscript editing. JRH participated in data collection and manuscript editing. ARW participated in data collection and manuscript editing. MEP participated in subject enrolment, data collection and manuscript editing. RRA participated in study design and manuscript editing. DAT participated in study design and manuscript editing. MM participated in study design, subject enrolment, data collection and manuscript editing.

  • Funding AF is supported by the Vitreoretinal Surgery Foundation (VRSF), the National Eye Institute K-12 (2K12EY022299-06), and the University of Michigan Department of Ophthalmology and Visual Sciences. MM is supported by the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Retina UK, and the Foundation Fighting Blindness (USA).

  • Competing interests ATF reports a grant from the Vitreoretinal Surgery Foundation and a K12 grant from the National Institute of Health, during the conduct of the study; other from Ionis Pharamceuticals, outside the submitted work. RRA reports a patent on RDH12 gene therapy. DAT reports a grant from the Foundation Fighting Blindness, during the conduct of the study; In addition, DAT has a patent for viral vectors comprising RDH12 coding regions and methods of treating retinal dystrophies pending.

  • Patient consent for publication Not required.

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

  • Data sharing statement Additional deidentified clinical data for the subjects presented in this manuscript are available from the corresponding author (ahteich@umich.edu) for 3 years after publication. However, a data transfer agreement may be required per institutional regulations.

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