Leber Congenital Amaurosis associated with mutations in CEP290, clinical phenotype, and natural history in preparation for trials of novel therapies
journal contributionposted on 11.02.2021, 22:18 by L Sheck, Wayne IL Davies, P Moradi, AG Robson, N Kumaran, AC Liasis, AR Webster, AT Moore, M Michaelides
© 2018 American Academy of Ophthalmology Purpose: To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. Design: Retrospective case series. Participants: Patients with mutations in CEP290 identified at a single UK referral center. Methods: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. Main Outcome Measures: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. Results: Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. Conclusions: Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches.
M.M.: Previously consulted for ProQR and Editas, and currently consults for Meira GTx; Supported by an Foundation Fighting Blindness Career Development Award. Supported by grants from the National Institute for Health Research Biomedical Research Center 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 (USA), Retinitis Pigmentosa Fighting Blindness (UK), the Wellcome Trust [099173/Z/12/Z], and Research to Prevent Blindness USA (unrestricted grant). WILD is supported by an Australian Research Council Future Fellowship (FT110100176) and an Australian Research Council Discovery Project grant (DP140102117).
Pagination10p. (p. 894-903)
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicineOphthalmologyRETINAL DYSTROPHYGENE-THERAPYDEGENERATIONTECHNOLOGIESBLINDNESSFEATURESDISEASESMOUSEHumansNeoplasm ProteinsAntigens, NeoplasmTomography, Optical CoherenceElectroretinographyMolecular Diagnostic TechniquesRetrospective StudiesFollow-Up StudiesDNA Mutational AnalysisVisual AcuityPhenotypeMutationIntronsAdolescentAdultMiddle AgedChildChild, PreschoolFemaleMaleClinical Trials as TopicLeber Congenital AmaurosisOptical ImagingCell Cycle ProteinsCytoskeletal ProteinsOphthalmology & Optometry