Retinal degeneration in CLRN1-associated Usher type 3A syndrome.

Abstract

Purpose : Biallelic mutations in CLRN1 could be responsible for Usher 3A syndrome (USH3A) (MIM # 276902) and non syndromic retinitis pigmentosa (RP61, MIM # 614180). Ocular and specifically retinal findings in USH3A are ill defined for the affection is rare (lesser than 2% of all Usher cases in recent meta-analysis). The purpose of the study was to report a detailed phenotypic description and evolution of retinal degeneration linked with CLRN1 mutations in a prospective natural history cohort of patients suffering from Usher syndrome(NCT01954953).

Methods : Patients with Usher syndrome harboring biallelic mutations in CLRN1 were clinically investigated at the reference center for rare ocular diseases of Quinze-Vingts hospital. Early Treatment Diabetic Retinopathy Study chart (ETDRS) assessed best corrected visual acuity (BCVA), slit-lamp examination, Goldman kinetic perimetry, full field electroretinography (ffERG) following ISCEV standards and multimodal fundus imaging including color photos, infrared reflectance (IRR), short-wave(SW-FAF) and near infrared autofluorescence(NIRAF), optical coherence tomography (OCT) were done for all patients.

Results : Four patients(2 males, 2 females, mean age at baseline: 18 years, range: 16 - 21) from four unrelated families were selected. Mean follow-up was 11 years for three patients while only baseline data available for one subject. Median BCVA at baseline was 20/32 (range: 20/40 – 20/20). ffERG was undetectable in all subjects; isopter III4e of Goldman visual field was constricted to 10°. Fundus was peculiar and similar in all patients: small whitish granular atrophic areas were organized in a reticular pattern around the macula, the optic disc and in the midperiphery. OCT showed presence of intraretinal microcrocysts in all patients. All patients experienced a progressive loss in BCVA and further visual field constriction overtime. All patients had a moderate hearing loss diagnosed in the first decade, requiring hearing aids; none had vestibular dysfunction. As for genetics, CLRN1-related USH represent 1.5% of our large USH cohort whereas no CLRN1 mutation was found in >1100 cases of non syndromic retinitis pigmentosa.

Conclusions : Retinal degeneration in USH3A has distinctive features including severe rod-cone dystrophy with a whitish granular posterior pole and macular edema. More patients need to be explored to better define the clinical picture and natural history of this nosological entity.

This is a 2020 ARVO Annual Meeting abstract.