Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy

Abstract

Purpose: To analyze the clinical characteristics, natural history, and genetics of Leber congenital amaurosis (LCA) early-onset severe retinal dystrophy (EOSRD) associated with uncommon genes.

Design: Single tertiary referral center, retrospective case series.

Methods: Review of clinical notes, ophthalmic images, and genetic testing results of 19 patients with disease-causing variants in genes that represent an unknown or <1% of all LCA/EOSRD cases: ALMS1, CABP4, KCNJ13, and OTX2.

Results: Six patients were included with ALMS1-LCA, 7 patients with CABP4, and 3 patients with OTX2 and KCNJ13, respectively. Nine previously unreported variants were identified. Disease and symptom onset were during early infancy in all patients, photophobia was seen in patients with ALMS1 and CABP4, and nyctalopia was observed in KCNJ13 and OTX2. Across all groups, using the World Health Organization visual impairment criteria, most patients (68%) were severely sight impaired at presentation and progressed to blindness during follow-up. Poorer vision was seen earliest in patients with ALMS1 and KCNJ13, with mean visual acuities of 2.2 and 2.8 logMAR in the second decade of life. Macular atrophy was present in all patients with KCNJ13 variants, and peripheral retinal pigment deposits were also densest in KCNJ13, followed by OTX2. Patients with ALMS1 and CABP4 had minimal retinal deposits, and adult patients with CABP4 had a foveal hyporeflective zone combined with generalized retinal involvement.

Conclusions: The detailed genetic and phenotypic characteristics of patients with LCA due to four rare genes are described. Cross-sectional and longitudinal analysis contribute to our understanding of these rare diseases, aiming at improving patient diagnosis, prognostication, and management.