Purpose: To investigate the natural history in patients with LRAT-associated retinal degenerations (RDs), in the advent of clinical trials testing treatment options.

Methods: A retrospective cohort of 13 patients with LRAT-RDs.

Results: Twelve patients from a genetic isolate carried a homozygous c. 12del mutation. One unrelated patient carried a homozygous c. 326G> T mutation. The mean follow-up time was 25.3 years (SD 15.2; range 4.8–53.5). The first symptom was nyctalopia (n= 11), central vision loss (n= 1), or light-gazing (n= 1), and was noticed in the first decade of life. Seven patients (54%) reached low vision (visual acuity< 20/67), four of whom reaching blindness (visual acuity< 20/400), respectively, at mean ages of 49.9 (SE 5.4) and 59.9 (SE 3.1) years. The fundus appearance was variable. Retinal white dots were seen in six patients (46%). Full-field electroretinograms (n= 11) were nondetectable (n= 2; ages 31–60), reduced in a nonspecified pattern (n= 2; ages 11–54), or showed rod–cone (n= 6; ages 38–48) or cone–rod (n= 1; age 29) dysfunction. Optical coherence tomography (n= 4) showed retinal thinning but relative preservation of the (para-) foveal outer retinal layers in the second (n= 1) and sixth decade of life (n= 2), and profound chorioretinal degeneration from the eighth decade of life (n= 1).

Conclusions: LRAT-associated phenotypes in this cohort were variable and unusual, but generally milder than those seen in RPE65-associated disease, and may be particularly amenable to treatment. The window of therapeutic opportunity can be extended in patients with a mild phenotype.

Translational Relevance: Knowledge of the natural history of LRAT-RDs is essential in determining the window of opportunity in ongoing and future clinical trials for novel therapeutic options.