Phenotypic Spectrum of Retinal Degeneration in X-Linked PRPS1-Related Retinopathy

Abstract

Purpose : The X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene is crucial for nucleotide metabolism. Pathogenic PRPS1 variants have been associated with a retinal dystrophy that can accompany any of the 3 systemic presentations: Arts syndrome (central nervous system deficits), Charcot-Marie-Tooth type 5 [CMTX5] (peripheral neuromuscular deficits), and isolated sensorineural hearing loss (SNHL). Larger studies on retinal degeneration are lacking. We present the phenotypic spectrum of PRPS1-related retinopathy in a large international cohort.

Methods : Patients with PRPS1 variants predicted to be deleterious were identified through chart review from an international consortium of retinal specialists and ophthalmic geneticists. Demographic and clinical information, multimodal imaging, and best-corrected visual acuity (BCVA, logMAR) were analyzed and grouped by the 3 systemic presentations.

Results : Fourteen patients, 3 within the same family, were identified. Eleven (78.6%) were female. Mean age of disease onset in known cases (n=13) was 9.1 years (range, 6 months-35 years). Common diagnoses prior to genetic testing were Leber congenital amaurosis (n=5), Usher syndrome (n=1), and retinitis pigmentosa (n=1). Arts syndrome and CMTX5 were the most common systemic presentations (both n=4). Two patients had isolated ocular disease. Mean BCVA was 0.74, 0.74, 0.85, and 0.96 for isolated ocular disease, CMTX5, SNHL, and Arts syndrome, respectively. Ten patients had a hyperopic refractive error and 8 had asymmetric BCVA >2 lines. Macular atrophy (n=13), optic atrophy (n=13), and bone spicules (n=10) were common exam findings. Parafoveal outer retinal atrophy (n=12) and peripheral hypoautofluorescence (n=10) were common imaging findings. Electroretinogram showed delayed and attenuated b-wave amplitudes (n=12) or undetectable signal (n=2). Mean follow-up of 4.1 years (range, 1.5-11.6 years) in 6 patients showed signs of disease progression in 2 patients, both with Arts syndrome.

Conclusions : PRPS1-related retinopathy may present as a bilateral asymmetric pigmentary cone and rod dystrophy and accompany any of the 3 known systemic presentations. Optic nerve atrophy and hyperopia are important diagnostic clues. Mean visual acuity is lowest in Arts syndrome. Skewed X-inactivation in females may explain asymmetric findings.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Table 1. Presentation by Phenotypic Group and Genotype Analysis

 

Figure 1. Multimodal imaging for CEI04