Phenotypic and genotypic spectrum of HGSNAT-related retinopathy

Abstract

Purpose : Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal membrane enzyme that has been historically associated with mucopolysaccharidosis type IIIC (MPS IIIC) or Sanfilippo C syndrome. The variant c.1843G>A (p.Ala615Thr) in HGSNAT has been recently associated with late-onset nonsyndromic pericentral retinitis pigmentosa (RP). The aim of this study is to expand the phenotypic and genotypic spectrum of HGSNAT-related retinopathy.

Methods : This retrospective study from the Casey Eye Institute and the Instituto de Genética Ocular found nine patients with variants in HGSNAT and who presented pericentral retinopathy. We reviewed ophthalmologic data extracted from medical records, color fundus photos, fundus autofluorescence (FAF), and optical coherence tomography (OCT).

Results : Of the nine patients, seven were female, and the median age was 55 (range: 24-77) years. The age of ophthalmologic symptoms onset varied from 15 to 70 (mean 48; median 50) years. The visual acuity varied from 20/20 to 20/80 (mean 20/25; median 20/20), and the plurality of the eyes were 20/20. Color fundus photos varied from normal to the presence of bone spicules in the mid-periphery. FAF showed a pericentral pattern of hypoautofluorescent changes, and two patients presented with hypoautofluorescent spots in the nasal periphery. OCT revealed cystoid macular edema in three patients and outer retinal atrophy surrounding the fovea area in all patients. Genetic testing found four homozygous patients with p.Ala615Thr variant. The remaining patients were compound heterozygous and had the following variants: c.1843G>A (p.Ala615Thr), c.32_46del (p.Leu11_Ser16delinsPro); c.1843G>A (p.Ala615Thr), c.715del (p.Arg239Alafs*37); c.1843G>A (p.Ala615Thr), c.1297A>G (p.Asn433Asp); c.1218G>T (p.Leu406Phe), c.1220C>T (p.Thr407Ile); and c.1726G>T (p.Gly576*), c.525dupT (p.Val176Cysfs*16), c.118G>A (p.Asp40Asn).

Conclusions : There were differences in age of onset between patients; however, all presented with late-onset retinopathy. FAF was more sensitive at demonstrating retinal changes than color fundus photographs. These findings suggest mutations in HGSNAT may cause retinal dystrophy with a late-onset and pericentral pattern.

This is a 2021 ARVO Annual Meeting abstract.