Histological Characterization of Retinal Degeneration in Mucopolysaccharidosis Type IIIC

Abstract

Purpose : Heparan-α-glucosaminide N-acetyltransferase (HGSNAT) participates in lysosomal degradation of heparan sulfate. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC (MPS IIIC) or Sanfilippo disease type C. MPS IIIC patients exhibit progressive neurodegeneration, leading to dementia and death before adulthood. Although some MPS IIIC patients exhibit incidences of non-syndromic retinitis pigmentosa and early signs of night blindness, majority of ocular phenotypes are not well characterized. The goal of this study was to investigate retinal degeneration phenotype in the Hgsnat knockout (KO) mouse model and correlate this phenotype with human ocular findings to understand the effects of Hgsnat mutation on the retina.

Methods : Heterozygous mice carrying mutation in the Hgsnat were crossed and offspring were sacrificed at 6 months of age. Cone and rod photoreceptors were analyzed using cone arrestin, S-opsin and rhodopsin antibodies. Outer nuclear layer (ONL) thickness and number of nuclei in the ONL layer were measured. Retinal OCT and fundus imaging was performed on an 11 year old MPS IIIC patient as a routine ophthalmic evaluation. Retinal histology was performed on the eye from 35 year old MPS IIIC donor and compared it to the age-matched control donor-eye.

Results : Our data suggest that loss of Hgsnat severely affects rod photoreceptors while cone photoreceptors are mainly unaffected at 6 months of age. We observed more than 30% reduction in the thickness and number of nuclei in the ONL in the Hgsnat KO retinas compared to those of the controls, indicating rod photoreceptor degeneration (P<0.05). We also observed thinner outer segment length in Hgsnat KO retinas indicating reduced levels of rod photo-pigment rhodopsin. An 11 year old patient showed intraretinal cystic macular edema with myelinated nerve fiber. Severe retinal degeneration was observed in a 35 year old eye-donor.

Conclusions : To our knowledge, these are the first reports characterizing ocular phenotypes arising from deleterious variants in the Hgsnat gene associated with MPS IIIC clinical phenotype. Together our findings indicate that retinal manifestations of MPS IIIC are present even before cerebral manifestations. Thus, ophthalmological evaluations could be used as early diagnostic indicators of disease progression as well as end-points for evaluation of future therapies for MPS IIIC patients.

This is a 2021 ARVO Annual Meeting abstract.