Non-syndromic retinal dystrophy associated with biallelic mutation of SUMF1 and reduced leukocyte sulphatase activity

Abstract

Purpose : Biallelic variants in the SUMF1 gene are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in infancy or childhood and marked by severe neurodegeneration and early mortality. In this study, we present a detailed clinical and molecular characterisation of three patients with milder clinical manifestations due to SUMF1 disease variants.

Methods : Whole genome sequencing (WGS) was performed for two adult patients (patients 1 and 2) aged 34 and 54 years with non-syndromic retinal dystrophy. A third patient aged 7 years with retinal dystrophy and an attenuated metabolic phenotype was later identified through clinical collaboration.

Results : Patients 1 and 2 had reduced visual acuities documented at hand motion and 3/60 Snellen, respectively. Fundus examination showed central macular atrophy with mixed hypo- and hyper-autofluorescent changes at the posterior pole, with outer retinal disruption on optical coherence tomography. Systems review identified no MSD-associated extraocular features.

Patient 3 featured a mild neurological presentation primarily characterised by autism. Additional associated features of MSD included oral aversion and feeding difficulties, short stature, and recurrent ear and throat infections. His visual acuity was maintained at 6/7.5 bilaterally, with only mild pigmentary mottling observed on fundus examination. ERGs in all three patients indicated a rod-cone dystrophy with additional possible inner retinal dysfunction, with severe macular involvement also noted in patients 1 and 2.

WGS identified biallelic SUMF1 variants in all three patients; patient 1 was homozygous for a complex allele c.[290G>T;293T>A]; p.[(Gly97Val);Val98Glu)], patient 2 was homozygous for c.866A>G; p.(Tyr289Cys), and patient 3 was compound heterozygous for c.726-1G>C and p.(Tyr289Cys). Biochemical studies confirmed reduced, but not abrogated, sulfatase enzyme activity in all three patients in the absence of extra-ocular disease or only mild systemic disease in patient 3.

Conclusions : These cases are suggestive that non-null genotypes in SUMF1 can cause an attenuated clinical phenotype including retinal dystrophy, without systemic complications in adulthood. Two of the three alleles observed here, not previously reported in MSD, are likely to confer reduced but not abrogated SUMF1 protein function.

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