M ucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a group of rare autosomal recessive inherited lysosomal storage diseases with an estimated prevalence of 1:50,000 to 1:250,000 depending on the population studied. ^, MPS III can be classified into 4 subtypes (MPS IIIA, B, C, and D), which are caused by pathogenic variants in SGSH, NAGLU, HGSNAT , and GNS , respectively. Each gene encodes for an enzyme crucial for the stepwise breakdown of heparan sulfate (HS) found on the surface of cells and in the extracellular matrix. The lysosomal accumulation of HS results in dysfunction at the organelle, cellular, and tissue levels.

It is now recognized that lysosomal disruption also causes secondary storage of other substances, including gangliosides, cholesterol, ceramides, and sphingomyelin. In addition, neuroinflammation seems to be a key feature of MPS III, marked by the activation of astrocytes and microglia in neuronal tissue. HS, known to bind to Toll-like receptor 4 and trigger microglial activation, is likely the main initiator of this process. Furthermore, the extracellular accumulation of HS interacts with adhesion molecules, further contributing to microglial activation.

Clinically, MPS III is a progressive neurodegenerative disease, with severe central nervous system (CNS) impairment, typically starting in early childhood. The course of disease is characterized by developmental and speech delay; behavioral abnormalities such as hyperactivity and loss of impulse control, and sleep disturbances; followed by the loss of previously acquired motor skills and the development of epileptic seizures, and severe childhood dementia in the later stage of the disease. ^,, Although all 4 subtypes of MPS III result from the dysfunction of different enzymes, the clinical phenotype of affected patients is similar in the different subtype, with varying severity and disease progression within and between subtypes. Patients with MPS IIIA typically present with a more severe and rapidly progressing disease, whereas MPS IIIB and IIIC patients may exhibit a slowly progressive course of disease, with stable intellectual disability over many years and, in some instances, adult-onset dementia. In comparison to other mucopolysaccharidoses, somatic symptoms tend to be less severe and more variable. A genotype–phenotype correlation has been found for some mutations in MPS IIIA and IIIB, but not for IIIC or IIID so far.

No disease-modifying therapy has been approved for MPS III, although various therapies, including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation are available for other MPS subtypes. Challenges in therapy development include effectively crossing the blood–brain barrier and targeting both somatic nervous and CNS tissue. However, several clinical trials are ongoing, including ERT and gene therapy trials, which have shown promising early results.

The ocular phenotype of MPS III has rarely been reported, even though it is known that pronounced visual impairment is common and that retinal disease is more frequent than in other MPS subtypes. ^, Reported ocular features include retinal dystrophy, retinitis pigmentosa (RP), optic nerve atrophy, peripheral cataracts, and corneal opacities. ^,, However, a systematic description of retinal disease, especially in relation to neurocognitive phenotype in large cohorts, is missing. A detailed understanding of the ocular phenotype, the incidence of retinal alterations, disease progression, and visual function appears crucial in the advent of novel therapeutic approaches. This study aims to assess the retinal phenotype in MPS III, providing insights into the pathophysiology and disease progression. Furthermore, the study assesses whether ocular changes could be used as a potential outcome measure in clinical trials.

RESULTS

This study included 27 patients (48% female) with MPS III; 16 subjects had MPS IIIA, 9 MPS IIIB, and 2 MPS IIIC. A severe neurocognitive phenotype was found in 18 patients (MPS IIIA: n = 13; MPS IIIB: n = 4; MPS IIIC: n = 1), whereas 9 patients showed an attenuated phenotype (MPS IIIA: n = 3; MPS IIIB: n = 5; MPS IIIC: n = 1). There were 2 sibling pairs in the MPS IIIA cohort and 3 sibling pairs in the MPS IIIB group. In total, 53 eyes were included, whereas 1 eye (MPS IIIB) was excluded because of insufficient imaging quality. The median age at last ophthalmic examination was 6.5 years (range, 1-16 years). The Table summarizes patients’ baseline characteristics.

TABLE

Patients’ Baseline Characteristics and Ophthalmological Findings

Patient ID/ Subtype	Sex	Age, y	Genotype	Phenotype	Previous Study Treatment	BCVA	Corneal Clouding	Fundoscopy	Foveal Atrophy	Parafoveal Atrophy of Outer Retina	Foveal Intraretinal Fluid Accumulation	Foveal ELM Thickening
A1	M	15	p.S66W; p.S66W	Severe	None	—	—	—	No	Yes	No	No
A2	M	4	p.P72R; p.P72R	Severe	None	—	Absent	—	Yes	Yes	No	No
A3	F	11	p.R74C; p.D235N	Severe	HSCT 06/2017	0.40	Absent	—	No	No	No	Yes
A4	F	2	p.L411P; p.L411P	Severe	AAV9 gene therapy ABO-102 (now UX111) 02/2022	—	—	—	No	No	No	Yes
A5	M	3	p.S66W; p.N389K	Severe	None	—	—	—	No	Yes	No	No
A6	M	1	p.R182C; p.V361Sfs*52	Severe	None	—	—	—	No	No	No	No
A7	F	5	p.R182C; p.V361Sfs*52	Severe	None	—	—	—	No	Yes	No	Yes
A8	F	3	p.R74C; p.R74C	Severe	None	—	—	—	No	Yes	No	Yes
A9	F	3	p.R245H; p.Q380R	Severe	None	—	—	—	No	Yes	Yes	Yes
A10	M	4	p.R245H; p.Q380R	Severe	None	—	—	—	No	Yes	No	Yes
A11	M	2	p.N389S; p.V361Sfs*52	Severe	None	—	—	—	No	Yes	No	No
A12	M	4	p.R74C; p.V379Cfs*34	Severe	None	—	—	—	No	No	No	No
A13	M	3	p.R245H; p.V379Cfs*34	Severe	None	—	—	—	No	No	No	No
A14	M	8	p.S298P; p.R245H	Severe	None	—	—	—	No	Yes	No	Yes
A15	M	8	p.S298P; p.R245H	Attenuated	None	—	—	—	No	No	No	Yes
A16	M	9	p.S298P; p.N389K	Attenuated	None	—	—	—	No	Yes	No	Yes
B1	F	6	p.R297*; p.G440V	Attenuated	ICV ERT BMN250-201/202;AX250-202/401: 07/2017- 10/2023 (on hold)	—	—	Normal	No	Yes	No	Yes
B2	F	14	p.R9565W; p.S612G	Attenuated	None	0.60	Absent	Normal	No	Yes	No	Yes
B3	M	10	p.R9565W; p.S612G	Attenuated	None	0.80	Absent	Normal	No	Yes	No	Yes
B4	F	16	p.R565Q; p.H227P	Attenuated	None	0.60	Absent	Normal	No	No	No	Yes
B5	M	3	p.M1T; p.Y140C	Severe	None	—	—	—	No	Yes	No	Yes
B6	F	5	p.M1T; p.Y140C	Severe	None	—	—	—	No	No	No	Yes
B7	M	6	p.E120Sfs*2; p.S573R	Attenuated	None	0.60	Absent	Normal	No	No	No	Yes
B8	F	9	p.E120Sfs*2; p.S573R	Attenuated	None	0.80	Absent	Normal	No	No	No	No
B9	F	15	p.Y140C; p.R674C	Severe	None	—	—	—	No	Yes	No	Yes
C1	M	4	c.1128+2T>C;c.1012+6T>C	Attenuated	None	—	—	—	No	No	No	No
C2	F	3	p.S539C; p.S541L	Severe	None	—	—	—	No	Yes	No	Yes

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