Ocular Findings in Mucopolysaccharidosis

Key Points at a Glance

Key Points of This Disease

• Mucopolysaccharidosis (MPS) is a group of inherited disorders caused by deficiency of lysosomal enzymes, leading to accumulation of glycosaminoglycans (GAGs) in systemic tissues.
• Major ocular findings include corneal opacity, glaucoma, retinopathy, and optic disc lesions, with different combinations depending on the type.
• Corneal opacity is common in types I, VI, and VII (80–100% in type I), and is generally mild in types II and III.
• The prevalence of retinopathy is 42% (32 out of 75 patients), with the youngest reported case being MPS I at 2 years of age. ⁷⁾
• Hematopoietic stem cell transplantation (HSCT) is the gold standard for MPS IH (Hurler syndrome) in children under 2 years, and early intervention determines neurocognitive prognosis. ⁴⁾
• Enzyme replacement therapy (ERT) cannot cross the blood-brain barrier, so its ability to prevent progression of corneal opacity is limited. ³⁾
• Regular ophthalmologic follow-up and comprehensive evaluation including electroretinography are essential for early diagnosis of retinopathy. ⁷⁾

1. Ocular findings in mucopolysaccharidosis

Mucopolysaccharidosis (MPS) is a group of diseases in which the breakdown of glycosaminoglycans (GAGs) is impaired due to genetic deficiencies of lysosomal enzymes. Undegraded GAGs accumulate in lysosomes throughout the body, causing damage to multiple organs including the eyes, skeleton, heart, and central nervous system.

The birth prevalence in Japan is approximately 1 in 50,000. In Asia, type II (Hunter syndrome) accounts for half of all MPS cases, and the birth prevalence of type II in Japan is 0.84 per 100,000 male births. ¹⁾ The prevalence of each type is reported as 1 per 100,000 births for type I (Hurler), ⁵⁾ and for type VII (Sly syndrome) 0.01 per 100,000 in Europe and 0.027 per 100,000 in the United States. ⁶⁾

MPS types differ in the deficient enzyme, the type of accumulated GAG, and the inheritance pattern. An overview of each type is shown below.

Type	Common name	Deficient enzyme	Accumulated GAG
Type I	Hurler/Scheie	alpha-L-iduronidase	DS・HS
Type II	Hunter	iduronate-2-sulfatase	DS・HS (X-linked)
Type III	Sanfilippo	4 subtypes (A-D)	HS
Type VI	Maroteaux-Lamy	—	DS
Type VII	Sly	—	CS, DS, HS

MPS type I has subtypes: Hurler (infantile onset, rapid progression) and Scheie (onset around age 7, slow progression). Only type II is X-linked recessive, and female onset is rare. ³⁾ Systemic symptoms include gargoyle facies, skeletal deformities, cardiac valvular disease, hepatosplenomegaly, hernia, and CNS disorders.

Q What types of mucopolysaccharidosis are there?

A

There are types I to VII (type V is missing), and the deficient enzyme and accumulated GAG differ by type. The inheritance pattern is X-linked recessive only for type II, and autosomal recessive for the others. ³⁾ In Japan, type II (Hunter syndrome) is the most common, accounting for half of all MPS cases. ¹⁾

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Decreased visual acuity: Caused by corneal opacity, retinopathy, or optic atrophy.
• Photophobia (glare): Caused by light scattering due to corneal opacity.
• Night blindness: Associated with retinopathy (rod dysfunction). Observed in 15 out of 75 patients. ⁷⁾
• Peripheral visual field loss: due to progression of retinopathy or glaucoma.

Clinical Findings

Corneal Opacity

Frequency: Common in type I (80–100%) and types VI and VII (63%). ⁶⁾In types II and III, it is generally mild or absent.

Appearance: IH type: diffuse gray punctate to ground-glass appearance. IS type: progresses from periphery to center.

Severity: Graded 0–3. ⁷⁾In MPS VI, corneal thickness may reach up to 1500 µm. In types I and VI, corneal transplantation may be required in adults.

Mechanism: DS-containing proteoglycans (decorin, biglycan) maintain collagen fiber arrangement, but DS accumulation causes corneal stromal cells to swell, disrupting the arrangement and leading to opacity. ³⁾

Glaucoma

Presentation type: Common in types I and VI. Prevalence 2.1–12.5%.

Mechanism: Both open-angle (outflow obstruction due to glycosaminoglycan accumulation in the trabecular meshwork) and angle-closure types exist. In mucopolysaccharidosis type VI, posterior glaucoma due to hydrocephalus may also occur.

Measurement notes: Due to corneal thickening, Icare (rebound tonometer) is useful. With applanation tonometry, attention to the effect of central corneal thickness (CCT) is necessary.

Clinical importance: Important as a cause of childhood glaucoma.

Retinopathy

Prevalence: 42% (32 of 75 patients). ⁷⁾The youngest cases were MPS I at 2 years, MPS II at 6 years, and MPS VI at 6 years. ⁷⁾

Electroretinogram findings: Progress from rod dystrophy to rod-cone dystrophy. ERG abnormalities were found in 21 of 36 patients, and 16 were diagnosed by ERG alone. ⁷⁾

Imaging findings: FAF shows foveal hyperautofluorescent dots and parafoveal rings; SD-OCT shows thickening of the external limiting membrane (ELM) and loss of photoreceptors. ⁷⁾Ultra-widefield fundus imaging (UWF) can detect additional cases. ⁷⁾

Night blindness: Present in 15/32 patients (46.9%). ⁷⁾

Optic disc lesions

Course: Transitions from edema to atrophy. In types I and VI, about half show papilledema, and atrophy occurs in 8–19%.

Mechanism: Involves glaucoma, glycosaminoglycan accumulation, optic nerve compression, and increased intracranial pressure (ICP) due to hydrocephalus.

Other ocular findings: Hyperopia (over 90% in types I and VI), exotropia (37% in type IH, 25% in type VI), and scleral thickening.

Q In which types is corneal opacity commonly seen?

A

Common in types I, VI, and VII; seen in 80–100% of type I and 63% of type VII. ⁶⁾In types II and III, opacity is generally mild or absent. The type of accumulated GAG (DS-predominant vs. HS-predominant) determines organ specificity, with DS-predominant types I and VI showing marked corneal opacity. ³⁾

3. Causes and Risk Factors

The root cause of MPS is a genetic deficiency of lysosomal enzymes, leading to impaired degradation and accumulation of GAG. The type specificity of ocular findings is determined by the type of accumulated GAG and differences in sulfation levels. ³⁾

• DS/HS ratio and organ specificity: In type I, the DS/HS ratio is >1 (DS predominant), so corneal and skeletal symptoms are prominent. In type II, the DS/HS ratio is <1 (HS predominant), so CNS impairment is predominant and corneal opacity is mild. ³⁾
• Inheritance pattern: Only type II is X-linked recessive. Female cases are extremely rare. ³⁾ Type III has four subtypes (A–D), all of which are deficiencies of HS-degrading enzymes. ²⁾
• Ocular risks: Accumulation of GAG in ocular tissues (cornea, trabecular meshwork, peripapillary matrix of RPE, sclera) causes multiple ocular findings to appear and progress over time regardless of type.

For parents and patients

• If diagnosed with MPS, it is important to have regular eye examinations even if you have no symptoms.
• Retinopathy can sometimes be detected by electroretinography before subjective symptoms (night blindness, visual field defects) appear.
• To maximize the effectiveness of systemic treatments (HSCT, ERT), collaboration between ophthalmology and other departments is important.

4. Diagnosis and Examination Methods

Systemic Diagnosis

• Urinary GAG quantification: Useful as a screening test. ⁶⁾
• Enzyme activity measurement: Identifies the deficient enzyme for each type in blood or skin fibroblasts. ¹⁾
• Genetic testing: Used for definitive diagnosis and carrier diagnosis. ⁶⁾
• Newborn screening (NBS): MPS IH was added to the USPSP Recommended Uniform Screening Panel (RUSP) in 2016. ⁵⁾

Ophthalmic examination

The indications and purposes of each examination are shown below.

Examination	Purpose/Notes
Slit-lamp microscope	Corneal opacity grading and gonioscopy
Intraocular pressure measurement	Icare (rebound) recommended. Note effect of CCT
Pachymetry	Quantitative assessment of corneal thickness
UWF fundus photography	Detects more retinopathy than standard fundus photography7)
FAF	Foveal hyperautofluorescent dots and perifoveal ring7)
SD-OCT	Assessment of ELM thickening and photoreceptor loss7)
Electroretinography	Detection of rod and cone-rod dystrophies. 16 patients were diagnosed by electroretinography alone7)

Expert supplement

Electroretinography can detect retinal dysfunction before symptoms or fundus findings appear. In a study by Noor et al. (2025), 16 of 36 patients (44%) were diagnosed with retinopathy only by electroretinography, highlighting the importance of performing electroretinography even in patients with normal fundus findings.⁷⁾

Q How is retinopathy diagnosed?

A

Multimodal assessment including fundus examination (including UWF), FAF, SD-OCT, and electroretinography is necessary. In the report by Noor et al. (2025), retinopathy was confirmed in 32 of 75 patients (42%), and nearly half of them were diagnosed by electroretinography alone.⁷⁾ Regular electroretinography is important even in the absence of symptoms.

5. Standard Treatment

Hematopoietic Stem Cell Transplantation (HSCT)

• Indications: The gold standard is for MPS IH (Hurler syndrome) under 2 years of age. Umbilical cord blood (UCB) transplantation is recommended. ⁴⁾
• MPS II: UCB transplantation before 18 months of age has been reported to improve cognitive function. ⁴⁾
• Ocular effects: Complete improvement of corneal opacity is difficult even after HSCT, and long-term follow-up is required.

Enzyme Replacement Therapy (ERT)

• MPS I: laronidase 0.5 mg/kg intravenously once weekly. ⁵⁾
• MPS II: idursulfase / idursulfase beta 0.5 mg/kg intravenously once weekly. Improvement has been confirmed to persist for 8 years. ^{1, 4)} Anti-drug antibodies are produced in about 50% of patients within the first year of treatment, and 21–35% become neutralizing antibodies. ¹⁾
• Blood-brain barrier (BBB) issue: ERT cannot cross the BBB, and its effects on the CNS and cartilaginous organs (bone, eye) are limited. ^{3, 4)} It cannot stop the progression of corneal opacification.

Corneal Transplantation

• Indications: Cases with severe corneal opacification causing visual impairment.
• Surgical technique: The success rate of penetrating keratoplasty (PK) is approximately 94%. If the endothelium is preserved, deep anterior lamellar keratoplasty (DALK) may also be chosen.
• Note: If systemic treatment (HSCT/ERT) has not been performed, there is a risk of GAG re-deposition on the graft.

Glaucoma Treatment

Eye drops (first-line) → laser → trabeculectomy (including with mitomycin C) → cyclophotocoagulation/tube shunt surgery are performed in this order.

Retinopathy and Optic Neuropathy

• Retinopathy: No effective treatment currently exists. Regular monitoring is the main approach.
• Optic neuropathy: If associated with hydrocephalus, consider VPS (ventriculoperitoneal shunt) or ETV (endoscopic third ventriculostomy) ± CPC.

Precautions in Treatment

• ERT does not cross the BBB, so its effect on neurological symptoms and corneal opacity is limited. ^{3, 4)}
• Ophthalmological follow-up should be continued after HSCT to regularly assess progression of corneal opacity, glaucoma, and retinopathy.
• If systemic treatment is not performed after corneal transplantation, attention should be paid to GAG re-deposition on the graft.

Q What are the types and indications of corneal transplantation?

A

In cases of severe corneal opacity causing visual impairment, penetrating keratoplasty (PK) is performed, with a success rate of approximately 94%. If the corneal endothelium is preserved, deep anterior lamellar keratoplasty (DALK) is an option. If systemic treatment (HSCT/ERT) has not been performed, there is a risk of GAG re-accumulation in the graft.

6. Pathophysiology and Detailed Pathogenesis

GAG Degradation Pathway and Enzyme Deficiency

GAG degradation proceeds as a stepwise enzymatic reaction within lysosomes. In type II (Hunter), iduronate-2-sulfatase (IDS) catalyzes the first step, while in type I (Hurler), alpha-L-iduronidase (IDUA) catalyzes the second step. ³⁾ Deficiency of either enzyme leads to accumulation of upstream GAGs.

Accumulated GAGs and Organ Specificity

When DS predominates (MPS types I and VI), corneal and skeletal symptoms are prominent. When HS predominates (MPS type II), CNS involvement is predominant, and corneal opacity is mild. This difference arises from the varying GAG composition in each organ. ³⁾

Pathology in Each Ocular Tissue

• Corneal opacity: DS-containing proteoglycans (decorin, biglycan) regulate normal collagen fiber arrangement. DS accumulation causes these to swell keratocytes, disrupting fiber arrangement and leading to opacity. ³⁾
• Glaucoma: GAG accumulation in the trabecular meshwork increases outflow resistance through Schlemm’s canal, causing elevated intraocular pressure. Scleral thickening-induced hardening of the eye wall and increased ICP due to hydrocephalus also secondarily contribute to elevated intraocular pressure.
• Retinopathy: GAG accumulation in the matrix between the RPE (retinal pigment epithelium) and photoreceptors impairs photoreceptor function. ⁷⁾
• Optic neuropathy: Scleral thickening causes optic nerve constriction, and increased ICP due to hydrocephalus leads to compression and impaired blood flow to the optic nerve.

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7. Latest Research and Future Perspectives (Reports at the Research Stage)

For patients: Please read this

The following content is currently under research or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

BBB-penetrating ERT

Intravenous ERT cannot cross the BBB, so its effect on CNS disorders has been a challenge. ^{3, 4)} Several approaches have been developed to address this issue.

• JR141 (pabinafusp alfa): A fusion protein with an anti-transferrin receptor antibody that crosses the BBB to supplement iduronate-2-sulfatase activity in the brain. It is approved in Japan for MPS II (Hunter syndrome) and has shown significant reduction in CSF HS. ⁴⁾
• AGT-182 and DNL310: Next-generation ERTs with similar BBB-penetrating mechanisms. Currently under development. ⁴⁾

Intrathecal ERT

Horgan et al. reported a trial of intrathecal ERT (IT-ERT) for MPS II. CSF GAG levels decreased by 80–90%, but the primary endpoint of cognitive improvement was not met. ⁴⁾

Substrate Reduction Therapy (SRT)

Alyazidi et al. reviewed SRT using genistein for MPS III (Sanfilippo syndrome) and reported that human clinical trials did not show improvement in neurocognitive function. ²⁾

Pharmacological chaperones (molecular chaperones) have shown that glucosamine partially restores HGSNAT (MPS III type C enzyme) activity, but clinical application has not been achieved. ²⁾

Gene Therapy and Stem Cell Gene Therapy

• MPS III: Gene therapy using viral vectors is being researched, with preclinical and early clinical trials ongoing. ²⁾
• MPS II: Stem cell gene therapy has shown improvement in brain pathology in preclinical models. ⁴⁾

Gene Therapy for Retinopathy

Noor et al. (2025) indicated that gene therapy may contribute to the prevention and stabilization of photoreceptor degeneration in retinopathy caused by GAG accumulation. Although currently at the preclinical stage, the importance of early intervention is emphasized. ⁷⁾

Q Is there an ERT that can cross the blood-brain barrier?

A

JR141 (pabinafusp alfa) for MPS II (Hunter syndrome) has been approved in Japan. ⁴⁾ It crosses the blood-brain barrier via fusion with an anti-transferrin receptor antibody and significantly reduces heparan sulfate (HS) in CSF. Next-generation agents such as AGT-182 and DNL310 are also under development.

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8. References

1. Chan MY, Lee JH, Choung HK, et al. Long-term experience with idursulfase beta (Hunterase) in two adolescent patients with MPS II. Mol Genet Metab Rep. 2023;36:100991.

2. Alyazidi AS, Alharthi SK, Almohammadi MA, et al. Current Concepts in the Management of Sanfilippo Syndrome (MPS III). Cureus. 2024;16(4):e58023.

3. Hampe CS, Eisengart JB, Lund TC, et al. Differences in MPS I and MPS II Disease Manifestations. Int J Mol Sci. 2021;22:7888.

4. Horgan C, Khan SA, Rhatigan E, et al. Current and Future Treatment of MPS Type II. Int J Mol Sci. 2022;23:4854.

5. Pillai NR, DeBrosse SD, McNutt M, et al. Early Neonatal Cardiac Phenotype in Hurler Syndrome. Genes. 2022;13:1293.

6. Oldham A, Harmatz P, Haslett P, et al. MPS VII - Extending the classical phenotype. Mol Genet Metab Rep. 2022;33:100922.

7. Noor M, Nightingale S, Ghosh A, et al. Retinopathy in Mucopolysaccharidoses. Ophthalmology. 2025;132:461-475.