Mucopolysaccharidoses (MPS) are a group of seven disorders caused by genetic deficiencies of lysosomal enzymes, leading to accumulation of incompletely degraded glycosaminoglycans (GAGs) inside and outside cells. The overall incidence of MPS in Japan is estimated to be about 1 in 50,000 live births.
Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, is an autosomal recessive disorder caused by deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B: ASB) due to mutations in the ARSB gene. Degradation of dermatan sulfate and chondroitin-4-sulfate is impaired, leading to accumulation of GAG in the lysosomes of tissues and organs 1). The incidence is very rare, ranging from 0.36 to 1.30 per 100,000 people 1).
It presents symptoms similar to Hurler syndrome, but an important difference from other MPS disorders is the absence of intellectual disability 2). In the rapidly progressive form, signs appear before age 3, while in the slowly progressive form, diagnosis often occurs in the 20s or 30s. Patients with the rapidly progressive form may die of heart failure in their 20s or 30s.
Unlike other mucopolysaccharidoses, MPS VI usually does not involve intellectual disability 2). However, in severe cases, physical limitations due to multi-organ involvement may affect academic performance and daily life.
Systemic Findings
Short stature and bone dysplasia: Presenting as dysostosis multiplex.
Coarse facial features: Macroglossia, flat nasal bridge, and macrocephaly are observed.
Umbilical and inguinal hernias: Often appear as initial symptoms.
Cardiac involvement: Includes valvular disease, cardiomyopathy, and arrhythmias.
Joint contractures: May be accompanied by carpal tunnel syndrome.
Hepatosplenomegaly and hearing loss: Appear as the disease progresses.
Ophthalmic Findings
Full-thickness corneal opacification: Due to GAG deposition in the entire corneal stroma. Corneal thickness can reach up to 1500 μm2).
Glaucoma: Both open-angle glaucoma due to GAG accumulation in the trabecular meshwork and angle-closure glaucoma due to GAG deposition in the cornea and iris can occur2).
Optic atrophy and papilledema: These may progress even under intraocular pressure control.
Ptosis: The frequency varies among cases.
Scleral GAG deposition: It appears as yellow-orange spots on EDI-OCT and is associated with choroidal thinning1).
Retinal changes are generally not considered related to MPS VI1), but recent reports have found retinal pigment epithelium changes in 50% of patients1). Severe corneal opacity makes accurate fundus evaluation difficult, which may contribute to oversight.
Corneal transplantation can improve corneal transparency, but cases have been reported where final visual acuity remains at light perception to hand motion even after transplantation 2). Factors other than the cornea, particularly optic nerve damage (see “Pathophysiology” section), hinder visual recovery.
The main diagnostic tests are shown below.
| Test method | Purpose | Notes |
|---|---|---|
| Urinary GAG | Screening | Elevated dermatan sulfate |
| Enzyme activity | Confirmatory diagnosis | Decreased ASB activity |
| Genetic testing | Genotype confirmation | Identification of ARSB mutations |
In ophthalmic examinations, accurate fundus evaluation is often difficult due to corneal opacity1)2). After corneal transplantation, EDI-OCT can be used to evaluate scleral deposits1). MRI can confirm enlargement of the optic nerve subarachnoid space and reduction in optic nerve thickness2). The iCare tonometer is used for intraocular pressure measurement, but attention should be paid to possible artifacts due to corneal thickening2).
The MPS VI management guidelines recommend regular ophthalmic examinations3).
Enzyme Replacement Therapy
Galsulfase (Naglazyme®): A recombinant form of human N-acetylgalactosamine-4-sulfatase. Administered intravenously at 1 mg/kg/week 2).
Early initiation is recommended: Starting treatment early in the disease process may slow the progression of systemic symptoms.
Corneal Transplantation
Penetrating Keratoplasty (PKP): Replacement of the full thickness of the cornea.
Deep Anterior Lamellar Keratoplasty (DALK): DALK may have fewer complications.
Reaccumulation risk: GAG may reaccumulate in the donor graft.
Hematopoietic Stem Cell Transplantation
Bone marrow transplantation/HSCT: Reported as a treatment to reduce lysosomal storage symptoms.
Multidisciplinary collaboration: Cooperation among ophthalmology, otorhinolaryngology, cardiology, orthopedics, and genetics is necessary3).
Corneal opacity progresses in types I and VI, and some adults require corneal transplantation. However, even after corneal transplantation, cases where BCVA remains at light perception to hand motion have been reported2), making it important to address non-corneal factors of vision loss.
The following medications are used to manage ocular hypertension2):
Glaucoma is important as a cause of pediatric glaucoma, and it is thought to be due to increased resistance to aqueous humor outflow into Schlemm’s canal caused by abnormal accumulation of extracellular matrix in the trabecular meshwork.
It is recommended to start early in the disease process. In reported cases, the age at initiation of enzyme replacement therapy (ERT) ranges from 2 to 18 years2), but earlier initiation is expected to better suppress the progression of systemic symptoms.
The diverse clinical manifestations of MPS VI result from GAG accumulation causing tissue damage through multiple mechanisms.
Mechanism of corneal opacity: Dermatan sulfate accumulates in all layers of the cornea, progressively reducing corneal transparency1)2). Corneal thickness can reach up to 1500 μm, about three times the normal value2).
Distribution pattern of scleral deposits: The peripapillary sclera is rich in dermatan sulfate, while the posterior sclera has a higher proportion of chondroitin sulfate. This normal GAG distribution pattern matches the distribution of scleral deposits observed in MPS VI1).
Mechanisms of increased intraocular pressure can be divided into two types2):
However, elevated intraocular pressure may be overestimated as a measurement artifact due to corneal thickening and hardening2).
Concept of “posterior glaucoma”: In MPS VI patients, optic atrophy may progress despite controlled intraocular pressure.
Magalhães et al. (2023) retrospectively reviewed 5 MPS VI patients and confirmed enlargement of the optic nerve subarachnoid space and reduction in optic nerve thickness on MRI in all cases. The atrophic optic nerve did not show typical glaucomatous cupping2).
Based on these findings, chronic posterior compression of the optic nerve due to hydrocephalus is considered a cause of optic atrophy independent of intraocular pressure. It has been proposed to name this mechanism “posterior glaucoma”2).
Swelling and atrophy of the optic disc may also occur due to accumulation of mucopolysaccharides in the sclera and dura, causing thickening and compression of the optic nerve.
This is because compression of the optic nerve behind the eye causes optic atrophy independently of intraocular pressure2). In this mechanism, called “posterior glaucoma,” the optic nerve is continuously compressed from behind by chronic hydrocephalus. MRI evaluation of the optic nerve is important.
Magalhães et al. (2024) systematically visualized scleral GAG deposition using EDI-OCT for the first time in a case series of three MPS VI patients. Scleral thickening and choroidal thinning, observed as yellow-orange spots, were confirmed in all cases 1).
This report indicates that with prolonged survival due to corneal transplantation and enzyme replacement therapy, previously unknown late ocular complications are being newly recognized 1)2).
The concept of “posterior glaucoma” suggests that intraocular pressure management alone is insufficient and that evaluation of posterior optic nerve compression using neuroimaging such as MRI is important 2).
Efforts are underway to reconstitute the management guidelines for MPS VI and MPS IVA as patient-friendly infographics, which are attracting attention as an attempt to convey specialized recommendations in plain language to patients and families 3).
