Clinical ocular manifestations of Taiwanese patients with mucopolysaccharidoses VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidoses (MPS) is a group of lysosomal storage disorders that lead to accumulation of glycosaminoglycans (GAGs) in many tissues and organs, resulting in different clinical features. In this study, we conducted the manifestation changes of refractive error, corneal clouding, and intraocular pressure in two Taiwanese MPS VI patients with enzyme replacement therapy (ERT) initiated at the age of eight. In case 1, hyperopia was noted before and after ERT. Clinical observation showed no significant improvement in corneal clouding after ERT. In case 2, hyperopia was also noted initially before ERT and unable to be measured due to severe corneal opacity. Clinical observation showed no significant improvement in corneal clouding in after ERT, and the best-corrected visual acuity worsen and keratoplasty was needed in both eyes. Case 2 also had ocular hypertension and suspect MPS VI-related. However, due to severe corneal clouding, optic disc changes were hard to examine, and visual field was unable to be tested. Although some literature shows that ERT may be effective in preventing and/or clearing corneal stromal GAGs, accumulation and the timing of treatment initiation cloud be a clinical prognosis predictor; in this experience, no significant improvement of corneal clouding was observed in patients with MPS IV after ERT. Hyperopia and glaucoma were noted, and showed no changes after ERT. Severe corneal clouding can lead to difficulties in diagnosis and monitoring of hyperopia and glaucoma. Copyright:

Introduction

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that lead to accumulation of glycosaminoglycans (GAGs) which can cause ocular diseases.[1] Little literature about MPS types VI patient of their change in refractive error were documented. Current treatment options for MPS type VI include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and support treatment.[2] However, the effects of ERT on the ocular manifestations in patients with MPS type VI are not well documented. In this study, we conducted the manifestation changes of refractive error and corneal clouding in patients with MPS VI before and after ERT.

Case Reports

This study reports two cases of MPS type VI diagnosed and treated at MacKay Memorial Hospital between 2001 and 2007. The diagnosis was achieved by detecting urinary GAGs levels with the dimethylmethylene blue method and confirmed by measurement of the enzyme activity of arylsulfatase B. Ophthalmologic examinations of visual acuity, intraocular pressure (IOP), refractive error, and corneal clouding were reviewed. ERT with intravenous Naglazyme® (galsulfase) once a week was given to both patients since 2006. Both patients were treated with Naglazyme® (galsulfase) (1 mg/kg/dose) administering intravenously once weekly until the end of this study. Table 1 summarizes the ophthalmological data of all the patients.

Table 1

Characteristics of the mucopolysaccharidoses VI patients on enzyme replacement therapy

Patient number	Age (years)/sex	Age at initial ERT	Laterality	First BCVA	Last BCVA	First refractiona	Last refractiona	Corneal opacityb,c	CCT (mm)
1	2/male	8	Right eye	8/20	20/20	SE + 3.25D	SE + 6.00D	+ ~ ++	0.659
			Left eye	8/20	20/25	SE + 2.50D	SE + 5.75D	+ ~ ++	0.698
2	4/male	8	Right eye	2/20	2/200	SE + 1.25D*	Unable to measure	+++	ND
			Left eye	2/20	HM/30 cm	SE + 1.25D*	Unable to measure	+++	ND

aRefraction: Measured under cycloplegia; × without cycloplegia, bDegree of corneal opacity: ±=Minimal, +=Mild, ++=Moderate, +++=Severe, cNo change of signs observed during follow-up. Age=Age at study entry, SE=spherical equivalent, CCT=Central corneal thickness, ND=Not done, ERT=Enzyme replacement therapy, BCVA=Best corrected visual acuity given in decimal format, Snellen notation in parenthesis

Case 1 was a 2-year-old boy and hyperopia was noted before and after ERT. Initial slit lamp examination showed that the bilateral diffuse corneal opacities with mild-to-moderate haze. Clinical observation showed no obvious improvement in a corneal haze after ERT. Other systemic associations include valvular heart disease, dysostosis multiplex, osteoporosis, umbilical and inguinal hernia, obstructive sleep apnea, and bilateral serous otitis media.

Case 2 was a 4-year-old boy and hyperopia was noted initially before ERT, but unable to be measured afterward due to bilateral corneal opacity. Initial slit-lamp examination showed that the bilateral diffuse mid-stromal pronounced corneal opacity. Clinical observation showed no obvious improvement in corneal haze after ERT. Keratoplasty was needed in both eyes. Case 2 also had ocular hypertension and suspect MPS VI-related. Initially, IOP measured with noncontact tonometer was 28.0 mmHg in the right eye and 33.7 mmHg in the left eye at the age of 4. However, due to severe corneal clouding, optic disc changes were hard to observe and visual field was unable to be tested. The left eye nystagmus was noted on the last examination. No other abnormalities were noted with slit-lamp examination. We believe that the severe cloudy cornea should play a major role in the amblyopia development. Other systemic associations include valvular heart disease, dysostosis multiplex, osteoporosis, obstructive sleep apnea, and bilateral serous otitis media.

Discussion

The MPS are a group of rare metabolic diseases characterized by defects of specific lysosomal enzymes involved in the degradation of GAGs. GAGs deposition is found in various tissues and organs throughout the body, results in a wide range of systemic clinical manifestations including dysmorphic facial features, vision and hearing impairment, cardiorespiratory disease, skeletal disease, neurological, and intellectual problems. Corneal opacification is an early clinical feature in several of the MPS subtypes including MPS type VI (Maroteaux–Lamy) and leads to significant visual impairment such as retinopathy, glaucoma, and optic may also contribute to visual impairment in patients with MPS.[1]

Children with MPS are recommended to receive an ocular assessment at the time of diagnosis and then be regularly followed at an interval of 6–12 months during preschool age and annually until 18 years of age. The frequency of follow-up should be modified due to patient's individual situation, considering patient's age, symptoms, and compliance. Basic ocular assessment recommended including best-corrected visual acuity, binocular function, slit lamp examination, IOP measurement, pupillary reactions, color vision, visual fields, refraction after cycloplegia, and fundus evaluation under dilation. Optional tests such as corneal thickness, optical coherence tomography, confocal microscopy, contrast sensitivity, axial length, tear breakup time, Schirmer I or II test, pattern visual evoked potentials, and/or electroretinography may be indicated in specific cases.[3]

Current treatment options for MPS type VI include ERT, HSCT, and symptom-based supportive treatment. ERT is recommended as first-line therapy in the majority of cases. HSCT has been limited due to the high procedure-related morbidity and mortality risk and the difficulty of finding matched donors.[4] HSCT appears to stabilize or improve visual acuity, corneal opacification, and optic nerve swelling in MPS patients. It may have no effect on retinal degeneration. However, besides the procedure-related risks, there are risks of HSCT of developing ocular diseases which include the development of cataract, epithelial punctate keratopathy, and dry eye syndrome. Graft-versus-host disease-causing conjunctivitis, keratoconjunctivitis sicca, corneal epithelial defects, and pseudomembrane formation is also an issue.[1]

ERT is known to be effective in increasing the lifespan of MPS patients.[2] However, the effects of ERT on the ocular phenotype in MPS are at present unclear. Pitz et al. reported on seven patients with MPS VI receiving ERT and showed six patients had stable levels of corneal opacification, while one continued to decline during follow-up.[5] Javed et al. reported on nine patients with MPS I (Hurler) or VI showed no significant change with objective judgment using the Iris camera in 59% all patient eyes. Within patients with MPS VI, no significant change in 50% patient eyes and 50% eyes had deterioration in corneal opacification measure, suggesting increased corneal clouding. One patient with MPS I, who was treated with HSCT, demonstrated significant improvement in corneal clarity and was associated with improved biomarker levels; however, no significant improvement in corneal clarity was noted with the patient treated with ERT.[6]

An animal study has demonstrated improved corneal clarity with high-dose, and intravenous ERT is effective at preventing and/or clearing cornea, particularly if initiated early after birth,[7] suggesting that earlier treatment with ERT/HSCT for patients with MPS I may result in improved visual outcomes. Chan et al. reported a case series with 10 MPS I patient treated with ERT/HSCT demonstrates that the severity of corneal haze at final follow-up correlated with the timing of treatment with either ERT or HSCT, suggesting that earlier treatment with ERT/HSCT for patients with MPS I may result in improved corneal clarity.[8] Early treatment with ERT may results in better ocular outcomes for patients with MPS I.

Some literature shows that ERT may be effective in clearing corneal stromal GAGs accumulation in this experience, one patient had stable levels of corneal opacification, while the other continued to progress during follow-up. This may be related to the timing of initiating the treatment. However, both our patients had their treatment initiated at the age of eight; however, their prognoses were very different. One with the stable condition of corneal clouding and the other progressed and keratoplasty of both eyes were needed. These results suggest that the severity of the disease at the time the treatment initiated or the ocular phenotype may serve as better clinical prognosis predictors than age.

To the best of our knowledge, this study is the first refractive errors changes in patients with MPS VI who have been treated with ERT. Pitz et al. reported hyperopia in MPS VI patients but did not show the change of the refractive errors. Schumacher et al. reported scleral thickness at the posterior pole in patients with MPS including 35 type VI patients. About 14 MPS VI patients were treated with ERT. Scleral thickening was noted in patients treated with and without ERT treatment. However, the age range is from 2 to 41 years, with children and adults pooled together.

Many of MPS patients have hyperopia. One of the possible reasons is that thickening of the sclera leads to reduced axial length. Another reason is that GAGs accumulation increases corneal rigidity, thereby straightening the curvature of the cornea, reducing its refractive power.[19] In our study, the central corneal thickness (CCT) numbers of case 1 patient were clearly thickened in comparison to normal values indicating a refractive hyperopia component. However, the lack of axial length is a limitation of this study.

Glaucoma was also noted in one of our patients and without significant changes after ERT. However, IOPs may be falsely elevated due to the increased corneal thickness or altered corneal resistance. Therefore, it is recommended that CCT measurements should be included in the evaluation for glaucoma in MPS patients.[13] It is our study's shortage not to have complete CCT measurements of our patients. Severe corneal clouding can lead to difficulties in diagnosis and monitoring of hyperopia and glaucoma. It is a great challenge for ophthalmologists and scientists to find out an appropriate time to start ERT or new methods to treat ocular diseases in MPS VI patients. In the future, we can compare the relationship between the biomarker and corneal opacities in our patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare that there are no conflicts of interests of this paper.