Novel Fundoscopic Features in Mucopolysaccharidosis Type VI: Multimodal Evaluation of Scleral Deposits

Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders. Lysosomes are present in all nucleated cells, and they are part of a complex intracellular recycling system involved in the degradation of large macromolecules. MPS are caused by inherited defects in lysosomal enzymes resulting in intra- and extracellular accumulation of glycosaminoglycans (GAGs) [1, 2]. Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a very rare disorder with an incidence ranging from 0.36 to 1.30 per 100,000 [3, 4]. It is an autosomal recessive disorder primarily attributed to the deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, responsible for the degradation of dermatan sulfate and chondroitin-4-sulfate. Therefore, there is a widespread accumulation of partially degraded GAGs. The classical clinical features of MPS VI involve the osteoarticular system (dysostosis multiplex, short stature, and motor dysfunction). Other features include organomegalies and cardiorespiratory disorders. Coarse facial features, ENT (ear, nose, throat), oral, dental, and ocular anomalies are commonly observed [5]. Corneal opacification due to transmural progressive accumulation of GAGs is the hallmark ocular feature in the MPS. Ocular hypertension, glaucoma, and other optic neuropathies are also common [6, 7]. Ocular motility impairment is another feature, leading to strabismus [8]. Retinal, choroidal [9], and scleral [10] involvement in this MPS are extremely rare. The purpose of this work was to describe novel fundoscopic alterations present in patients with MPS VI.

We describe a case series involving three non-related patients referred to our department from the Unit of Inherited Metabolic Diseases. Multimodal imaging was performed in every patient. True color fundus photography and enhanced depth imaging optical coherence tomography (EDI-OCT) were performed after surgery. The CARE Checklist has been completed by the authors for this case series, attached as an online supplementary (for all online suppl. material, see https://doi.org/10.1159/000540015).

A 26-year-old Caucasian female patient with a biochemical (evidenced by increased urinary GAG and reduced arylsulfatase B/N-acetylgalactosamine-4-sulfatase activity) and genetic diagnosis of MPS VI (homozygous c.944G>A; pR315Q mutation in the ARSB gene) was under enzyme replacement therapy (ERT) with galsulfase since the age of ten. At presentation, she presented a severe form of the disease, with short stature, coarse facial features, obstructive and restrictive sleep apnea, requiring tracheostomy, mild hearing loss, cardiac valvular disease, umbilical hernia, hepatosplenomegaly, musculoskeletal developmental changes with dysostosis multiplex and joint contractures. Ocular pathology included moderate and progressive corneal opacification with visual impairment (best-corrected visual acuity [BCVA] of 3/10 in the right eye [OD] and 1/10 in the left eye [OS] and an intraocular pressure of 34 mm Hg and 32 mm Hg in the OD and OS, respectively, measured using Goldmann applanation tonometry). Due to the corneal opacities, a clear ocular fundus evaluation was not possible. At 2 years of follow-up, the patient underwent bilateral central penetrating keratoplasty. Fundoscopic evaluation became feasible. True color fundus photography and EDI-OCT were performed (Fig. 1a). Fundus photography revealed multiple yellow/orange patches in the macular area and around the optic disc and the temporal retinal vessels. The retinal periphery appeared normal. The optic nerves displayed a slight symmetrical pallor. EDI-OCT imaging at the location of these patches revealed scleral thickening associated with choroidal thinning. Notably, the retinal pigment epithelium and retina displayed no apparent changes even in areas where choroidal thinning and scleral thickening were evident. At 8 years of follow-up after the corneal transplant, the patient’s grafts remained transparent, and her BCVA was 3/10 OD and 2/10 OS. Intraocular pressure had been controlled without medication (measuring 10 mm Hg in both eyes).

A 25-year-old Caucasian male patient was diagnosed with MPS VI when he was 18 months old. He presented phenotypic features suggestive of the disease, confirmed by deficient enzymatic arylsulfatase B/N-acetylgalactosamine-4-sulfatase activity and genetic testing (heterozygous compound of LT2R and R315Q + S384N mutations in the ARSB gene). He was under ERT since the age of 9 years old. He presented a severe form of the disease, with short stature, dorsolumbar kyphosis, small neck and limbs, coarse facial features, macroglossia, dental abnormalities, severe obstructive sleep apnea and restrictive respiratory disorder, hepatosplenomegaly, cardiac valvular disease, umbilical hernia, hearing loss, and musculoskeletal developmental changes including dysostosis multiplex and joint contractures. Ocular involvement included corneal opacification in both eyes with visual impairment, more pronounced in the OS. The patient was submitted to penetrating keratoplasty in his left eye last year. At the last follow-up, he had a BCVA of 3/10 in the OD and 5/10 in the OS with an IOP of 24 mm Hg and 21 mm Hg in the OD and OS, respectively, under latanoprost in both eyes and fluorometholone in the OS. Similar to patient 1, recent fundus photography (Fig. 1b) revealed multiple yellow/orange patches in the macular area and around the optic disc, with sparing of the peripheral retina. These findings also matched with areas of scleral thickening and choroidal thinning observed in EDI-OCT.

A 20-year-old Caucasian male patient was diagnosed with MPS VI at 14 months old. He presented phenotypic features suggestive of the moderate to severe form of the disease, confirmed by enzymatic and genetic testing (heterozygous compound of the pathogenic variants c.149T>A/c.1143–8T>G in the ARSB gene). He was under ERT, galsulfase 1 mg/kg IV weekly since the age of 7 years old. He presented a short stature, some coarse facial features, macrocrania, dental abnormalities, and multisystem involvement with respiratory involvement (restrictive and obstructive ventilation syndrome), valvular heart disease (mitral and tricuspid insufficiency), operated umbilical hernia, hypovision, hearing loss, musculoskeletal involvement with dysostosis multiplex and joint contractures. Ocular features included moderate corneal clouding in both eyes with a BCVA of 2/10 in the OD and 3/10 in the OS and an IOP of 21 mm Hg in the OD and 20 mm Hg in the OS, with no IOP-lowering medication. The patient was not submitted to corneal transplant. At the last follow-up, fundus photography (Fig. 1c) also demonstrated multiple yellow/orange patches around the optic disc and along the proximal portion of the temporal retinal vessels, anatomically correlating with areas of scleral thickening and choroidal thinning in EDI-OCT.

Corneal clouding is a major reason for visual impairment in patients with MPS VI. Additionally, this condition interferes with accurate ophthalmological examination for other conditions, such as glaucoma, optic neuropathies, and retinopathy [11]. Excluding optic nerve anomalies, documentation of posterior segment involvement is extremely rare. Some authors previously stated that retinal findings are not associated with MPS VI [1, 2, 11]. With the advent of systemic therapies (ERT and hematopoietic stem cell transplantation), the life expectancy of these patients has increased. Depending on the severity of the disease, mortality ranges from the late teens to the fifth decade of life [12]. Therefore, other secondary outcomes such as vision and quality of life are gaining importance. The advancements of new technological tools along with corneal transplantation have allowed the observation and detection of novel ocular findings, namely in the retina, choroid, and sclera. Concerning retinal involvement, recently, Lin et al. [13] described retinal pigment epithelium changes in half (6 in 12) of the patients with MPS VI. However, the authors did not describe specific fundus characteristics for MPS VI patients, nor they relate alterations to the OCT changes that we observed. Macular retinochoroidal folds were also described in two siblings with MPS VI [9], and we found a similar case in our center [14]. However, no scleral involvement was previously described until we characterized the first case in the literature of a patient with MPS VI presenting these novel fundoscopic features presumably secondary to scleral deposition of GAGs [10]. To date, this is the first case series involving three non-related patients with MPS VI with similar fundoscopic characteristics. We hypothesize that scleral thickening and underlying choroidal thinning may be a result of the deposition of GAGs within the sclera. Although we cannot definitively determine the source of scleral thickening without postmortem analysis, Kenyon et al. [15] reported the presence of scleral GAG deposits in postmortem histology cases of 2 patients with MPS VI. Trier and colleagues also analyzed the composition and distribution of GAGs in the normal human sclera. They found that the sclera around the papilla was rich in content of dermatan sulfate and the sclera from the posterior eyeball showed a higher percentage of chondroitin sulfate as compared to the sclera from equator and limbus [16]. In MPS VI, those are the GAGs which degradation is impaired. This distribution seems to corroborate the fundoscopic pattern of our findings.

To our knowledge, this is the first case series in the literature encompassing patients with MPS VI with suspected deposits of GAGs in the sclera. The better control of the systemic comorbidities, the increase in life expectancy, and the timely management of corneal disease have allowed the identification of new, late-onset ocular manifestations in MPS patients. In addition, new imaging techniques have introduced the possibility of better characterizing and understanding these manifestations.

The study was conducted in accordance with the Helsinki Declaration. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Due to their cognitive impairment, the participants were unable to provide consent for themselves. Written informed consent was obtained from the patients’ legal guardians for publication of the details of their medical case and any accompanying images.

All authors do not have any conflict of interest.

The authors declare they have not received any funding for this work.

The authors confirm their contribution to the paper as follows: study conception and design and draft manuscript preparation: A.M. and M.R. Data collection and analysis and interpretation of results: A.M., M.R., A.F.M., J.M., E.R., and E.L.-T. All authors reviewed the results and approved the final version of the manuscript.

Augusto Magalhães and Margarida Ribeiro contributed equally to this work and are the first joint authors.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.