The mucopolysaccharidoses

DEFINITION/OVERVIEW AND ETIOLOGY

The mucopolysaccharidoses (MPSs) are a diverse group of disorders which, due to different enzymatic defects, result in the inability

to break down glycosaminoglycans (GAGs).61,62 For the most part, affected

individuals will appear normal at birth with progressive physical changes slowly becoming apparent. To date, six different MPSs have been identified including MPS I (Hurler syndrome) (248), MPS II (Hunter syndrome), MPS III (Sanfilippo A syndrome), MPS IV (Morquio syndrome), MPS VI (Maroteaux–Lamy syndrome), and MPS VII (Sly syndrome) (Table 15, see page 206).

The clinical presentation of MPS I ranges from a severe form (with the onset of clinical findings in the first year of life) to an adult variant (formerly called Scheie’s disease). Most have recurrent otitis media, sinusitis, and pharyngitis starting in the first year of life. Developmental delays are common. Over time, coarse facial features, along with thickening of the skin, macrocephaly, corneal clouding, and bony abnormalities (especially gibbus deformity, kyphosis, or scoliosis) also become more apparent. Hepatosplenomegaly is a common finding. Dysostosis multiplex becomes apparent on radiologic examination (large skull, deep elongated sella, hook-shaped lower thoracic and lumbar vertebrae, pelvic dysplasia, and shortened tubular bones). Cardiac valve involvement is common. Although all of the MPSs involve some coarsening of facial features, it is important to remember that there are some distinctions. For example, patients with milder forms of MPS I, MPS II, MPS IV, and MPS VI can have normal or near normal intelligence. In fact, both MPS IV (Morquio) and MPS VI (Maroteaux– Lamy) may have very little CNS involvement. MPS III (Sanfilippo A), on the other hand, can have severe behavioral issues and hearing loss as its major presenting features.

Biochemically, all forms have excessive urinary excretion of quantitative mucopolysaccharides. The pattern of mucopolysaccharide excretion depends on the disorder and the

affected enzyme. Molecular analyses are not necessary to make the diagnosis; however, they can be helpful in confirming the diagnosis and useful for prenatal diagnosis, if desired. All of the mucopolysaccharidoses, with the exception of MPS II (Hunter), are inherited in an AR fashion; MPS II is an X-linked trait.

In the past, the only treatment for the MPSs was supportive. With the identification of the enzymatic defect and the subsequent technology to produce the enzyme that can be targeted to the appropriate intracellular compartment (the lysosome), enzyme replacement therapy has now become available for several of these disorders.63 MPS I (Hurler) is initially treated with enzyme replacement therapy (Aldurazyme) followed by bone marrow transplantation. There is evidence that bone marrow transplantation helps to slow the course of the disease64 and may even have a positive CNS effect;65 however, bone marrow transplantation has not been shown to be effective for any of the other MPSs. Enzyme replacement therapy is now available for MPS II (Elaprase) and MPS VI (Naglazyme). Both have been shown to improve quality of life by decreasing liver and spleen size and increasing exercise tolerance. Enzyme replacement therapy is still in the experimental stages for MPS III (Sanfilippo A).

CLINICAL PRESENTATION

This heterogeneous group is characterized by a spectrum of ophthalmic findings, including corneal clouding, pigmentary retinopathy, glaucoma, chronic papilledema, and optic atrophy.

Corneal clouding is the most common feature for which an ophthalmic consultation is sought. It results from an accumulation of GAGs (both intraand extracellular) in the cornea with subsequent disruption of the optically important arrangement of collagen fibrils. These fibrils are essential for clear vision. It appears early in life and continues to progress. This finding is best documented in MPS I (Hurler).

The pigmentary retinopathy that occurs is also felt to be secondary to the accumulation of GAGs in the retinal pigment. This retinal dysfunction is progressive and can lead to an extinguished electroretinogram (ERG) and blindness as early as 5 years of age.

Glaucoma and ocular hypertension can occur due to GAG accumulation within the anterior chamber structures and lead to outflow difficulties. A correlation has been shown between increased corneal thickness and IOP in patients with MPS I (Hurler) following bone marrow transplantation.66 Increased corneal thickness can give an erroneously high intraocular reading and lead to a misdiagnosis of glaucoma. Special attention needs to be paid to all diagnostic features of glaucoma, including optic disc appearance, before starting antiglaucoma medications.

In a study of 108 patients with all types of MPS, optic nerve head swelling (chronic papilledema) was found in each type, with the exception of MPS I (Hurler).67 This is thought to be secondary to the compression of the optic nerve by a posterior sclera thickened by the accumulation of GAGs.22 Chronic papilledema eventually leads to optic atrophy and vision loss. Amblyopia and strabismus occur more frequently in patients with MPS than in the average population.

MANAGEMENT/TREATMENT

Enzyme replacement therapy does not appear either to significantly improve or to worsen the ocular complications of patients with MPS I (Hurler).68 The long-term benefit of bone marrow transplantation on the evolution of ophthalmic manifestations remains controversial. If bone marrow transplantation is performed, then secondary complications such as cataracts or ocular hypertension can occur. Corneal grafting can be considered in children with MPS I (Hurler), and even though it has been associated with good outcomes, it should be approached cautiously because of the high rejection rate among children.