horizontal saccadic initiation failure with loss of optokinetic quick phases,37 and horizontal saccades that are slower, smaller, and longer than normal.143 This ocular motor deficit may be accompanied by horizontal head thrusting and thereby simulate congenital ocular motor apraxia.61,243 Patients with Gaucher type 3 also have “upward looping” horizontal saccades with upward trajectories.61,243 While many disorders cause saccadic initiation failure, its presence in a patient with known Gaucher disease is widely considered to be diagnostic of type 3.143

The advent of enzyme replacement therapy has significantly changed the management of Gaucher disease but has made early and correct diagnosis imperative.143 In adult patients, slow saccades may be a prominent finding and may provide a therapeutic index during enzyme replacement therapy for this disorder.8,193,243,338 Substrate reduction therapy and chaperone-mediated enzyme reduction therapy are also being explored.120

Mucopolysaccharidoses

The mucopolysaccharidoses are a heterogeneous group of disorders caused by widespread accumulation of intracellular and extracellular glycosaminoglycans (GAG) systemically and in ocular tissues. MPS are caused by reduction in the activity of specific lysosomal enzymes involved in the breakdown of GAG, which results in a wide spectrum of clinical phenotypes, ranging from disorders that are fatal in the first months of life to those compatible with a normal lifespan.13 The most obvious defects are intellectual and motor retardation, bone and joint deformities, and a typical coarse facies. Ocular signs include progressive corneal clouding and retinal degeneration varying with subgroups. The early clinical classification of MPS has been supplanted by a biochemical scheme: MPS1H (Hurler syndrome), MPS1S (Scheie syndrome), and MPS1HS (Hunter–Scheie syndrome); MPS2 (Hunter-severe and Hunter-mild) and MPS3 (Sanfilippo A, B, C); MPS4 (Morquio A, B); MPS5 (no longer used); MPS6 (Maroteaux-Lamy); MPS7 (Sly); and MPS8 (diferrante). Retinal degeneration is found in MPS1H, MPS1S, MPS2, MPS3, and MPS7.

Although the diagnosis is confirmed by enzyme and genetic studies, screening includes examination of lymphocytes for vacuolated inclusions, a skeletal survey to look for boney changes, and screening for glycosaminoglycans in the urine.342 New treatments resulting in a longer lifespan and better intellectual function for many MPS patients have made the long-term ocular management of these patients crucial for optimum quality of life. Enzyme replacement therapy is now approved for use in Hurler’s, Hunter’s, and Maroteaux–Lamy syndromes. Although bone marrow transplantation and enzyme

replacement therapy improved the clinical prognosis, they do not arrest neurological deterioration.249 Bone marrow transplantation has produced corneal clearing in a small subset of patients,136,291,301,332 but most of them still have significant corneal clouding.13,68 Potentially promising therapeutic avenues in development include intrathecal enzyme replacement therapy and gene therapy, which has also been investigated in animal models.13

MPS1H (Hurler Syndrome)

Children with this condition are normal at birth but begin to develop the characteristic coarse facies (Fig. 10.5) and corneal clouding within the first year of life. Distinct physical characteristics include frontal bossing, saddle nose, short neck, claw-shaped hands, oar-shaped ribs, and bullet-shaped phalanges. Mental retardation becomes obvious during the first few years of life. As motor development progresses, a peculiar stance and gait are noted due to lumbar lordosis, thoracic kyphosis, and flexion contractures at the elbows and knees.306 The abnormality is progressive, and survival beyond 10 years of age is rare. Bone marrow transplantation in younger patients and enzyme replacement therapy in older ones produces clinical improvement and longer survival; however, cognitive deficits continue to progress.349,350 Death usually results from cardiac failure.

Corneal clouding, the predominant ophthalmological feature in this condition, starts at approximately 6 months of age and is not associated with photophobia or increased corneal diameter. However, these children frequently develop glaucoma and have retinal degeneration. ERG changes show a rod-cone degeneration, with the rod function more severely affected.49 Optic disc abnormalities may include papilledema, pseudopapilledema, and optic atrophy.28,29,67 Histopathologic examinations have shown that optic disk

Fig. 10.5  Hurler syndrome. Characteristic facial appearance includes frontal bossing, saddle nose, coarse features, and short neck

swelling may result from infiltration of the lamina cribrosa, leading to narrowing of the scleral canal and prelaminar axonal stasis (pseudopapilledema).28,29 Children with Hurler syndrome may also have papilledema secondary to hydrocephalus. Optic atrophy can be secondary to previous swelling or occur as a secondary effect to retinopathy.13,65

Although usually not required for the diagnosis of these conditions, ERG can provide valuable objective evidence of retinal function in patients with cloudy corneas. Gills et al123 described 21 patients with Hurler syndrome using the older classification. Subnormal ERGs were found in types I (MPS1H), II (MPS2), and III (MPS3). Visual electrophysiologic studies are recommended as part of the preoperative and postoperative evaluation for penetrating keratoplasty. With the advent of bone marrow transplantation and enzyme replacement therapy, the ERG and VEP have begun to play an increasing role in the quantification of visual pathway improvement or deterioration during treatment.13

When corneal transplantation or glaucoma surgery is contemplated, it is well to remember that many patients with mucopolysaccharidosis are at major anesthetic risk, and complications occur relatively frequently. For example, Hurler patients often have airway obstruction secondary to abnormal cervical vertebra, short neck, high epiglottis, and GAG infiltration of soft tissues, and these problems tend to increase with age. A fiberoptic endoscope may be required for intubation.

Macrocephaly may result from intracranial mucopolysaccharide deposition, hydrocephalus, or a combination of the two.17 MR imaging shows white matter abnormalities, including focal and diffuse areas of prolonged T1 and T2 relaxation times, with focal lesions in the corpus collosum, basal ganglia, and cerebral white matter.179 Cerebral atrophy and white matter changes occur earliest in types I, II, III, and VII and may not be seen until the second decade of life in types IV and VI.189 Imaging of the spine in patients with Hurler syndrome is often indicated because spinal cord compression is a common and serious complication of the disease.17

Pathological changes from stored mucopolysaccharide occur in virtually every organ in this condition. The lysosomes of neurons are enlarged with material that resembles lipid. Electromicroscopy shows mucopolysaccharide granular inclusions in lysosomes in tissues throughout the body.262 The enzymatic defect in MPS1H is an absence of a L-idu- ronidase activity. Large quantities of dermatan sulfate and heparan sulfate accumulate because the a L-iduronic acid portions of these compounds are not cleaved. Clinical characteristics lead to suspicion of the diagnosis and are confirmed by assaying a L-iduronidase activity in leukocytes or cultured fibroblasts.137 Screening studies can be performed on urine assessing mucopolysaccharide content and dermatan sulfate and heparan sulfate. The gene for both Hurler and Scheie syndrome is on chromosome 4p16.342

MPS1S (Scheie Syndrome)

These patients differ from MPH1H in that the CNS is relatively spared from the condition, corneal clouding is severe, and retinal degeneration may occur. Dermatan sulfate and heparan sulfate are excreted in the urine, and the enzymatic deficiency appears to be similar to MPH1H.346

MPS2 (Hunter Syndrome)

Hunter syndrome is an X-linked recessive condition producing a phenotype that is similar to but milder than Hurler syndrome. Hunter syndrome has also been described in females who have mutations of the X chromosome.43 Corneal clouding is absent or mild, and pigmentary retinopathy and optic disk elevation have been reported.28,29 Patients with normal intellectual function may live for decades but eventually die of cardiac disease. Iduronate sulfatase activity is deficient, and this enzymatic abnormality can be assayed in leukocytes, fibroblasts, and hair roots.56 Progressive exophthalmos and hypertelorism has been reported in this condition.1 The gene for Hunter syndrome is on chromosome Xq28.342

MPS3 (Sanfilippo Syndrome)

This subgroup has more severe psychomotor abnormalities, is hyperactive, and sleeps very little. In this context, the clinical diagnosis is usually established on the basis of a skull X-ray. These children show no corneal clouding, less severe physical changes than types I and II, and a later-onset retinal dystrophy. There are four enzymatic subgroups, inherited as autosomal recessive traits. ERG changes are more severe than in MPS1H, and examination of retinal pathology shows evidence of rodcone degeneration, with rod degeneration predominating.49 Characteristic coarse hair is a singular feature of MPS3A. The biochemical defects can be assayed in leukocytes or fibroblasts.137 The genes for Sanfillippo syndrome type A is located on 17q25.31, while those for type B are located on17q21 and 12q14.342

MPS4 (Morquio Syndrome)

Children with Morquio syndrome are normal early in life but develop short stature and bone dysplasia at about 18 months of age. This subcategory is relatively mild when compared with the first three groups; however, progressive but mild intellectual deterioration occurs, and characteristic connective tissue abnormalities are noted. There is a characteristic abnormality of tooth enamel leading to discoloration and a rough surface. Corneal opacification is mild. Visual loss is not as severe as