The mucopolysaccharidoses (MPSs) are transmitted as autosomal recessive traits, with the exception of Hunter syndrome (MPS II), which is inherited in an X-linked recessive fashion.^6,7 They are caused by deficiency of lysosomal enzymes needed for the degradation of mucopolysaccharides and glycos-aminoglycans.^8,9 The catabolism of dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate may be blocked singly or in combination, depending on the enzymatic deficiency. The storage process eventually results in cell, tissue, and organ dysfunction. Glycosaminoglycan fragments are excreted in the urine.

A defect in 1 of 10 enzymes gives rise to each of the seven distinct clinical forms of MPS and their subtypes.Table 2 presents the classification, major systemic features, and ophthalmologic findings of the MPSs.

The MPSs share several clinical features that are variable in severity in individual diseases. These findings include skeletal abnormalities, coarse facial features, mental deficiency, cardiac disease, hepatosplenomegaly, ocular abnormalities, and deafness. A chronic and progressive course is typical. Ocular manifestations include progressive corneal clouding, retinal pigmentary degeneration, optic nerve head swelling, optic atrophy, and glaucoma.

Tissue-specific differences in the structure of mucopolysaccharides account for the variability in clinical manifestations. Excess dermatan and keratan sulfates appear in the cornea, whereas heparan sulfate accumulates in the retina and central nervous system (CNS). The accumulation of these substances is the result of the faulty catabolism of mucopolysaccharides in lysosomes due to defective lysosomal acid hydrolases. The large storage vacuoles in histiocytes, lymphocytes, or leukocytes show metachromasia.

In patients whose disease leads to the storage of heparan sulfate in the retina, a retinal pigmentary degeneration associated with night blindness develops. Early in the course of their disease, patients with MPS IH, IS, IH-S, IV and VI report moderately severe photophobia. Papilledema is a frequent finding, occurring in one third or more of patients with certain types of MPS, such as Hunter syndrome.¹⁰ Optic nerve head swelling has been attributed to the hydrocephalus that results from meningeal thickening with the storage material. Collins et al¹⁰ postulated that it could be caused by narrowing of the scleral canal at the optic nerve head, as a result of posterior scleral thickening with mucopolysaccharide accumulation. Acute and chronic glaucoma may be seen in MPS IH, IS, and IH-S.

Conjunctival biopsy, a simple and applicable procedure, is a reliable screening test for patients with suspected lysosomal storage diseases.¹¹ The diagnosis of MPS is based primarily on the characteristic clinical findings and on the detection of mucopolysaccharides in the urine. For definite diagnosis and for further categorization of the types and subtype of MPSs, specific enzymatic assays or gene analysis should be performed.

Infants with Hurler syndrome appear healthy at birth. Signs of progressive organ dysfunction and dysostosis multiplex appear in the first year of life. Hurler syndrome has been the prototype for the description of the MPS and is the most severe form, with unfortunate death of all patients in the first decade of life. Clinical features include dwarfism, coarse facial features (Fig. 1), severe mental retardation, hirsutism, cardiovascular disease, skeletal abnormalities, and hepatomegaly.¹² Acute cardiomyopathy has been described as the presenting feature in some infants younger than 1 year of age.¹³ Respiratory infection and cardiac failure are the usual causes of death.

Progressive diffuse punctate stromal corneal opacities occur in all patients. They may conceal retinal degeneration and result in progressive visual loss.^14,15 When the retina can be evaluated, a retinitis pigmentosa-like picture indistinguishable from other forms of heredofamilial retinal pigmentary dystrophies usually is present. The electroretinogram is diminished or nonrecordable.¹⁶ Glaucoma is relatively rare¹⁷ but has been reported in some patients.^14,18 Optic nerve head swelling and optic atrophy are common¹⁰ (Fig. 2). Congenital cataracts occasionally have been observed.¹⁹

Hurler syndrome is caused by the absence of α-L-iduronidase, which catalyzes the cleavage of iduronic acid residues from polysaccharide chains. As a result, heparan sulfate and dermatan sulfate accumulate and are excreted in the urine.²⁰ The gene maps to 4p16.3.²¹ Residual α-L-iduronidase activity in Hurler fibroblasts is heat stable, whereas that in Scheie fibroblasts is heat labile. The enzyme from Hurler-Scheie compound fibroblasts is of inter—mediate activity between Hurler and Scheie-syndromes.

Bone marrow transplantation was performed in two patients homozygous for the relatively common W402X α-L-iduronidase mutation at the ages of 14 and 11 months, respectively. As opposed to untreated patients homozygous for this mutation who have a very severe clinical phenotype with rapid clinical deterioration and death before 6 years of age, the transplanted children were alive at 12 and 14 years of age, respectively. One showed limited mobility but was coping well at school; the patient was wheelchair-bound with severe disability and attended a school for the physically handicapped.²² Transfer and expression of the normal gene in autologous bone marrow may become an alternative method of treatment in the future.²³

The clinical features of Scheie syndrome²⁴ aremilder than those of Hurler syndrome. Signs and symptoms of the disease usually appear after the age of 5 years, leading to the diagnosis at about 15 years of age. α-L-Iduronidase is deficient, and the disease is allelic with Hurler syndrome.²⁰ Patients have claw-hand deformities, joint stiffness, aortic valve insufficiency, hernias, and deafness. They are of normal height and intelligence and have a relatively normal life span. Facial features are only slightly coarse.

The predominant ocular feature is a peripheral corneal opacification that progresses centrally with age, eventually resulting in visual loss.²⁵ Mucopolysaccharides accumulate in all cellular components of the cornea, with profound alteration of Bowman’s layer and of the corneal lamellae. Ophthalmologic manifestations include glaucoma and pigmentary retinal degeneration that occurs in the first decade of life and is accompanied by night blindness and visual field constriction in the teens and 20s. If vision is reduced markedly, penetrating keratoplasty may be considered even though poor results have been reported, presumably because of the accompanying retinal degeneration.²⁴

As in MPS I-H, dermatan sulfate and heparan sulfate are present in the urine. Scheie syndrome should be differentiated from mild MPS VI-B.

Patients with MPS IH-S have a phenotype of intermediate severity between Hurler and Scheie syndromes.⁸ The disease is a genetic compound of the two alleles, H and S. Most patients have severe bone involvement, with little or no intellectual impairment. They have a longer life expectancy than those with Hurler syndrome. Micrognathia is a prominent clinical feature and leads to a characteristic facial appearance (Fig. 3). Arachnoid cysts with spinal rhinorrhea are characteristic and may lead to the enlargement of the sella turcica. The cervical cord may be compressed as a result of MPS accumulation in the dura. Symptoms appear at about 5 years of age, and survival to adulthood is common.

There is progressive corneal clouding, chronic disc edema, retinal degeneration, and a diminished or extinguished electroretinogram. When there is advanced vision loss, penetrating keratoplasty can be very helpful. Glaucoma is rare. Biochemical and enzymatic assays are identical to those in MPS I-H and I-S.

The residual α-L-iduronidase activity in Hurler fibroblasts is heat stable; it is labile in Scheie fibroblasts. The enzyme activity in MPS IH-S is intermediate between the two. Four novel mutations underlying mild or intermediate forms of α-L-iduronidase deficiency have been discovered, providing insight into genotype-phenotype correlation in this group of patients.²⁶

There are mild (type B) and severe (type A) forms of Hunter syndrome. They are distinguished on clinical grounds only and have a wide spectrum of clinical severity. The two types are allelic and are caused by mutations at the X-linked locus for the enzyme iduronate sulfate sulfatase. Wilson et al²⁷ localized the gene to Xq28, distal to the fragile X site. Characteristic pebbly, ivory-colored skin lesions over the back, neck, scapula, and thigh are present in patients with MPS II (Fig. 4).

Individuals with the severe form have many features of Hurler syndrome, but of lesser severity and with slower progression of somatic and CNS disease. Only males are affected. Death usually occurs before the age of 15 years.

In the milder type B, survival may extend past the age of 45 years.²⁸ The longest known survival is to 87 years of age.²⁹ Intelligence is normal and skeletal involvement moderate, with minimal or no CNS involvement. Corneal clouding usually is absent in type B,²⁸ although deposits of acid mucopolysaccharides are found histologically, even in clinically clear corneas.³⁰ Pigmentary retinopathy with an abnormal or extinguished electroretinogram may lead to visual impairment of varying degrees in all patients.³¹ In patients with mild Hunter syndrome without raised intracranial pressure, elevated and blurred disc margins lead to the diagnosis of chronic-papilledema, which may culminate into optic-atrophy.^10,28,32,33

Dermatan sulfate and heparan sulfate are present in the urine. Definitive diagnosis is made by assaying for the activity of sulfoiduronate sulfatase in fibroblasts. The enzyme defect can be corrected in vitro using an amphotropic retroviral vector containing the human gene.³⁴

Patients with this autosomal recessive syndrome have severe CNS degeneration but only mild somatic disease. Onset of clinical features occurs between 2 and 6 years of age. Significant delay in diagnosis is caused by the mild somatic (Fig. 5) and radiographic features. There may be moderate dwarfism, minimal skeletal dysostosis, and moderate hepatosplenomegaly. The presenting problem may be that of marked hyperactivity, destructive tendencies, and other behavioral aberrations. Four biochemically distinct types of MPS III are difficult to differentiate clinically. Type A is most severe, with an earlier onset, more rapid progression of symptoms, and earlier death than types B, C, or D.³⁵ Types B and D are heterogeneous.^36,37. Type C is intermediate between A and B. Excessive heparan sulfate, but not dermatan sulfate, is excreted in the urine. N-sulfated glucosamine residues are removed during the degradation of heparan sulfate through the sequential action of four enzymes that are defective in Sanfilippo syndrome. In Type A, there is a deficiency of heparan N-sulfatase or sulfamidase; in type B, α-N-acetyl-glucosaminidase (NAG) is lacking; in type C, acetyl CoA: α-glucosaminidase is deficient; and in type D, the defect is in N-acetyl glucosamine 6-sulfatase.

The corneas are clear clinically but show similar but less severe ultrastructural abnormalities as other forms of MPS.¹⁵ A retinitis pigmentosa-like fundus picture frequently is present.³⁸ Optic atrophy may be present.

The MPS urine spot test is positive, and the urine contains excessive amounts of heparan sulfate. The four types of Sanfilippo syndrome can be differentiated by enzymatic assays. Type A has been mapped to 17q25.3,³⁹ type B to 17q21,⁴⁰ type C to chromosome 14, and type D to 12q14.⁴¹

Two types of Morquio syndrome are recognized with a wide spectrum of clinical manifestations. Type A is caused by deficiency of N-acetyl galactosamine 6-sulfatase,⁴² and type B is caused by deficiency of β-galactosidase.⁴³ As with most MPSs, no clinical abnormalities are apparent at birth. An awkward gait, retarded growth, knock knees, sternal bulging, and flaring of the rib cage become evident in the second year of life. Patients with Morquio syndrome have short trunk dwarfism (Fig. 6). They are of normal intelligence, and their distinctive skeletal abnormalities become prominent in the first 10 years of life. The predominant clinical features are related to the effect of the disease process on the spinal cord.⁴⁴ The joints are loose and hyperextensible, the wrists enlarged, and the hands misshapen,⁸ and there is genu valgum and kyphosis. The facies is characteristic with a broad mouth, prominent maxilla, short nose, and widely spaced teeth.⁷ Odontoid hypoplasia may lead to atlantoaxial subluxation and spinal cord compression later in the course of the disease. Cervical myelopathy develops early. Death occurs late in childhood from respiratory paralysis secondary to spinal cord compression or from recurrent pneumonia.

Corneal clouding, the most common ocular feature, generally is not present before 10 years of age⁴⁵ (Fig. 7), but one of us (EIT) has observed it in three Lebanese siblings younger than 10 years of age. The corneal epithelium and Bowman’s layer appear normal under the slit lamp, and there is a homogeneous clouding of the corneal stroma. There is no retinal dystrophy.⁴⁶

The gene for type A maps to 16q24.3.⁴⁷

This autosomal recessive disease was first recognized in 1963.⁴⁸ Severe and mild phenotypes have been described.⁷ Type A, or classic form, is more severe than its allelic form, type B. The deficient enzyme is arylsulfatase B (N-acetylgalactosamine 4-sulfatase).⁴⁹ Heparan sulfate and dermatan sulfate are excreted excessively in the urine. The extent of corneal clouding is the same in both types, but skeletal dysplasia is less pronounced in the latter. The clinical features, except for normal intelligence, are reminiscent of those of Hurler syndrome, especially in the severe form (Fig. 8).

Growth retardation is first noted at 2 or 3 years of age. Restriction of joint movement develops in the first year of life. Significant cardiomyopathy may arise, and hepatosplenomegaly may be present. Hypoplasia of the odontoid process can cause spinal cord compression and spastic paraplegia.⁵⁰ Umbilical and inguinal hernias are common. Patients with type A Maroteaux-Lamy syndrome die in their teens from hydrocephalus secondary to meningeal infiltration with mucopolysaccharides. Radiographic findings are similar to those of patients with Hurler syndrome and are striking examples of dysostosis multiplex.

Diffuse corneal stromal opacification develops early in life. The cornea increases in thickness, especially in its periphery, where the clouding is most dense.¹¹ Papilledema and optic atrophy occur.^10,51 Retinal degeneration with electroretinographic abnormalities is a feature of the disease. Corneal transplantation has been performed in patients with-Maroteaux-Lamy syndrome, but the long-term visual outcome is poor.^52,53 Vision may be poor despite clear corneal grafts because of associated retinal or optic nerve disease.

The gene maps to 5q11–q13.⁵⁴

β-Glucuronidase is deficient in this type of mucopolysaccharidosis.⁵⁵ There may be two allelic forms leading to two clinical phenotypes with a wide range of severity of signs and symptoms.

The gene map for β-glucuronidase was refined to 7q21.11 by Ward et al⁵⁶ using dosage analysis of chromosomal aberrations. There is excessive urinary excretion of glycosaminoglycans and coarse granulocyte inclusions in a variety of tissues.

The severe form of the disease is characterized by rapidly progressive mental, motor, and growth retardation. Patients have hepatosplenomegaly, massive ascites, inguinal hernias, thoracolumbar gibbus, and skeletal radiographic changes similar to those of the other mucopolysaccharidoses. Individuals with the milder phenotype exhibit hepatosplenomegaly, skeletal abnormalities, and an unusual facies. Mental retardation is not present at birth but develops with aging. Corneal clouding is variable and usually mild.⁵⁷ A mild pigmentary retinopathy develops later in life.

In MLS I, there is deficiency of the enzyme sialidase that leads to a syndrome characterized by a retinal cherry-red spot and myoclonus. MLS I was reclassified as sialidosis type 1⁵⁹ and is discussed later in this chapter.

Patients with this rare and severe autosomal recessive mucolipidosis display many of the clinical and radiographic features of Hurler syndrome.⁶⁰ There are striking fibroblast inclusions, hence the name I-cell disease.⁶¹ There is no mucopolysacchariduria.^62,63 The disease results from the absence of the enzyme that attaches a recognition phosphate group onto a mannose residue in hydrolases. There is abnormal lysosomal enzyme transport in cells of mesenchymal origin. Severe progressive psychomotor retardation occurs. MLS II is differentiated from Hurler syndrome by the earlier onset of signs and symptoms, the absence of mucopolysacchariduria, the early and striking gingival hyperplasia, and the rapidly progressive course leading to death in the first decade.⁶⁴

Early in development, congenital dislocation of the hips, thoracic deformities, hernia, and gingival hyperplasia are evident.^65,66 Radiographic studiesshow bony changes of dysostosis multiplex more severe than in MPS I. Patients have coarse facial features, craniofacial abnormalities, and restricted joint mobility.

Early in the course of the disease, the corneas are clear. Late corneal clouding is common; it correlates positively with survival and occurs in 40% of cases.⁶⁷ Corneal opacities are evident on slit-lamp examination as diffuse stromal granules. Glaucoma occurs in 6% of patients.⁶⁸ No cherry-red macula is present. Conjunctival biopsy is diagnostic.⁶⁸

The diagnosis can be made biochemically by demonstration of elevated serum and urine lysosomal enzyme levels and by measuring the UDP-N-acetylglucosamine lysosomal enzyme N-acetylglucosamine phosphotransferase (GNPTA) in fibroblasts. The gene for this enzyme maps to 4q21–q23.⁶⁹ Prenatal diagnosis is reliable and carrier detection is possible. There is no definitive treatment.

Mucolipidosis III results from the same enzyme deficiency as MLS II. N-acetylglucosamine 1-phosphotransferase is composed of at least two distinct polypeptides: a recognition subunit that is defective in the MLS III variant and a catalytic subunit that is deficient or altered in the classic forms of MLS II and III as well as in the MLS II variant.⁷⁰

Onset of clinical signs and symptoms is later than in MLS II. The clinical course progresses more slowly, and survival into adulthood is possible.^71,72 Most patients have been Ashkenazi Jews. Children usually present at about 3 years of age with joint stiffness, coarse facial features, and short stature.⁷³ They have many of the features of Hurler syndrome but with a much slower clinical evolution and no mucopolysacchariduria. The arms and hands are involved most markedly, and carpal tunnel syndrome with wasting of the thenar eminence is common (Fig. 9). Aortic valve disease occurs in most cases. The pathology of MLS III is not well documented. Cultured fibroblasts have inclusion bodies similar to, but not as prominent as, MLS II cells.

Nearly 50% of reported patients have some learning disability or mental retardation.⁷⁴ Life expectancy and the natural course of the illness beyond the third decade are unknown.

Corneal clouding (Fig. 10), hyperopic astigmatism, and a mild retinopathy with surface-wrinkling maculopathy (Fig. 11) appear to be the constant ocular triad.⁷⁵ Some patients have retinal vascular tortuosity, optic nerve head swelling (Fig. 12), visual field defects, and abnormalities in color vision. Visual complaints are uncommon.

Prenatal diagnosis by means of amniocentesis is possible. There is no specific or definitive treatment.

Mucolipidosis IV was first described by Berman.¹² It is characterized by psychomotor retardation, lack of skeletal deformities and organomegaly, and variable ophthalmologic abnormalities in the form of corneal opacities and retinal degeneration. Patients have been described with onset of clinical findings from 1 year of age to the mid 20s. Life span and prognosis beyond this age remain to be determined. The disease is seen mainly among Ashkenazi Jews.⁷⁶ MLS IV differs from most other lysosomal storage disorders in the apparent lack of progression in some patients. In most, however, there is marked psychomotor and physical retardation. Biochemically, MLS IV is characterized by the accumulation of gangliosides,⁷⁷ phospholipids,⁷⁸ and acidic mucopolysaccharides.⁷⁹ Deficiency of ganglioside sialidase was reported as the possible metabolic defect causing this disorder, and partial reduction in activity of this enzyme was noted in obligate heterozygotes.⁸⁰ Conjunctival biopsy shows characteristic-intracellular inclusions.⁸¹

There is progressive severe visual impairment from corneal opacification^12,82 and from progressive retinal degeneration.^83,84 The age of appearance and the extent and severity of the clinical course of these abnormalities are variable. The superficial corneal opacification is a characteristic feature of MLS IV and leads to the clinical diagnosis in most children. The opacities are not congenital in all patients, as suggested previously.¹² With time, the corneal opacities may increase in density, with poor fundus visualization leading to the erroneous diagnosis of cataracts in some patients. Epithelial edema also hasbeen noted. Corneal clearing may occur after epithelial removal, but clouding returns after a few days or weeks. A progressive rod-cone dystrophy is present with a subnormal or extinguished electroretinogram (ERG).^82,84 The static nature and, at times, improvement in the degree of corneal opacification in more than 50% of cases is characteristic of MLS IV. In other lysosomal storage disorders, corneal clouding and visual impairment are progressive. Deterioration of visual function in MLS IV correlates with retinal degeneration rather than with worsening of corneal opacities. Prenatal diagnosis is possible.^81,82

There are α and β types of mannosidosis.⁸⁵ We restrict our comments to α-mannosidosis because of the associated ophthalmologic abnormalities. α-mannosidosis results from a deficiency of the lysosomal enzyme α-mannosidase. There are elevated serum levels and excretion of small mannose-richoligosaccharides. Patients with α-mannosidosis excrete a unique pattern of increased amounts of several oligosaccharides.^86,87 The gene for α-mannosidase was mapped to chromosome 19p13.2-q12.⁸⁸ In severe infantile type I mannosidosis, there is rapidly progressive mental retardation, hepatosplenomegaly, severe dysostosis multiplex, and often death between the ages of 3 and 10 years.⁸⁹ The milder juvenile and adult type II mannosidosis is characterized by a more slowly progressive course with survival into adulthood.⁹⁰ Hearing loss is a prominent feature of this disease, but clinical heterogeneity is evident.⁹¹ Recurrent bacterial infections and hernias are seen.^92,93 Types I and II are not clearly separated. Ophthalmologic manifestations are present in both types and consist of superficial corneal opacities and posterior spoke-like lens opacities.⁹⁴

The diagnosis of mannosidosis can be confirmed by direct measurement of α-mannosidase in leukocytes, fibroblasts, or cultured amniotic fluid cells. There are several reports of successful prenatal diagnosis.^95,96

Fucosidosis is caused by deficiency of the lysosomal enzyme α-fucosidase.⁹⁷ This results in accumulation and excretion of a variety of glycoproteins, glycolipids, and oligosaccharides containing fucoside moieties. The disorder is panethnic, with a higher incidence in Italy and in the Southwestern parts of the United States.⁹⁸ There is faulty degradation of both sphingolipids and polysaccharides.⁹⁹ Urine samples from individuals with fucosidosis contain excessive amounts of several fucoglycoconjugates.¹⁰⁰ The most precise way of diagnosing fucosidosis is based on enzymatic assay of α-L-fucosidase in cells of any type.

There is a spectrum of severity of the clinical findings with mild to severe phenotypes. The more severely affected patients exhibit psychomotor retardation, coarse facies, growth retardation, dysostosis multiplex, and neurologic retardation in the first year of life. The milder phenotype is characterized by angiokeratomas (Fig. 13) and by a longer survival. The gene for fucosidosis maps to chromosome 1p24.¹⁰¹

The ocular features of fucosidosis are not prominent. There may be tortuosity of conjunctival vessels and a mild pigmentary retinopathy.^102,103,104

Sialidosis is a rare lysosomal storage disease with clinical features resembling those of Hurler syn-drome, but milder. The two forms of the disease, sialidosis type 1 and type 2, result from deficiency of neuraminidase. The gene defects of the two types are not allelic. Complementation studies between sialidosis type 1 and type 2 fibroblasts result in restoration of both β-galactosidase and sialidase activities in fused cells. Moderate but progressive mental retardation, cerebellar signs, peripheral neuropathy, myoclonic jerks, tremor, dysostosis multiplex, and peculiar inclusions are present in cultured fibroblasts,^8,105,106 but there is no mucopolysacchariduria. There is accumulation of syalyloligosaccharides in various tissues and organs of the body and deficiency of the enzyme α-N-acetylneuraminidase in cultured fibroblasts.¹⁰⁷

Diagnosis is based on electron microscopy. Fibroblasts in conjunctival biopsy specimens contain small membrane-bound vacuoles containing fibrillogranular and membranous lamellar bodies detectable by electron microscopy.¹⁵ The differential-diagnosis must include other diseases causing a cherry-red macula. There is no known treatment, but prenatal diagnosis is possible.

Sialidosis type 1 is characterized by the cherry-red spot myoclonus phenotype (cherry-red spot myo-clonus syndrome) and is the milder form of sialidosis. There are at least 15 confirmed patients.^108,109 The disease results from a defect in the structural gene for sialidase, which maps to 10pter-q23.¹¹⁰ Retinopathy and myoclonus occur simultaneously at the onset of the disease, which tends to be in early adolescence but can be variable. The striking neurologic manifestation is a stimulus-sensitive myoclonus that limits daily activities. Ataxia and generalized grand-mal seizures also may occur. Intellect is preserved, and patients with this rare disorder can survive beyond 30 years of age.

The presenting symptom may be a reduction in visual acuity; visual loss is progressive and often severe. It may be associated with impaired color vision and night blindness.¹¹¹ The macular cherry-red spot is consistent but can be atypical. Punctate lens opacities can occur.^109,112,113 Nystagmus, optic-atrophy, and visual field constriction have been-described.

An important diagnostic screening test in this disorder is the examination of the urine for excessive excretion of sialic acid-containing compounds. Urine thin-layer chromatography stained with resorcinol gives a blue color, suggesting the presence of sialylated oligosaccharides. The definitive test is the demonstration of deficient sialidase in fresh cultured skin fibroblasts.

Sialidosis type 2 is distinguished from sialidosis type 1 by the early onset of a severe progressive muco-polysaccharidosis-like phenotype with visceromegaly, dysostosis multiplex, and mental retardation. The disease may be the result of a defect in the gene for a protective protein on chromosome 20.¹¹⁰ There are several subtypes with marked variability in clinical manifestations. Recognized are a congenital, or hydropic form, an infantile form, and a juvenile form, the latter of which is the most common and which is described in this chapter under the title of galactosialidosis.

Congenital sialidosis type 2 patients all have been stillborn infants with hydrops fetalis, ascites, hepatosplenomegaly, stippling of the epiphyses, and periosteal cloaking of the long bones. There are no documented ophthalmologic findings.

Patients with infantile-onset sialidosis type 2 are relatively healthy at birth.¹¹⁴ Later, a progressive severe MPS-like phenotype develops. Development is slow, with mental retardation and gait ataxia. Myoclonus is present. Grandmal seizures, deafness, and a peripheral neuropathy may occur. Skeletal abnormalities are prominent with dysostosis multiplex. Vision is retained despite the presence of a macular cherry-red spot and punctate lens opacities.

Peripheral blood lymphocytes are vacuolated, and foam cells are present in the bone marrow. Sialidase is deficient in cultured fibroblasts.

Juvenile sialidosis type 2 is described under β-galactosialidosis.

Aspartylglucosaminuria is an autosomal recessive disorder that occurs primarily in Finland.¹¹⁵ Rare, isolated cases are reported from other countries. The accumulation of aspartylglucosamine results from a deficiency of the lysosomal enzyme, aspar—tylglucosaminidase, which maps to chromosome 4q32–q33.¹¹⁶

Patients are healthy for the first few months of life. Recurrent infections, diarrhea, and hernias are noted during the first year of life. Coarsening of facial features and saggy skin folds occur in the first decade. Mental deterioration begins between the ages of 6 and 15 years. Crystal-like lens opacities are observed.¹¹⁷ Aspartylglucosamine is the major storage compound found in tissues and fluids of patients with this disease.¹¹⁸ There may be vacuolated lymphocytes and neutropenia. The urine contains large amounts of aspartylglucosamine. No treatment is known.

Niemann-Pick disease (NPD) results from impaired sphingomyelin metabolism. The disease was first reported by Niemann in 1914.¹²³ Thirteen years later, Pick described the characteristic vacuolated or foam cells in many body tissues.¹²⁴ NPD results from deficient activity of acid sphingomyelinase (ASM) that maps to 18q11–q12.¹²⁵

Crocker¹²⁶ categorized the NPD phenotypes into four clinical entities designated A to D. The broad classification of NPD into five phenotypic variants (A through E) followed and was based on the age of onset, the severity and type of neurologic involvement, and the evolution of the disease. Hepatosplenomegaly and foam cells in the bone marrow are constant features in all variants. Type A is the infantile neurodegenerative form. Type B is distinguished from the severe neuronopathic type A by the absence of neurologic involvement, by the presence of hepatosplenomegaly, and by survival into adulthood. Patients with type C NPD are healthy for the first 1 or 2 years of life and then experience a slowly progressive and variable neurodegenerative course, with less severe hepatosplenomegaly and survival into adulthood; they often present with prolonged neonatal jaundice. Type D patients share a common ancestry traceable to Acadians from Nova Scotia. Neurologic symptoms develop later in childhood, and these patients have a slower neurodegenerative course than those with type C. Type E is the adult form with a mild degree of visceral sphingomyelin storage, mild splenomegaly, foam cells in the bone marrow and absence of neurologic signs.

ASM is deficient in types A and B, which are believed to be allelic.¹²⁷ In type A NPD, ASM is reduced dramatically,^128,129 whereas in type B, there is residual ASM activity.¹³⁰ In type C, sphingomyelinase activity usually is normal.¹³¹ The metabolic block in type C is in the intracellular trafficking of cholesterol.¹³² The biochemical defects in type D and type E NPD remain to be determined.

The pathologic hallmark of types A and B is the Niemann-Pick cell, which is a lipid-laden foam cell¹³³ (Fig. 14). Sphingomyelin accumulates in the brain and autonomic ganglia. The neurons become swollen and have a pale cytoplasm. Ultrastructurally, the cells contain concentric lamellated bodies representing storage cytosomes. Inclusion profiles in the viscera, lymph nodes, and foam cells also correlate with an increase in sphingomyelin content. Diagnosis can be made readily by enzymatic determination of ASM activity in cells and tissues. More than 300 cases of type A and B NPD have been reported. Prenatal diagnosis has been accomplished by enzyme assays of cultured amniotic fluid cells in types A and B.

Type A NPD is fatal in infancy. It is characterized by failure to thrive, hepatosplenomegaly, and severe CNS involvement, with loss of motor function leading to death by 2 to 3 years of age. A higher incidence is seen in the offspring of Ashkenazi Jews compared with the general population.¹³⁴

A cherry-red macula is present in 50% of infants in the first and second year of life.¹³⁵ There is no distinction between the appearance of the cherry-red spot in infantile NPD and in Tay-Sachs disease.^136,137 Occasionally, a macular halo syndrome with a gray, granular-appearing macula is observed.¹³⁸ Optic atrophy develops with time. Subtle lens opacities and corneal clouding can occur.¹³⁷ ERG is abnormal. The stored lipid is localized to the ganglion and amacrine cells of the retina, most conspicuously in the parafoveal region. The other retinal layers appear unaffected.¹³⁵

Type B NPD has a variable phenotype, with only visceral involvement. It is diagnosed in childhood between 3 and 11 years of age, or in adult life with hepatosplenomegaly and progressive pulmonary infiltrates that cause the major disease complications.¹³⁹ Most patients have a normal intellect and survive into adulthood. Patients with type B NPD are of mixed ethnic backgrounds. Harzer and associates¹⁴⁰ were first to demonstrate a low sphingomyelinase level in this disease.

A unique retinal abnormality, the macular halo syndrome, has been reported in type B NPD by Cogan and Kuwabara¹³⁵ and consists of a ring of opacities around the macula that causes no visual impairment (Fig. 15). This abnormality has been reported by several authors.^141,142,143 The crystalloid halo which measures about half the disc diameter occurs at the outer edge of the retina mainly in Henle’s fiber layer causing only minor obstruction of the overlying vessels. Matthews and associates¹⁴⁴ proposed that the macular halo represents the mildest form of a cherry-red spot in the ganglion cell layer of the retina. Their findings are in conflict with those of Cogan et al.¹³⁸ The precise location of the opacities in the retina remains uncertain because of the lack of histopathology. The available clinical data suggest that such opacities are permanent.

Bone marrow transplantation has been successful in type B NPD. Enzyme replacement and somatic gene therapy using macrophage-targeted recombinant enzyme may be available in the future.

Type C NPD is a panethnic autosomal recessive lipidosis associated with lysosomal accumulation of unesterified cholesterol. It was first recognized in 1958¹⁴⁵ and is biochemically distinct from type A and type B NPD.¹⁴⁶ It is as common as types A and type B NPD combined. This distinction was supported by somatic cell hybridization studies.¹⁴⁷ Genetic isolates have been described with the Nova Scotia form, formerly type D NPD,¹²⁶ and in southern Colorado.¹⁴⁸ There is no evidence of genetic heterogeneity. Sea-blue histiocytes in the bone marrow are common but nonspecific.¹⁴⁹ The metabolic block results from defective intracellular cholesterol trafficking.¹³² The disease is diagnosed by filipin staining and by demonstration of fluorescence around the nucleus after low-density lipoprotein (LDL)-cholesterol loading.¹⁵⁰ Cultured fibroblasts from patients and carriers have high levels of unesterified cholesterol. There is no macular cherry-red spot or a macular halo in type C NPD. The differentiating clinical features of type C NPD (ophthalmoplegic neurovisceral lipidosis, vertical supra’s disease) are its three main clinical features, which led Cogan et al¹⁵¹ to recommend the acronym DAF syndrome to denote downgaze paralysis, ataxic athetosis, and foam cells in the spleen, liver, and bone marrow. There is extensive infiltration of bone marrow, spleen, liver, and other tissues with foam cells. Sphingomyelinase activity in leukocytes and cultured fibroblasts is decreased or normal.^152,153

Type C NPD has a subacute clinical course and presents in infancy with neonatal hepatitis or later in childhood with moderate splenomegaly and gradual neurologic deterioration. Most patients have seizures and limitation of vertical gaze. The presence of downgaze paresis is characteristic¹⁵⁴ and has been noted in all juvenile and adult cases.¹⁵⁵ Subtle slowing of vertical saccades begins in late infancy. Voluntary vertical gaze is completely paralyzed in late stages of the illness.¹⁵⁶ Horizontal eye movements may be affected with a total supranuclear ophthalmoplegia. Patients usually die before the end of the second decade.

Type D NPD is caused by a defect in cholesterol metabolism, and although few biochemical studies have been published, it may be allelic with type C.^157,158 The underlying metabolic defect in type D and type E NPD still is not understood, but these two variants cannot be diagnosed by a single laboratory test. Increase in organ sphingomyelin content or presence of foam cells in the bone marrow helps to corroborate clinical suspicions. Neurologic symptoms develop later in childhood in patients with type D disease, and they have a slower neurodegenerative course than type C patients.¹⁵⁹ They share a common ancestry traceable to Acadians. There are no ocular abnormalities in type D. Patients with the type E variant may have a macular cherry-red spot. In 1978, Schneider et al¹⁶⁰ described two patients with a heat-labile form of ASM and classified it as type F NPD.

Fabry’s disease results from a defect in glycosphingolipid catabolism. The disease has an incidence of approximately 1 in 40,000.¹²² The gene is X-linked recessive and has been localized to Xq22.¹⁶¹ It codes for the lysosomal hydrolase α-galactosidase A.¹⁶² Most heterozygous female carriers have an intermediate level of enzymatic activity.^163,164 There is progressive and systematic accumulation of the glycosphingolipid ceramide trihexaside, particularly in vascular endothelial cells.¹⁶⁵ Carrier females in a pedigree can be examined clinically and biochemically for heterozygote identification.

The disease usually has its onset during childhood or adolescence. Classically, affected hemizygotes have pain and paresthesia of the extremities (acroparesthesia) around the time of puberty¹⁶⁶; vascular cutaneous lesions (angiokeratomas) of the scalp, mucous membranes, skin, and inguinal and umbilical regions; hypohidrosis; and the characteristic corneal and lens opacities. Severe renal impairment leads to hypertension and uremia. Death occurs from renal failure or from cardiac or cerebrovascular disease.¹⁶⁷

The ocular deposition of glycosphingolipids results in unique and diagnostic eye findings in severely affected hemizygous males and minimally affected heterozygous carrier females.¹⁶⁸ The ocular findings have been recognized as one of the distinctive hallmarks of this disease and among its earliest clinical manifestations.¹⁶⁹ The corneal opacities appear as whorled streaks from a central vortex and have been called cornea verticillata^170,171 (Fig. 16). Bilateral inferior granular anterior capsular or posterior subcapsular lens opacities occur in one third of hemizygous males but rarely in heterozygous females. Mild to severe conjunctival (Fig. 17) and retinal vessel tortuosity are present early in life. Visual acuity is not impaired. However, acute visual loss has occurred in hemizygotes as a result of unilateral central retinal vascular occlusion.¹⁷¹ Other ocular findings include lid edema, myelinated nerve fibers, mild optic atrophy, papilledema, nystagmus, and internuclear ophthalmoplegia.^171,172 (Fig. 18). Confirmation of the clinical diagnosis in hemizygotes and heterozygotes requires the demonstration of deficient α-galactosidase A activity in plasma, leukocytes, or tears or increased levels of ceramide trihexaside in plasma or urinary sediment. The diagnosis in female heterozygotes can be established by linkage analysis.^163,174 These carriers may have some of the systemic manifestations of the disease, but they usually are milder than in affected males. The most frequent clinical finding in females is the characteristic whorl-like corneal epithelial dystrophy. Corneal opacification in female carriers may be more prominent than in male patients because of the admixture of corneal epithelial cell lines with the normal gene and those with the abnormal gene (lyonization). Abnormal glycosphingolipid deposits are found in all ocular and orbital vessels, in smooth muscle of iris and ciliary body, and in perineural cells and connective tissue of the lids and cornea.¹⁷⁵

Prenatal diagnosis is possible by demonstration of the specific α-galactosidase A mutation in chorionic villi or cultured amniotic cells.¹⁷⁶

Gaucher disease is an autosomal recessive lysosomal glycolipid storage disorder characterized by the accumulation of glucocerebroside (glucosylceramide) in reticuloendothelial cells.^177,178 The gene coding for the deficient enzyme glucocerebrosidase (acid beta-glucosidase) is located on chromosome 1q21.¹⁷⁹ The disease is common in the Ashkenazi Jewish population.¹⁷⁸ Three phenotypes are recognized based on the absence (type 1) or presence and severity (types 2 and 3) of primary central nervous involvement.¹⁸⁰

Type 1 is most common. It is a chronic, non-neuronopathic disorder of adult onset and it accounts for 90% of cases. Splenomegaly, anemia thrombocytopathic, pathologic bone fractures, bleeding episodes, and a yellow skin pigmentatipon and features the disease. The absence of cerebral involvement ditinguishes it from types 2 and 3. Brownish piguecula-like masses containing Gaucher cells are the only significant ocular feature.¹⁸¹ These lesions enlarge and assume a yellow color. The nasal and temporal bulbar conjunctiva are involved with equal frequency in only one fourth of patients. Their presence and significance in this disease has been questioned by Chu et al,¹⁸² who did not find any pingueculae in a group of 10 patients.

Type 2 is the acute neuronopathic infantile form. It has an early onset, with severe CNS involvement, failure to thrive, progressive hepatomegaly, splenomegaly, and dysphagia. Later, persistent retroflexion of the head and signs of pseudobulbar palsy develop. Early and late onset varieties have been delineated.¹⁸³ The classic Gaucher triad consists of trismus, strabismus, and opisthotonus. Oculomotor abnormalities often are the first manifestation of the disease, with strabismus or oculomotor apraxia.¹⁸³ Most infants with type 2 disease die within the first 2 years of life.¹⁸⁴

Type 3 is the subacute, juvenile neuronopathic form, with onset in the teenage years and a chronic course. The severity of type 3 is intermediate between types 1 and 2. The neurologic features are milder and have a later onset. The first symptoms are the result of massive visceral involvement.¹⁸⁵ The disease is common in Norrbottnian Swedes. As in type 2, disorders of eye movements are the usual presenting signs.

An additional variant with cardiac valvular calcifications, abnormal eye movements, and corneal opacification that does not interfere with vision is associated with homozygosity for the D409H mutation in the glucocerebrosidase gene.^186,187

A tentative diagnosis is based on the detection of Gaucher cells (storage cells) in the bone marrow. Decreased tissue levels of glucocerebroside activity confirm the diagnosis.¹⁸⁸ Mutation analysis of the glucocerebrosidase gene also can be performed. The quality of life of patients with Gaucher disease can be improved by a variety of medical and surgical procedures. The clinical abnormalities can be ameliorated and reversed by repeated infusions of modified acid β-glucosidase (ceredase). Cure theoretically is possible using bone marrow transplantation¹⁸⁹

Metachromatic leukodystrophy (MLD), known for many years as “diffuse brain sclerosis,” is an autosomal recessive disorder of myelin metabolism.^190,191 It is characterized by accumulation of cerebroside sulfate in the CNS and peripheral nerves. Late infantile, juvenile, and adult forms are recognized, based on the age of onset. Heterogeneity exists within each group. The MLD group of diseases also is classified according to the individual biochemical defect. The more common forms are associated with deficiency of arylsulfatase A. The enzyme is absent in all tissues.^192,193 This results in abnormal sulfatide metabolism with demyelination and storage of sulfatides in the central and peripheral nervous systems and increased excretion of sulfatides in the urine. The gene for arylsulfatase A maps to 22q13.31-qter.¹⁹⁴ The prevention of MLD mainly relies on identifying carriers in known MLD families and on providing genetic counseling, with the possibility of prenatal diagnosis.