Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

Chronic open-angle glaucoma in a child with MPS IH/S has been reported; ultrastructural changes consistent with mucopolysaccharide deposition were found in tissue obtained at trabeculectomy.180

Hunter’s Syndrome: MPS II

In Hunter’s syndrome, the only X-linked MPS, there is deficiency of iduronate sulfatase, with urinary excretion of dermatan sulfate and heparan sulfate. The gene for this defect has been mapped to Xq 28.186

Phenotypic manifestations of Hunter’s syndrome closely resemble those of Hurler syndrome, but are generally less severe, and Hunter’s syndrome is distinguished clinically by longer survival and the absence of gross corneal clouding. The features are coarse. Dwarfing and joint stiffness are prominent findings. There is usually hepatosplenomegaly; the abdomen is protruberant. Hernias are common. Cardiac involvement is a regular feature of MPS II, and respiratory disability is evident in most patients. Neurological manifestations vary. Spastic quadriplegia may develop from impingement on the cervical spinal cord. Hydrocephalus may develop. Mental deterioration may occur. Progressive deafness is common. Nodular or pebbly ivorycolored skin lesions are a distinctive feature of Hunter’s syndrome. Adults also tend to have a rosy or ruddy complexion.

Based on severity, Hunter’s syndrome can be classified into subtypes. Patients with the more severe form, type A, show more rapid neurological deterioration and usually die before age 15 years. The milder form, type B, is characterized by slower mental deterioration and is compatible with survival into the fifth or sixth decade.

The major ophthalmologic manifestation of MPS II is progressive retinal degeneration with impairment of vision.98 Fundus signs include retinal pigmentary changes, sometimes spicule formation, retinal arteriolar attenuation, and disc pallor. The ERG usually is reduced or extinguished.35,98 Bilateral epiretinal membranes with tortuosity of the retinal vessels have been reported as an unusual finding in siblings with type B Hunter’s syndrome.184

Swelling of the optic nervehead, attributed to increased intracranial pressure or mucopolysaccharide deposition in and around the optic nerve, and potentially leading to optic atrophy, is a frequent finding.16,54,236

Obvious corneal clouding is not a feature of Hunter’s syndrome. However, slight corneal changes may be detected by slit lamp examination in older patients, and histological and ultrastructural evidence of corneal mucopolysaccharide accumulation has been reported.262 In addition, clinically visible corneal opacities have been documented in a child with severe MPS II, and fine corneal opacities have been seen on slit lamp examination in a young patient with mild MPS II.249 Glaucoma has been reported in some patients with Hunter’s syndrome.133,249

Light and electron microscopic studies have documented widespread changes in the eye in both severe and mild forms of

MPS II.170,262

Sanfilippo’s Syndrome: MPS III

Four biochemically different but clinically indistinguishable forms of Sanfilippo’s syndrome occur: in type A there is deficiency of heparan N-sulfatase, the gene for which has been localized to 17q 25.3; in type B, deficiency of -N- acetylglucosaminidase, which has been localized to 17q 21; in type C, deficiency of acetyl-CoA: -glucosaminide-N- acetyltransferase; and in type D, deficiency of N–acetyl glucosamine 6-sulfatase, which has been localized to 12q 14.186 In all forms, there is urinary excretion of heparan sulfate.

Mental retardation, the predominant clinical manifestation of MPS III, usually becomes evident in the first 3 years of life. There is progressive deterioration of intellect and behavior with increasing age. Somatic abnormalities tend to be mild or inconspicuous. There is some coarseness of facial features. Synophrys is common. Generalized hirsutism may be marked. Dwarfing, joint stiffness, and claw-hand deformity are usually evident but not as severe as in Hurler syndrome. Slight to moderate hepatosplenomegaly develops. The abdomen tends to be protuberant. Respiratory problems are common. Heart involvement may occur. Hearing loss occurs in moderate to severely affected patients. Hydrocephalus may develop.

Corneal clouding is not a feature of MPS III, although fine opacities were noted on slit lamp examination in one of Sanfilippo’s patients, and histological and ultrastructural corneal and scleral changes have been reported in other cases.132,223

Retinal involvement and progressive vision loss may occur in MPS III. Narrowing of retinal vessels and pigmentary changes have been noted.35,98,155 Decreased ERG responses have been

recorded in type A and type B.35,98 Optic atrophy may develop.54 In addition, papilledema has been found in some cases.54 Corresponding histopathological and ultrastructural changes of the retina and optic nerve have been documented in type A and type B Sanfilippo’s syndrome.36,68,158 There is evidence for mucopolysaccharide accumulation in virtually every ocular

tissue.36,86,158

Morquio Syndrome: MPS IV

Clinically similar but enzymatically different forms of Morquio syndrome occur. In the classic form of Morquio syndrome, designated MPS IV-A, there is deficiency of N-acetylgalactosamine 6-sulfatase; the gene encoding this enzyme has been localized to chromosome 16q 24.3.186 In the later-onset variant of Morquio syndrome, designated MPS IV-B, there is deficiency of - galactosidase, which has been localized to chromosome 3p 21.33.186 Both mild and severe forms of MPS IV-A and MPS IV-B occur. There is excessive urinary excretion of keratan sulfate in all forms.

Morquio syndrome is characterized by severe dwarfism and skeletal deformity, often with neurological complications, and a number of extraskeletal abnormalities. Patients appear normal in the first months of life, although radiologic signs may be present. During the early years, abnormalities such as retarded growth, knock-knees, prominent joints, dorsal kyphosis, sternal bulging, flaring of the rib cage, and awkward gait become evident, and worsen with age. Joint stiffness, however, is not a feature; rather joints may be abnormally loose, causing instability. The face is abnormal with somewhat coarse features, a broad-mouthed appearance, prominent jaw, and widely spaced teeth. Aortic regurgitation may develop. Progressive hearing loss is common. Invariably there is absence or hypoplasia of the odontoid process and usually ligamentous laxity of the spinal column. Atlantoaxial subluxation and spinal cord and medullary compression are frequent complications; signs may range from minimal long-tract signs to spastic paraplegia, respiratory paralysis, and death. Intellect usually is normal or mildly impaired. The course is one of progressive incapacitation.

Corneal clouding is a feature of Morquio syndrome, occurring in both MPS IV-A and MPS IV-B.11,265,273 It is relatively mild, having the appearance of a fine haze. It may not become clinically evident to the unaided eye for several years, often not

before age 10 years. The slit lamp appearance is that of diffuse involvement of the stroma with punctate or granular opacities, usually with sparing of epithelium, Bowman’s layer, and endothelium. Histopathological and ultrastructural studies of the eye in Morquio syndrome have documented evidence of MPS accumulation in cornea, and also in conjunctiva and

sclera.11,97,130

Fundus abnormalities have been reported infrequently in Morquio syndrome. Optic atrophy has been noted.64 There has been mention of blurring of the discs.62 Narrowing of retinal arterioles and ERG changes have been documented.4,62 In most cases the fundi and ERG are normal.

Cataracts have been reported in siblings with MPS IV-A.196 Mesodermal anomalies have been described in one patient with MPS IV.273 Glaucoma may occur.30 In addition, mydriasis attributed to sympathetic involvement in Morquio syndrome has been noted.62

Maroteaux–Lamy Syndrome: MPS VI

In this MPS, there is deficiency of N-acetylgalactosamine-4- sulfatase, with urinary excretion of predominantly dermatan sulfate. The gene encoding this enzyme has been localized to chromosome 5q13–q14.186 Metachromatic granulation of circulating leukocytes is a characteristic finding in MPS VI. In addition to the classic severe form of Maroteaux–Lamy, milder variants with the same enzyme deficiency occur.

In the classic form of MPS VI, there is severe dwarfism. Growth retardation affecting both the trunk and limbs is usually evident by age 2 or 3 years. Genu valgum, lumbar kyphosis, and anterior sternal protrusion develop. The lower ribs are flared. Joint movement is restricted. Claw-hand deformity develops. Carpal tunnel syndrome is common. The head appears relatively large. Facial features tend to be coarse. There is often mild hypertrichosis. Hepatomegaly usually develops in patients older than 6 years, splenomegaly develops in many, and the abdomen usually is protruberant. Cardiac involvement, particularly valve lesions, may develop. Deafness occurs in some patients. The principal neurological manifestations are hydrocephalus and spinal cord compression from atlantoaxial subluxation consequent to hypoplasia of the odontoid process. Survival is variable; most patients with the severe form of MPS VI die by their second or third decade.

The principal ophthalmologic manifestation of MPS VI is progressive corneal clouding, usually evident within the first few years of life. The appearance is that of ground glass haziness throughout the stroma, sometimes more dense peripherally, and usually evident grossly.103,141 In addition to stromal opacities, some epithelial and endothelial changes may be seen on slit lamp examination.141 Corneal opacities have been found in the mild variant of MPS VI as well as in the severe form.198 A decrease in corneal clouding after bone marrow transplantation has been reported.154

Papilledema in association with hydrocephalus in MPS VI has been reported.54,103,236 Optic atrophy may develop.54 Retinal vessel tortuosity also has been noted.103 As a rule patients with MPS VI do not develop signs of retinal degeneration, and the ERG usually is normal.144,204 However, pigmentary alteration and ERG abnormalities have been reported in an adult with a mild form of MPS VI.73 Glaucoma has been described in several patients.32

The ocular pathology of MPS VI has been well documented.144,204

Sly Syndrome: MPS VII

In Sly syndrome, there is deficiency of -gluc-uronidase, with urinary excretion of both dermaten sulfate and heparin sulfate. The gene encoding -gluc-uronidase has been localized to chromosome 7q 21.11.186

A variable spectrum of clinical manifestations occurs, including short stature, progressive skeletal deformity and radiologic signs of dysostosis multiplex, coarse facial features, hypertelorism, hepatosplenomegaly, diastasis recti, protruberant abdomen, hernias, cardiovascular involvement and respiratory problems, and intellectual impairment. Coarse inclusions are found in circulating lymphocytes. A severe neonatal form associated with fetal hydrops has been described.

In many patients with Sly syndrome, the corneas are clear.66,233,242 With phenotypic variation, however, corneal clouding may occur; it may be evident grossly or only on slit lamp examination.15,271

Optic nerve swelling, without increased intracranial pressure or hydrocephalus, has been reported.54

THE GANGLIOSIDOSES

Gangliosides are sialic acid-containing glycosphingolipids normally present in neural and extraneural tissues throughout the body; they are found in highest concentration in gray matter of the brain. Defects in lysosomal degradation of gangliosides can result in abnormal accumulation of these lipids and related products in brain and other tissue, producing a spectrum of clinical manifestations. Two major types of ganglioside storage disease occur: GM1 and GM2 gangliosidoses (Table 7-2).109,257

The GM1 gangliosidoses are caused by deficiency of acid - galactosidase; the gene for this enzyme has been localized to chromosome 3p21.33.256 There is storage of GM1 ganglioside in the nervous system and abnormal accumulation of galactosecontaining oligosaccharide and keratan sulfate degradation products in somatic cells. Infantile, late infantile/juvenile and adult/chronic variants of GM1 gangliosidoses occur.257 The most familiar of these is the acute infantile form (GM1 type I), commonly referred to as generalized gangliosidosis. This disorder affects patients of various ethnic groups.257

The various GM2 gangliosidoses are due to a number of enzymatic variants; there may be deficiency of hexosaminidase A, deficiency of hexosaminidase A and B, or deficiency of the GM2 activator protein that is needed for degradation of GM2 by hexosaminidase A.109 There is an underlying defect in one of three genes: HEXA, which encodes the subunit of hexosaminidase A; HEXB, which encodes the -subunit of hexosaminidase A and B; or GM2 A, which encodes the GM2 activator.109 HEXA has been mapped to chromosome 15; HEXB and GM2 A have been mapped to chromosome 5.109 Phenotypic variability of the GM2 gangliosidoses ranges from infantile-onset rapidly progressive disease to later-onset subacute or chronic forms.109 The most familiar of the GM2 gangliosidoses is Tay–Sachs disease (GM2 type I). The incidence of Tay–Sachs disease has been reported to be highest in patients of Ashkenazic Jewish descent, but it does occur in other ethnic groups.109

The GM1 and GM2 gangliosidoses are autosomal recessive conditions.109,257 Diagnosis can be confirmed by enzyme assay of tissues, body fluids, and cells. The heterozygote state also can be detected by these methods. Prenatal diagnosis is possible by assay of cultured amniotic cells and chorionic villi. As yet there is no specific treatment, such as enzyme replacement or effective cell therapy, for the gangliosidoses.110,256

Usually slowly progressive with long-term survival

Generalized Gangliosidosis: Infantile

GM1 Gangliosidosis

In generalized gangliosidosis (GM1 type I), there is both neuronal lipidosis and visceral histiocytosis as a result of profound deficiency of acid -galactosidase. Manifestations can be evident at birth or appear in the early months of life. The disease is characterized by dysmorphism, prominent bony abnormalities, visceromegaly, and neurological degeneration in infancy.257 Signs include coarse facial features, frontal bossing, depressed nasal bridge, large low-set ears, gingival hypertrophy and macroglossia, and hirsutism of the forehead and neck. There may be edema of the extremities. Hepatomegaly usually develops within the first months of life. Dorsolumbar kyphoscoliosis is common. The hands are broad, the fingers short. Joint contractures develop. Firm nontender enlargement of the epiphyseal joints occurs. Radiologic findings are those of dysostosis multiplex, with deformities of vertebral bodies and long bones. Seizures commonly develop. There is rapidly progressive neurological deterioration, often to a state of decerebrate rigidity, spastic quadriplegia, blindness, deafness, and unresponsiveness. Death usually occurs by age 2 years.

Macular cherry-red spots occur in approximately 50% of patients with generalized gangliosidosis (Table 7-3).193 There may be tortuosity of retinal vessels, retinal hemorrhages, and optic atrophy.82 The cornea usually is clear, but mild diffuse corneal clouding has been documented in some cases.82,281 Histopathological evidence for ganglioside accumulation in the retina and mucopolysaccharide accumulation in the cornea has been well documented.50,82 Loss of vision occurs.193 Strabismus and nystagmus are common.193 Tortuosity and saccular microaneurysms of conjunctival vessels have been noted in some cases.23

Late Infantile/Juvenile GM1 Gangliosidosis

In late infantile/juvenile GM1 gangliosidosis (GM1 type 2), as in the infantile form (GM1 type 1), there is deficiency of -galac- tosidase.257 The onset, however, is later, the course is slower, and skeletal abnormalities are milder; in most cases there is no dysmorphism or visceromegaly. Neurological manifestations usually appear by age 1 year or so. Common early signs are generalized weakness, locomotor ataxia, strabismus, and loss of

TABLE 7-3. Cherry-Red Spot and Related Macular Signs in Metabolic

Disorders.

Gangliosidoses

Infantile GM1 gangliosidosis: generalized gangliosidosis Classic cherry-red spot in 50% of cases

Late infantile/juvenile GM1 gangliosidosis Atypical cherry-red spot a rare finding

Acute infantile GM2 gangliosidosis: Tay–Sachs disease and Sandhoff variant Classic cherry-red spot in most cases.

Subacute GM2 gangliosidosis

Cherry-red spot or diminished foveal light reflex Niemann–Pick Disease

Type A: sphingomyelin lipidosis

Cherry-red spot in many cases, often extension of retinal haze beyond macula

Type B: sphingomyelin lipidosis

Macula halo syndrome; infrequently a cherry-red spot Type C: cholesterol lipidosis

Cherry-red-like spot in some cases Gaucher’s Disease

Type 3: subacute neuronopathic form Macular grayness in some cases

Metachromatic leukodystrophy Infantile form

Macular grayness; cherry-red-like spot in some cases Krabbe’s Disease

Infantile onset variant Cherry-red-like spot

Farber disease

Macular grayness or cherry-red-like spot in some cases Sialidosis

Type I and Type II Cherry-red spot

Galactosialidosis Cherry-red spot

Neuronal ceroid lipofuscinosis Juvenile form: Spielmeyer–Sjögren

Bull’s-eye maculopathy Fucosidosis

Bull’s-eye maculopathy

speech. Progressive mental and motor deterioration, spasticity, seizures, and in time decerebrate rigidity follow. Recurrent infections, particularly bronchopneumonia, are common. The life span usually is only 3 to 10 years.

Ocular abnormalities, particularly cherry-red spots, are not a feature of infantile/juvenile GM1 gangliosidosis. Atypical cherry-red spots, however, have been described in one case.260 Disc pallor has been noted.101,256 In another case, microscopic and

ultrastructural signs of lysosomal storage in the retina in the absence of clinically evident cherry-red spots were reported, and atrophic changes of the optic nerve were documented.101 Loss of vision can occur late in the course of the disease.194

Adult/Chronic GM1 Gangliosidosis

Patients with -galactosidase deficiency classified as having adult/chronic GM1 gangliosidosis (GM1 type 3) have a protracted course, with variable age of onset, ranging from childhood to adulthood.257 Dystonia and progressive pyramidal or extrapyramidal disease are the principal neurological manifestations. Intellectual deterioration is not remarkable. Dysmorphism is not obvious. Slight vertebral changes are described. Visceromegaly is not observed.

Ocular abnormalities are not a feature of chronic GM1 gangliosidosis. Corneal clouding has been reported in some cases.256

Tay–Sachs Disease: Acute Infantile

GM2 Gangliosidosis

In Tay–Sachs disease (GM2 type I), there is nearly total deficiency of hexosaminidase A, leading to abnormal accumulation of ganglioside GM2.107 Pathological changes of lipidosis are seen throughout the nervous system. Neurons become distended. Axonal degeneration, demyelination, and gliosis occur. Visceral changes, however, are not a feature of this disorder.

Clinical manifestations appear in infancy, often insidiously with listlessness, hypotonia, feeding difficulties, or irritability. The startle reaction, an extensor response to sudden sharp sound, is a characteristic early sign. Psychomotor development is retarded. Increasing weakness and decreasing attentiveness become evident in the early months. After age 18 months, spasticity and seizures develop. There is progressive deterioration to a state of decerebrate rigidity, deafness, and blindness. Death usually occurs by age 3 to 4 years.

Many affected patients have a doll-like facial appearance with pale translucent skin, delicate pink coloring, fine hair, and long eyelashes.

Macular cherry-red spots develop in virtually all cases of Tay–Sachs disease.109 This characteristic finding was first described by the British ophthalmologist Warren Tay in 1881.261 With accumulation of lipid, there is loss of transparency of the