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

multilayered macular ganglion cells, producing a creamy-white, yellow, or hazy gray halo around the fovea, accentuating the red blush of the ganglion cell-free central region (Fig. 7-5A).119 The macular haze is usually evident by the time other neurological signs appear in infancy. The distinctive features of a cherry-red spot may fade as ganglion cell destruction progresses (Fig. 7- 5B).150 Pathological changes in the retina are similar to those in the brain; there is lipid loading and degeneration of ganglion cells, and the presence of membranous cytoplasmic inclusions has been documented.6,47,49,119 Deficiency of hexosaminidase A in the retina and optic nerve has been reported.57 There is demyelination and degeneration of the optic nerves, chiasm, and tracts.47 Optic atrophy is often clinically evident. Progressive loss of vision is common early; blindness is usually complete by age 2 years.109 VEP responses are altered early, whereas the ERG is not affected until late in the course of the disease.109 There may be deterioration of eye movements.131 The enzyme defect can be detected in tears, a finding potentially useful in diagnosis and heterozygote detection.34,239

Sandhoff Variant of Infantile GM2 Gangliosidosis

In this variant of Tay–Sachs disease, there is severe deficiency of both hexosaminidase A and hexosaminidase B activity, with neuronal lipidosis of GM2, and some visceral accumulation of a globoside, due to HEXB mutation.109 The clinical features of Sandhoff disease are like those of Tay–Sachs.

The principal ophthalmologic manifestations of Sandhoff disease are macular cherry-red spot, optic atrophy, and progressive vision loss leading to blindness.194 Evidence of ganglioside storage in the retina and optic nerve has been documented by histopathological and ultrastructural examination.27,75,96,189,263 Storage cytosomes also have been found in corneal keratocytes.27,263 The corneas usually are clear clinically, but in one case appeared slightly opalescent.263

Subacute GM2 Gangliosidosis

Patients with later-onset (late infantile or juvenile) subacute forms of GM2 gangliosidosis may have HEXA or HEXB mutations.109 The pathological findings are those of neuronal lipidosis with abnormal storage of GM2; cytoplasmic inclusions like those of Tay–Sachs disease and other inclusions called pleo-

morphic lamellar bodies are present. Clinical signs generally appear between 2 and 10 years of age. Ataxia and incoordination develop. There is progressive psychomotor deterioration, with increasing spasticity and development of seizures in the first decade, leading to a vegetative state with decerebrate rigidity and death within a few years, often due to intercurrent infection.

Ophthalmologic signs vary somewhat from those of the infantile onset GM2 gangliosidoses. Vision loss occurs later in the subacute form.24,109,173 Macular cherry-red spot may develop but is not a consistent feature.24 Pigmentary retinal changes may develop.24,194 Optic atrophy develops in some cases.24,173 There may be strabismus.24

Chronic GM2 Gangliosidosis

The spectrum of later-onset, more slowly progressive or chronic forms of GM2 gangliosidosis includes a variety of clinical presentations, reflecting predominant involvement of one or another part of the central nervous system.109 Patients may exhibit primarily dystonia; signs of spinocerebellar degeneration; motor neuron disease; or psychiatric abnormalities. Onset may range from childhood to adulthood. These chronic forms generally are compatible with long-term survival.

Vision is rarely affected and the fundi usually are normal, but abnormalities of eye movement occur.182,210 These problems include impairment of convergence, loss of optokinetic nystagmus, and vestibular nystagmus.210 Defects of horizontal smooth pursuit movements, varying defects in vertical gaze (hypometric and hypermetric saccades), and inability to suppress the vestibulo-ocular reflex by fixation have been documented.182

The chronic variants of GM2 gangliosidosis are more commonly caused by hexosaminidase A deficiency (HEXA mutations) then by combined hexosaminidase A and B deficiency (HEXB mutations); GM2 activator defects in this group are rare.109

METACHROMATIC LEUKODYSTROPHY

Melachromic leukodystrophy is an inherited disorder of myelin metabolism characterized by lysosomal accumulation of glycolipids, predominantly sulfatides, in white matter of the central nervous system and in peripheral nerves, with progressive

degeneration of myelin and progressive deterioration of mental and motor function.151 In histological preparation, the accumulated lipid granules exhibit metachromasia, giving rise to the descriptive term metachromatic leukodystrophy (MLD).

Based on variation in clinical and biochemical features, several forms of MLD are described (Table 7-4).151 Most common is the late infantile form. Presenting by age 1 to 2 years, this form is characterized by relatively rapid deterioration, leading to death within 1 to 7 years. Major manifestations are deveopmental retardation and regression, generalized weakness, ataxia, progressive spastic quadriparesis, and bulbar and pseudobulbar palsies. Optic atrophy is common, often developing as the disease progresses.51,53,166,230 There may be grayness of the macular region, in some cases a cherry-red-like spot.51,166 Progressive loss of vision and impairment of the pupillary response to light have been documented.166,230 VEP changes can be detected as the disease progresses.69 Strabismus and nystagmus may develop.51,166,230

Histopathological and ultrastructural studies of the eye in late infantile MLD have documented atrophy of the optic nerve

TABLE 7-4. Forms of Metachromatic Leukodystrophy (MLD).

and degeneration of the myelin sheaths, with accumulation of metachromatic material between nerve fibers and the presence of inclusions in glial cells51,53,99,166,230; the presence of metachromatic material and a variety of cytoplasmic inclusions within the retinal ganglion cells and other retinal layers51,53,99,166,230; vacuolization of nonpigmented epithelial cells of the ciliary body and accumulation of metachromatic material in Schwann cells of the ciliary nerves166; and the presence of inclusions within corneal epithelial and endothelial cells, in keratocytes, lens fibers and epithelial cells, trabecular meshwork, and peripheral iris macrophages.230

The juvenile form presents usually by age 4 to 6 years, sometimes later. The course tends to be protracted, lasting 20 years or more, but some patients do not live beyond their teens. Early signs include decline in school performance, confusion, abnormal behavior, clumsiness, and incontinence. Progressive ataxia, spasticity, pseudobulbar palsy, and seizures develop. Optic atrophy is common.166 The pupillary response to light may be diminished.166 Macular changes have not been documented.166 Histopathological and ultrastructural study of the eye in juvenile MLD has documented degeneration of the optic nerve and myelin sheaths and alteration of the ciliary nerves as in the late infantile form, and some depletion of retinal ganglion cells, but no evidence of abnormal retinal ganglion cell storage.166

Adult-onset MLD can manifest in the teens, twenties, thirties, or later. This form is characterized by progressive mental deterioration, progressive pyramidal and extrapyramidal signs, and in some cases seizures. Optic atrophy and nystagmus can develop, and in time vision may decrease.102,203 Studies of the eye by light and electron microscopy in the adult form of MLD have shown loss of optic nerve axons and myelin sheaths and the presence of inclusions in glial cells of the optic nerve,203 loss of retinal ganglion cells and retinal nerve fibers,203 and the presence of membranous lysosomal residual bodies in retinal ganglion cells.102

In the late infantile, juvenile, and adult forms of MLD, there is profound deficiency of arylsulfatase A, the heat-labile component of cerebroside sulfate sulfatase.151 Galactosyl sulfatide (cebroside sulfate), a constituent of myelin and cellular membranes, accumulates in the central and peripheral nervous system. Galactosyl sulfatide, and to a lesser extent lactosyl sulfatide, also accumulate in kidney, gallbladder, and other organs

and are excreted in excessive amounts in urine. The arylsulfatase A gene has been mapped to the long arm of chromosome 22 band q13.272 A number of disease-related mutations have been identified.

Several patients having many features of juvenile MLD, including sulfatiduria, but having normal arylsulfatase activity have been described. These patients have deficiency of the cebroside activator protein, saposin B, necessary in the hydrolysis of sulfatide.151

The classification of MLD also includes a rare variant resembling the infantile form, but having in addition features of mucopolysaccharidosis, including coarse facies, deafness, hepatosplenomegaly, skeletal abnormalities, and mucopolysacchariduria. In this variant, at least nine different sulfatases are deficient.151 The condition is referred to as mucosulfatidosis or multiple sulfatase deficiency (MSD). Ocular manifestations in this variant include degenerative retinal pigmentary changes, macular grayness, optic atrophy and vision loss, strabismus, nystagmus, and other abnormal eye movements.14,51,113,117,166,212 Corneal clouding has been reported but is uncommon.51,268 Circumferential opacities of the peripheral anterior lens capsule have been noted.14 ERG and VEP abnormalities have been documented.14,117,212

Light and electron microscopic study of the eye in MSD has shown partial demyelination of the optic nerve; accumulation of metachromatic material in the interstices of the optic nerve fibers, mostly within macrophages; similar changes of ciliary nerves; accumulation of metachromatic material in retinal ganglion cells; and the presence of numerous inclusions within retinal ganglion cells.51

All forms of MLD are autosomal recessive.151 In the major forms, heterozygotes can be identified by assay of leukocytes or cultured skin fibroblasts for arylsulfatase or cebroside sulfate sulfatase activity, and prenatal diagnosis can be made by enzyme assay of cultured amniotic fluid cells or chorionic villus cells. Arylsulfatase deficiency also can be detected in tears.166

As yet there is no effective specific treatment for MLD. Vigabatrin, an inhibitor of GABA-aminotransferase, can be used to reduce spasticity and ataxia in children, but the drug does not alter the progression of the disease process. The possible benefits of bone marrow transplantation and gene replacement therapy are being investigated.272

NIEMANN–PICK DISEASE

The term Niemann–Pick disease (NPD) describes a group of biochemically and clinically distinct lipid storage disorders characterized by abnormal accumulation of predominantly sphingomyelin and cholesterol, the presence of foamy histiocytes in affected tissues and organs, and a broad spectrum of visceral and neurological manifestations.228 The current classification includes two primary sphingomyelin lipidoses, designated NPD types A and B, and a cholesterol lipidosis, designated NPD type C (see Table 7-3).

Types A and B Niemann–Pick Disease

In types A and B NPD, there is deficiency of acid sphingomyelinase, a hydrolase important in metabolic degradation of sphingomyelin; this phospholipid is a common constituent of plasma membranes, subcellular organelles, endoplasmic reticulum, and mitochondria and a major lipid of myelin sheaths and erythrocyte stroma.228 The enzyme defect leads to lysosomal accumulation of sphingomyelin, cholesterol, and other metabolically related lipids throughout the body.

The histopathological hallmark of NPD types A and B is a large lipid-laden foam cell referred to as the Niemann–Pick cell, found particularly in tissues and organs of the monocytemacrophage system. In types A and B NPD there is infiltration of spleen and lymph nodes, marrow, liver, lung and kidney; endocrine glands and heart also may be affected. In addition, neuronal lipidosis occurs in type A, but not in type B.

Clinically type A NPD is characterized by failure to thrive, hepatosplenomegaly, and rapidly progressive neurological deterioration and debilitation in infancy, leading to death by age 2 to 3 years. Type B is characterized primarily by hepatosplenomegaly in childhood with little or no neurological involvement, and survival into adulthood. Progressive pulmonary infiltration can be a major problem in more severely affected type B patients.

Ocular manifestations are more frequent in type A NPD than in type B. Macular cherry-red spots occur in up to 50% of patients with type A58,228,276; a distinguishing feature in many cases is extension of retinal haze far beyond the parafoveal region. Cherry-red spots are infrequent in type B, but a distinctive “macula halo syndrome” has been described; this is char-

acterized by a ring of crystalloid or granular opacities around the fovea, sometimes haziness of the macula.43,86,169,248 Mild corneal haze and fine lens deposits may be clinically evident in patients with type A NPD.86 In addition, periorbital fullness has been noted in patients with type B NPD.86 Vision loss occurs late in the course of type A NPD; the retinal changes in type B are not usually associated with vision loss.43

Evidence of widespread lipid storage in the eye has been well documented by light and electron microscopy in type A NPD.107,127,157,165,215 Granular cytoplasmic birefringence has been demonstrated in keratocytes, corneal endothelial and epithelial cells, and sclerocytes; in lens epithelium; in nonpigmented ciliary epithelium, fibrocytes of choroid, and endothelial cells of ciliary, choroidal, and retinal vessels; and in retinal ganglion cells, plexiform and nerve fiber layers, and retinal pigmented epithelium. Membranous cytoplasmic inclusion have been found in similar distribution, particularly in retinal ganglion cells and axons.

The inheritance of types A and B NPD is autosomal recessive. Type A NPD is more frequent in Ashkenazic Jews. The acid sphingomyelinase gene has been mapped to chromosome region 11p 15.1–p 15.4229; 18 mutations have been identified that cause types A and B NPD. Diagnosis is confirmed by assay of sphingomyelinase activity in cells and tissue extracts. Heterozygote detection requires molecular studies. Prenatal diagnosis by enzymatic or molecular assay of cultured amniocytes or chorionic villus cells is possible. As yet there is no effective specific treatment for NPD types A and B, although enzyme replacement and gene therapy have been under investigation.229

Type C Niemann–Pick Disease

This form of NPD is distinguished by a unique cellular disorder of cholesterol processing associated with abnormal lysosomal accumulation of unesterified cholesterol and other lipids.200 The underlying molecular defect has not yet been defined. The pathological features are those of visceral and neuronal storage; characteristic inclusion-laden histiocytes referred to as foam cells and sea-blue histiocytes are found in affected tissues and organs.

Clinical manifestations of type C NPD vary. The “classic” phenotype is characterized by progressive dementia, ataxia, dystonia, gaze paresis, and hepatosplenomegaly. Manifestations appear in late childhood. There is gradual worsening of physical

and intellectual disabilities, eventually leading to incapacitation. Death occurs in the teens. Other type C NPD presentations include self-limited or rapidly fatal liver disease in the newborn, hypotonia and delayed motor development in infancy, and late-onset variants with progressive neurological deterioration and cognitive and psychiatric disturbances in adolescents and adults.

The ophthalmologic hallmark of type C NPD is progressive supranuclear vertical gaze palsy.45,58,111,187,190 There may be associated blinking or head thrusting on attempted upward or downward gaze. Horizontal gaze movements and convergence also may be affected. Macular cherry-red-like spots occasionally occur in type C NPD.81,174 VEP abnormalities have been noted in type C NPD.122 Electron microscopic examination of the eye from a child with presumed type C NPD demonstrated intracytoplasmic inclusions in conjunctival cells, keratocytes, lens epithelium, nonpigmented ciliary epithelium, retinal ganglion cells, choroidal fibrocytes, and optic nerve astrocytes,197 whereas there was no evidence of intraocular lipid storage in another well-studied case.81 Conjunctival inclusions, however, have been found in other patients with type C NPD.163,174

The inheritance of type C NPD is autosomal recessive. Linkage of type C to an 18p genomic marker, D 185 40, has been found in some patients.199 Diagnosis of type C NPD requires demonstration of abnormal intracellular cholesterol esterification and documentation of intralysosomal accumulation of unesterified cholesterol. Generalized screening for type C is not yet available. Prenatal diagnosis is possible in some cases. Currently there is no specific treatment for type C NPD.199 Symptomatic treatment of seizures, dystonia, and catoplexy may be helpful.

Type C NPD is panethnic, but genetic isolates have been described in the French Acadians of Nova Scotia (formally NPD type D) and in Spanish Americans in southern Colorado.200

GAUCHER’S DISEASE

Gaucher’s disease a lysosomal storage disease in which there is abnormal accumulation of glucosylceramide (glucocerebroside), primarily in cells of the reticuloendothelial system. The underlying defect is impaired intracellular hydrolysis of the glycolipid glucosylceramide and related glucosphingolipids due to defi-

ciency of -glucosidase (glucocerebrosidase).19 The gene encoding this enzyme has been localized to chromosome 1.19 A variety of mutations have been found to cause Gaucher’s disease.

A hallmark of the disease is the presence of distinctive lipidladen cells of the monocyte-macrophage system throughout the body; these so-called Gaucher cells are distinguished by cytoplasmic inclusions having a twisted tubular appearance.19 The condition affects predominantly spleen, liver, and bone marrow, and in certain forms of the disease, the nervous system. Many patients develop ocular manifestations. Based on clinical variation, three major forms of Gaucher’s disease are described: a chronic nonneuronopathic form, type 1; an acute neuronopathic form, type 2; and a subacute neuronopathic form, type 3 (Table 7-5).20 All forms are autosomal recessive. The disease is paneth-

TABLE 7-5. Forms of Gaucher’s Disease.

Type 1: Nonneuronopathic form

•Visceral and skeletal involvement without primary neurological involvement

•Onset in childhood or adulthood

•Broad spectrum of severity

•Ocular lesions resembling pingueculae in some patients

•Ashkenazi Jewish predilection

Type 2: Acute neuronopathic form

•Severe neurological involvement, extensive visceral and skeletal involvement

•Paralytic strabismus, conjugate gaze impairment

•Infantile onset, early death

•Panethnic

Type 3: Subacute neuronopathic form

•Neuronopathic involvement of later onset, more gradual progression, and lesser severity than type 2

•Usually visceral involvement

•Three subtypes:

3a

Progressive neurological disease dominated by myoclonus and dementia Of Northern Swedish predilection

3b

Aggressive visceral and skeletal disease

Neurological manifestations largely limited to horizontal supranuclear gaze palsy

Panethnic 3c

Neurological manifestations largely limited to horizontal supranuclear gaze palsy

Cardiac valve calcifications and corneal opacities Generally little visceral involvement

Panethnic