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

nic, but type 1 is more frequent in Ashkenazic Jews. Estimates of the disease incidence vary widely.

Diagnosis can be made by demonstration of Gaucher cells in marrow aspirates, by measurement of glucosylceramide in tissue samples, and by measurement of -glucosidase activity in leukocyte or cultured skin fibroblasts of affected patients. Heterozygotes can be identified by enzyme assay, and prenatal detection is possible by amniocentesis.19

A variety of treatment modalities, including splenectomy, can be helpful. Accumulation of glucosylceramide and the associated clinical manifestations can be reversed by repeated infusions of modified -glucosidase (alglucerase).19 Results of bone marrow transplantation have been encouraging in some cases.19

Type 1 Gaucher’s Disease: Chronic

Nonneuronopathic Form

This form is characterized primarily by visceral and skeletal involvement.19 Age of onset and severity vary widely. Manifestations may appear in childhood or in the adult years. The course may be rapid, slowly progressive, or protracted. The initial sign usually is splenomegaly; frequently there is hypersplenism with thrombocytopenia, anemia, and leukopenia. There may be hepatomegaly; there can be evidence of hepatic dysfunction. Osteoporotic erosions, aseptic necrosis of the femoral head, vertebral collapse, and pathological fractures of long bones are common. Patients may suffer episodic bone pain, sometimes accompanied by fever. Pulmonary hypertension and cor pulmonale may develop. Also, pulmonary involvement can predispose to pneumonia, a major cause of death in young patients. In older patients, yellowish pallor or yellow-brown pigmentation of the skin of the face and lower extremities may be noted. Primary neurological manifestations are not a feature of type 1 Gaucher’s disease, but secondary neurological signs due to vertebral collapse, fat emboli, and coagulopathy may develop. There is an increased incidence of neoplastic disease in this disorder.19

Ocular lesions resembling pingueculae have been noted in patients with type 1 Gaucher’s disease.33,77,201 These lesions are described as yellow or brownish triangular areas of infiltration and thickening of the bulbar conjunctiva adjacent to the limbus nasally and temporally. Although some lesions have been reported to contain foamy histiocytes, other studies have not confirmed the presence of Gaucher cells.33,42,77 Gaucher cells

have been found in choroid.201 Occasional reference has been made to macular or perimacular abnormalities.46,201 Progressive retinal degeneration with optic atrophy and vision loss has been reported in an adult.171 Retinal hemorrhages and retinal edema may occur.33 Impairment of eye movements in association with seizures and mental deterioration has been reported in adult siblings,175 although neurological involvement characteristically does not occur in type 1 Gaucher’s disease.

Type 2 Gaucher’s Disease: Acute

Neuronopathic Form

Also referred to as the classic, infantile, or cerebral form, type 2 Gaucher’s disease is characterized by severe neurological involvement and extensive visceral involvement.19 The average age of onset is 3 months, with a range from birth to 18 months. Hepatosplenomegaly is an early presenting feature. Neurological manifestations develop within a few months, usually by age 6 months. Most patients show signs of cranial nerve and extrapyramidal tract involvement. The triad of trismus, strabismus, and retroflexion of the head is classic. Feeding problems and difficulty handling secretions are common. Progressive spasticity, hyperreflexia, and pathological reflexes develop. Seizures may occur. Osseous lesions may develop. The course is rapidly progressive. Death occurs early, often between age 1 month and 2 years, usually as the result of pulmonary infection or anoxia.

The principal ocular manifestation of type 2 Gaucher’s disease is paralytic strabismus due to cranial nerve involvement.19 Progressive impairment of conjugate movements has been noted.45,112 The report of keratoconus in a family with Gaucher’s disease is of interest.219

Type 3 Gaucher’s Disease: Subacute

Neuronopathic Form

In this form, sometimes referred to as the juvenile form, neurological involvement is of later onset than in type 2 and the course is more chronic.19 There is usually marked visceral involvement; hepatosplenomegaly occurs as in types 1 and 2. Major neurologic manifestations are spasticity, ataxia, retardation, and seizures. An important neuro-ophthalmic manifestation is progressive disorder of horizontal gaze.45,264 The signs may simulate those of congenital ocular motor apraxia, including

impairment of voluntary horizontal saccades with retention of slow pursuit movements, compensatory head thrusting, and contraversive deviation of the eyes during rotation of the body. In some patients with type 3 Gaucher’s disease, ocular motor abnormalities are the primary or only neurological manifestations of the disorder.237

Retinal abnormalities also may occur. Multiple small white spots situated superficially in the retina or on the surface of the retina in the posterior region of the fundus have been described,44,216 and histopathological changes also have been documented.44,216 Cherry-red spots are not a feature of Gaucher’s disease, but grayness of the macular region has been noted.44 Discrete stromal opacities of the cornea have been reported in some patients who may have had a variant of type 3 Gaucher’s disease.5,83,267 Myopia is a finding in many patients with Gaucher’s disease.84

KRABBE’S DISEASE

Also referred to as globoid cell leukodystrophy, Krabbe’s disease is a rare metabolic neurodegenerative disease that affects predominantly white matter, leading to rapidly progressive mental and motor deterioration and early death. The underlying defect is profound deficiency of galactosylceramidase (galactocerebrosidase- -galactosidase); this enzyme normally catalyzes degradation of galactosylceramide (galactocerebroside), a sphingolipid involved in myelination.258 A number of related galactolipids including galactosylsphingosine (psychosine) also are substrates for this enzyme, and it is postulated that accumulation of a toxic metabolite (psychosine) leads to destruction of oligodendroglia, the cells that produce myelin. Characteristically there is widespread loss of myelin and oligodendrocytes, and degeneration of axons and severe gliosis in the brain; spinal cord and peripheral nerves also are affected. The histopathological hallmark of he disease is the presence of distinctive multinucleated macrophages that contain undegraded galactosylceramide; these are referred to as globoid cells.

Clinical manifestations usually appear by age 3 to 6 months, sometimes later in infancy, childhood, or even adulthood. The clinical course of classic infantile-onset Krabbe’s disease is often described as occurring in three stages.258 The early stage is characterized by irritability, hypersensitivity to external stimuli, and

some stiffness of the limbs; episodic fevers of unknown etiology, feeding difficulties, vomiting, and seizures may develop, and slight retardation or regression of psychomotor development may be evident. The next stage is characterized by rapidly progressive mental and motor deterioration, hypertonicity, hyperreflexia, and seizures. In the final or “burnt-out stage,” the infant is decerebrate, often blind and deaf. The final stage may last years, but affected infants rarely survive beyond 2 years.

The major ophthalmologic manifestations of Krabbe’s disease are optic atrophy, attendant impairment of the pupillary reaction to light, and progressive loss of vision, leading to blindness.258 Loss of the foveal reflex may be evident.84,255 In addition, subtle cherry-red-like macular changes have been reported in a child with an unusual variant of Krabbe’s disease.183 Histopathological and ultrastructural studies of the optic nerve have shown loss of axons, loss of myelin, gliosis, and the presence of globoid cells.26,84,118 Degenerative changes of the retinal nerve fibers and ganglion cell layers also have been well documented.26,84,118 Some patients with Krabbe’s disease may exhibit an abnormality of saccadic eye movements resembling ocular motor apraxia.120

The inheritance of Krabbe’s disease is autosomal recessive. Diagnosis is confirmed by assay of galactosylceramidase activity in leukocytes or cultured fibroblasts. Carriers also can be detected by enzyme assay, and prenatal diagnosis is possible by enzyme assay of amniotic fluid cells or chorionic villi.258 The galactosylceramidase gene has been mapped to chromosome 14.258

Bone marrow transplantation offers some hope in the treatment of Krabbe’s disease.279

FABRY’S DISEASE

Also referred to as angiokeratoma corporis diffusum universale, Fabry’s disease is characterized by angiectatic lesions of the skin, cerebrovascular abnormalities, peripheral neuropathy, and autonomic symptoms related to lipid deposits throughout the body.70 Vascular lesions of the eye and distinctive opacities of the cornea and lens are important signs of the disease.

This disease is an X-linked disorder of glycosphingolipid catalolism resulting from deficient activity of the lysosomal hydrolase, -galactosidase A.70 There is profound deficiency of enzymatic activity in the plasma and tissues of affected hem-

izygous males, and partial deficiency in heterozygous females, resulting in progressive systemic accumulation of neutral glycosphingolipids with terminal -galactosyl moieties, predominantly trihexosylceramide (globotriaosylceramide), and to a lesser degree, galabiosylceramide and blood group B substances in most tissues, organs, and fluids of the body.70 Birefringent lipid crystals are found in the lysosomes of blood vessels; in reticuloendothelial, connective tissue, and myocardial cells; and in epithelial cells of kidney, the adrenal glands, and eye. Lipid also accumulates in ganglion cells of the brain and peripheral nervous system and in peripheral cells of the autonomic system. Vascular changes are prominent throughout the nervous system.

Clinical manifestations of Fabry’s disease usually develop during childhood or adolescence in hemizygous males; heterozygous females can be asymptomatic or show attenuated manifestations of the disease.

Characteristic flat or elevated angiectatic lesions of the skin, referred to as angiokeratomas, develop early and increase in size and number with age. The lesions tend to be most numerous between the umbilicus and knees. Mucosal areas, particularly the oral mucosa and conjunctiva, are commonly involved. Paroxysmal episodes of severe burning pain in the extremities are typical; crises may last minutes to days, and may be accompanied by low-grade fever. Patients may also experience parasthesias of the hands and feet. Hypohidrosis is common. With increasing age there is progressive involvement of the cardiovascular and renal systems. Angina, myocardial infarction, arrhythmias, valvular disease, cardiac enlargement, and heart failure may develop. Albuminuria, uremia, and systemic hypertension are common. Cerebrovascular complications including aneurysms, thromboses, and hemorrhage are frequent; patients may develop seizures, hemiplegia, aphasia, and personality or behavioral changes. Death usually occurs in adult life from renal failure or cardiovascular or cerebrovascular complications.

Distinctive corneal opacities resulting from accumulation of lipid in the epithelial cells are the ocular hallmark of Fabry’s disease.91,167,234,244 They are seen in almost all affected males and in many carrier females and may develop early in childhood or in infancy. On slit lamp examination, the typical appearance is that of a fine stippling of intra-or subepithelial opacities arranged in a whorl-like pattern of radiating lines, often more prominent inferiorly. The opacities may appear brownish, tan, or cream colored. The opacities do not seem to interfere with vision.

388 HANDBOOK OF PEDIATRIC EYE AND SYSTEMIC DISEASE

Lens changes also occur in Fabry’s disease. Granular anterior capsular or subcapsular opacities arranged in a radiating wedge-shaped or “propeller” pattern may be seen in affected males.91,234 In addition, fine whitish opacities arranged in a linear spokelike pattern on or near the posterior lens capsule may be seen in affected males and in some carrier females.91,234,244

Numerous ocular signs of vascular involvement occur in Fabry’s disease. Some patients develop orbital and lid edema.91,234,244 In the conjunctiva, aneurysmal dilatation, vessel tortuosity, sludging, and telangiectasis are common.91,234,244 In the retina one may see tortuosity and segmental dilatation of retinal vessels.91,234,244 There may be retinal edema, retinovascular signs of systemic hypertension, and in some patients papilledema.91,244 Central retinal artery occlusion can occur as a severe complication of the disease.234,235 Central retinal artery occlusion and ischemic neuropathy have been documented in female carriers as well as in males with Fabry’s disease.3,8 Internuclear ophthalmoplegia, presumably related to cerebrovascular involvement, has been reported.123 Other neuro-ophthalmic manifestations such as nystagmus, ocular motor palsy, and strabismus also have been documented.91 Optic atrophy has been noted in some cases.234

Pathological examination of the eye by light and electron microscopy and by histochemical study in Fabry’s disease has documented accumulation of lipid material primarily within smooth muscle cells in the media of arterioles in choroid, retina, ciliary body, iris, limbus, and conjunctiva; similar deposits in endothelial cells and pericytes of small vessels and capillaries throughout the choroid, ciliary body, and iris; and in the basal cell layers of corneal epithelium, in the pigmented epithelium of the iris, and in the epithelium of the lens.89 On light and electron microscopic examination of the eye of a female carrier, the whorl-like corneal lesion was found to consist of a series of subepithelial ridges composed of bands of reduplicated basement membrane and deposits of amorphous material between the basement membrane and Bowman’s membrane, with intracellular deposits in the corneal epithelium above the ridges.280 The demonstration of lipid inclusions by conjunctival biopsy can be useful in the diagnosis of the disease and the carrier state.164

The diagnosis of Fabry disease is confirmed by demonstration of deficient -galactosidase A activity in plasma, leukocytes, or tears, or increased levels of globotriosylceramide

in plasma or urinary sediment.67,70,164 Heterozygote detection and prenatal diagnosis are possible.70 The gene encoding - galactosidase A has been localized to the X-chromosomal region Xq22.70

Management of Fabry’s disease includes the use of medication for pain and discomfort, anticoagulants for stroke-prone patients, and renal dialysis and transplantation for end-stage renal disease. Enzyme replacement therapy is being investigated.71

FARBER DISEASE

The familiar descriptive term for Farber disease is disseminated lipogranulomatosis. The disorder is characterized by accumulation of lipid-laden macrophages and granuloma formations in many organs and tissues.177 There is usually prominent involvement of periarticular tissues, skin, and larynx, with variable involvement of lung, heart, liver, spleen, lymph nodes, and other sites. Painful and progressive joint deformity, subcutaneous nodules, and progressive hoarseness are major manifestations of the disease. There also may be signs of neuronal lipid storage.

The underlying defect is deficiency of lysosomal acid ceramidase leading to accumulation of ceramide.177 Ceramide plays a key role in sphingolipid metabolism; it is an intermediate for synthesis and degradation of gangliosides, myelin constituents, and membrane components such as sphingomyelin and complex glycolipids. The human acid ceramidase gene has been mapped to chromosomal region 8p 21.3/22; several mutations have been identified.178

The classical form of Farber disease presents in infancy. Signs include painful swelling of joints and, in time, joint contractures; palpable subcutaneous nodules, particularly in relation to affected joints and over pressure points, sometimes involving the mouth, nostrils, external ear, or conjunctiva; hoarseness that may progress to aphonia; feeding difficulties, vomiting, and poor weight gain; and respiratory distress and intermittent fever. There may be lymphadenopathy, hepatomegaly, splenomegaly, or cardiac disease. In some cases there are neurological manifestations including psychomotor retardation or deterioration, seizures, peripheral neuropathy, and myopathy. The disease is progressive, often leading to death early in childhood, although in some cases the course is pro-

tracted. There is considerable phenotypic variability and several subtypes of Farber disease have been described, differing in severity and site of involvement.177

A number of ocular abnormalities are associated with Farber disease, including xanthoma-like conjunctival lesions, corneal opacities, lenticular opacities, retinal changes, and vision loss.177,290 There may be parafoveal grayness or cherry-red-like spots of the maculae.52,290 Retinal pigmentary changes and disc pallor also have been noted.52 Evidence for lipid storage in various tissues of the eye has been well documented, including the presence of inclusions of various morphological types in retinal ganglion cells, glia of the optic nerve, fibrocytes of sclera, epithelial cells and keratocytes of the cornea, endothelial cells of the trabecular meshwork, fibrocytes of the iris, nonpigmented epithelial cells of the ciliary body, some epithelial cells of the lens, epithelial and stromal cells of the conjunctiva, and in some nonmuscle cells of the extraocular muscles.52,290

Farber disease is rare. The inheritance is autosomal recessive. The diagnosis is confirmed by demonstration of the enzyme defect in cultured skin fibroblasts or white blood cells. Heterozygotes usually show reduced ceramidase activity. Prenatal diagnosis by enzyme assay of cultured amniotic fluid cells is possible. Although there is no specific treatment for the disease, corticosteroids may provide some relief, and surgery for the granulomas may be helpful.177 The possible benefit of bone marrow transplantation has been under investigation.178 Gene therapy also has been studied.178

NEURONAL CEROID-LIPOFUSCINOSES

The neuronal ceroid-lipofuscinoses (NCL) are a group of disorders in which the characteristic pathological findings are (1) accumulation of autofluorescent lipopigments (ceroid and lipofuscin) in neural and nonneural cells, (2) the presence of distinctive membrane-bound cytoplasmic inclusions having granular, curvilinear, or fingerprint patterns, and (3) progressive neuronal degeneration, particularly in the cerebral cortex and cerebellum; there is also demyelination of white matter with reactive gliosis.211 The underlying biochemical defects have not yet been fully delineated. However, a number of genes for NCL have been identified; these genes encode either lysosomal enzymes or lysosomal membrane proteins.124

The familiar eponym applied to this group of disorders is Batten disease. Infantile, late infantile, and juvenile forms occur, referred to respectively as Santavuori–Haltia, Jansky–Bielschowsky, and Spielmeyer–Sjögren disease; there is also an adult form of NCL referred to as Kufs’ disease. All are autosomal recessive. Occurring worldwide, the NCL are probably the most frequent of the hereditary neurodegenerative disorders of childhood. By some, the eponym Batten is reserved for juvenile-onset NCL, alternatively referred to as Batten–Spielmeyer–Vogt disease.

The principal clinical manifestations of the childhood forms of NCL are developmental retardation and progressive psychomotor deterioration, ataxia, seizures, and progressive vision loss with signs of retinal degeneration and optic atrophy (Fig. 7- 6).211 Atrophy of the brain is often evident on computed tomography and magnetic resonance imaging.

Confirmation of the diagnosis is often dependent on demonstration of the distinctive cytosomes by biopsy, usually of skin, sometimes conjunctiva. Enzymatic assays are available for the infantile and classical late infantile forms.124 Prenatal diagnosis is possible in many cases. There is no specific treatment for the neuronal lipofuscinoses.124

FIGURE 7-6. Pigmentary retinal degeneration of neuronal ceroid lipofuscinosis.

Santavuori–Haltia Disease: Infantile NCL

Beginning by age 12 to 18 months, sometimes as early as 8 months, affected children show mental and motor regression, hypotonia, ataxia, myoclonus, and micrencephaly. There is progressive deterioration to a vegetative state within several years. Death occurs usually by age 5 to 10 years. Vision loss, ultimately leading to blindness, is an early and prominent manifestation. There is retinal degeneration characterized by pigmentary changes (hypopigmentation and/or pigment aggregation), attenuation of retinal vessels, and optic atrophy (see Fig. 7-6).13,207 The ERG is reduced or extinguished and the VEP is diminished.207,211 Histopathological studies have documented atrophic changes of the retina and optic nerve.211

In infantile NCL there is deficiency of lysosomal palmitoylprotein thioesterase, which removes fatty acids attached in thioester linkage to cystine in proteins. The gene has been localized to chromosome 1p32.124

Jansky–Bielschowsky Disease: Late Infantile NCL

Clinical signs usually appear between age 2 and 4 years, sometimes as early as 1 year. Seizures are a prominent manifestation of the disease. Ataxia develops early, followed by rapidly progressive motor and mental regression. Death occurs usually by age 8 to 14 years. Visual symptoms are not prominent early, but blindness occurs later in the course of the disease. Signs of retinal degeneration may be evident, including pigmentary changes, attenuation of retinal vessels, optic atrophy, and diminished ERG.211,226 Photoreceptor degeneration and lipopigment storage in the retina have been documented by light and electron microscopy.226

In late infantile NCL there is deficiency of a lysosomal protease, pepinase.124 The gene location for classical late infantile NCL is 11p15.124

Spielmeyer–Sjögren Disease: Juvenile NCL

Clinical manifestations usually appear between 5 and 10 years of age. The course is protracted, with survival into the second or third decade. Early signs include intellectual deterioration, decline in school performance, behavioral changes, and in time motor dysfunction. Seizures occur later in most patients.