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Morphologic Changes in the Nervous System in Gaucher's Disease, GM2

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Morphologic Changes in the Nervous System in Gaucher's Disease, GM2 ANNALS OF C LINICAL AND LABORATORY SCIEN CE, Vol. 5, No. 6 Copyright © 1975, Institute for Clinical Science The Lipidoses: Morphologic Changes in the Nervous System in Gaucher’s Disease, GM2 Gandliosidoses and Niemann-Pick Disease JAMES B. AREY, M.D., Ph.D. St. Christopher’s Hospital for Children, Department of Pediatrics and Pathology, Temple University School of Medicine, Philadelphia, PA. 19140 ABSTRACT The present paper presents, in tabular form, most of the inborn errors of lipid metabolism (exclusive of the hyperlipoproteinemias); some may, with further studies, be removed from this category. Three of the lipidoses and their subtypes which are associated with severe neurologic disorders are discussed, i.e., infantile Gaucher’s disease, Niemann-Pick disease and the GM2 gangliosidoses. Particular emphasis is placed on the importance of careful biochemical and enzymatic studies of either surgical or autopsy material of any patient suspected of having one of the lipidoses. Only by such studies can an exact diagnosis of virtually all of these inborn errors of lipid metabolism be established. Such a diagnosis is im­ portant, since in many instances an antenatal diagnosis is possible by demon­ stration of the enzymatic defect in cells grown in tissue culture from the amniotic fluid. Introduction cludes their normal catabolic cycle; the nature of many of these enzymatic defects The lipidoses, here defined as inborn er­ has been elucidated only within the past 5 to rors of metabolism characterized by an in­ 10 years and can often be demonstrated not crease of one or more lipids in the tissues, only in the tissues in which the major mor­ and sometimes in the plasma as well, are phologic changes are present but also in usually transmitted as autosomal recessive other viscera, in circulating leukocytes, in characteristics, with only the homozygously fibroblasts grown in tissue culture and in involved person having the overt disease. cells grown from tissue cultures of amniotic Fabry’s disease, which will not be discussed fluid. Thus, an antenatal diagnosis of many further in this paper, is, however, transmit­ of the lipidoses is now possible. In table I is ted by an X-linked mode of inheritance. an incomplete listing of the lipidoses, only a Many of the lipidoses are associated with few of which will be discussed in this severe mental and motor retardation, some­ manuscript. In some of those included in this times accompanied by blindness. The stored tabulation, the nature of the enzymatic de­ lipid(s) are generally ones normally present fect is currently unknown and in some, e.g., in the body which have accumulated as the Farber’s disease, the nature of the stored result of an enzymatic defect which pre­ substances is not entirely clear. Thus, it is 4 7 6 AREY TABLE I vertebral bodies, or pain, limp and limitation The Lipidoses of motion, sometimes followed by os­ teoarthrosis as a result of destruction of the Gaucher's disease femoral head. Since it is not accompanied by Infantile or cerebral Adult or non-cerebral neurologic manifestations, it will not be dis­ Tay-Sachs disease (GM2 gangliosidosis type 1) Sandhoff's disease (GM2 gangliosidosis type 2) cussed further here, except as to its enzy­ Juvenile GM2 gangliosidosis (GM2 gangliosidosis matic relationship to the infantile form of type 3) GM^ gangliosidosis type I (Landing's disease: Gaucher’s disease. pseudo-Hurler's disease) Acute, infantile or cerebral Gaucher’s GM^ gangliosidosis type II (juvenile GM^ ganglio­ sidosis; Derry's disease) disease has no predilection for Jews. It is a Niemann-Pick disease Classical infantile form (Group A) very rare disorder characterized by the early Non-cerebral form (Group B) onset of impaired mental and motor de­ Late infantile form (Group C) Nova Scotian form (Group D) velopment, prominent neurologic manifes­ Fabry-Anderson disease (angiokeratoma corporis diffusum) tations and abdominal enlargement second­ Globoid cell leukodystrophy (Krabbe’s disease) ary to hepatosplenomegaly. Hyperextension Metachromatic leukodystrophy (sulfatide leuko­ dystrophy) of the neck, strabismus, hypertonicity, dys­ Late infantile phagia, apathy or somnolence with cata­ Juvenile Adult tonia, increased deep tendon reflexes and "Variant" form Refsum's disease (phytanic acid storage disease) laryngeal spasm are among the more com­ Cholesteryl ester storage disease mon neurologic manifestations. These Cerebrotendinous xanthomatosis Tangier disease (familial high density lipoprotein usually appear by the age of six months and, deficiency) Abetalipoproteinemia (Bassen-Kornzweig syndrome) rarely, some may be present at birth. There Wolman's disease may be microcytic anemia as well as Sudanophilic leukodystrophy Farber's disease thrombocytopenia. The serum acid phos­ phatase is increased, most of it being non- tartrate-inhibitable. Increased amounts of glucosylceramide are present in the urinary quite possible that some of those here tabu­ sediment.5 Roentgen examination of the lated may be subsequently removed from chest often reveals a hazy reticular or coarse, the classification of lipidoses. miliary-like pattern. Aspirates of the bone marrow almost always reveal typical Gaucher’s Disease Gaucher cells, the morphology of which is Gau cher’s disease is characterized by the indistinguishable from that encountered in accumulation of glucocerebrosides in the the adult, non-cerebral form of the disease. cells of the reticuloendothelial system. In­ The disease is usually rapidly fatal, most of frequently, presumably similar deposits have the patients dying by the age of one year. been identified in neurons in the central Thanatopsy reveals severe splenomegaly, nervous system in infants with the cerebral the weight of the spleen often being ten or (infantile) form of the disease.1 more times that expected. The liver is simi­ Chronic, non-cerebral or the adult form of larly but not so massively enlarged. His­ Gaucher’s disease, which accounts for at tologically large numbers of Gaucher cells least 80 percent of the recorded instances of are present in the reticuloendothelial cells of this disorder, involves principally Ashkenazi the spleen, liver, bone marrow, lymph Jews. Its manifestations are predominantly nodes, tonsils, thymus and Peyer’s patches. those of hypersplenism and osseous changes, In the lungs, similar cells may be present e.g., vague pains in the bones, sharply lo­ both in the alveolar septa and spaces. These calized pain as the result of pathologic frac­ cells, in contrast to most of the lipidoses, are tures, kyphosis secondary to collapse of not vacuolated, but instead tend to have a LIPIDOSES: MORPHOLOGIC CHANGES IN NERVOUS SYSTEM 4 7 7 Figure 1. Infantile Gau­ cher s disease. Section of the thymus reveals a Hassell’s corpuscle on the right and Gaucher cells with a fibrillary type of cy­ toplasm on the left. Pe­ riodic acid Schiff x 390. fibrillary type of cytoplasm (figure 1). They cells may be present in the leptomeninges are large, pale cells, 20 to 100 micra in and in Virchow-Robin spaces. diameter, with one or more dark, ec­ The enzymatic defect responsible for the centrically placed nuclei. The fibrillary cyto­ adult or noncerebral and the infantile or ce­ plasm stains a bright rose purple by the pe­ rebral form of Gaucher’s disease is qualita­ riodic acid leukofuchsin (Schiff) technique tively similar. In the adult form, glucocere- following fixation in formalin and embed­ brosidase activity is present but is greatly ding in paraffin as well as after freeze reduced, whereas in the infantile form it is drying.16 virtually absent. The two diseases, neverthe­ In spite of the prominent neurologic less, appear to be distinct entities, and adults manifestations, specific changes in the with Gaucher’s disease do not give birth to central nervous system are often absent. infants with the acute, cerebral form of the There is, however, usually widespread de­ disease. Heterozygous carriers may be de­ generation of neurons with chromatolysis tected by enzyme assays performed on ex­ and neuronophagia and, by electron mi­ tracts of skin fibroblasts grown in tissue cul­ croscopy, “ Gaucher bodies” are sometimes ture as well as upon sonicated white blood identifiable in the cytoplasm of the shrunken cell preparations;2 heterozygous carriers of neurons.1 Small accumulations of Gaucher the adult form of the disease may also be de­ 4 7 8 AREY tected by the demonstration in tissue cul­ present in the neonatal period but may al­ tures of the skin of giant fibroblasts con­ ready be visible by the second month of taining metachromatic material.4 life.26 It is present at some time in the course of the disease in almost all of the patients but may disappear when the disease Tay-Sachs Disease is prolonged. The infant becomes flaccid Tay-Sachs disease (GM2 gangliosidosis with increased reflexes and obvious Type I) was initially described in 1881 by blindness, followed by increasing dementia, Waren Tay, a British ophthalmologist.32 In intense spasticity with greatly increased 1884, he noted the occurrence of the disease reflexes, extensor plantar responses and in two siblings of the infant first reported by seizures. A completely vegetative state is him33 and in 1892 he reported a fourth finally reached, with death usually occurring instance of the same disease in a different by three or four years of age. family.34 Sachs, a New York neurologist, Although the measurements of the head described the clinical and pathologic find­ are initially normal, in patients surviving ings in a child with this disease in 188723 and more than 18 to 24 months after the onset of in 1896 designated the illness as amaurotic symptoms there is usually a progressive in­ family idiocy.24 Prior to this last report, crease in its size, its circumference at the however, Kingdon11 in 1892 had reported an time of death often being about 20 percent additional patient and had collected from above normal. This is not primarily the re­ the literature6,8,12'15,23,35 and from personal sult of hydrocephalus, although initially correspondence 10 to 12 infants and young there may be slight dilation of the lateral children with the disease, including the one and of the fourth ventricles.
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