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NEUROPATHOLOGY MINI-COURSE Presented by William I. Rosenblum, MD CHAPTER 4 DEMYELINATING DISEASES; LEUKODYSTROPHIES; STORAGE DISEASES INVOLVING MYELIN OR NEURONS This chapter contains four interrelated sections. They are related because some diseases of myelin are storage diseases and some storage diseases involve not myelin primarily but the neuron instead. In many cases the storage diseases are related in the sense that they depend upon a lack of an enzyme normally found in lysosomes, or sometimes in peroxisiomes. Each enzyme deficiency disease is characterized by its own enzyme deficiency, but the fact that lysosomal enzymes are involved has led many writers to lump these diseases together as lysosomal disorders. The problem with this method of classification is that it loses the distinction between diseases primarily affecting grey matter [neuronal cell bodies] and diseases primarily affecting white matter [myelin]. Since this anatomic difference helps make a diagnosis when the brain is examined by imaging or at autopsy and also has some effect on early symptoms, we prefer to emphasize the older classification of white matter diseases [ADE, MS and leukodystrophies] on the one hand and the other storage diseases which have been called neuronal lipidoses on the other. Indeed a traditional term for the neuronal storage diseases has been the term "lipidoses". Because of the pathogenetic similarity between some of the leukodystrophies [white matter lipid storage or lysosomal disorders of white matter] and the neruonal lipidoses [lysosomal disorders] we have included a section concerning the latter in this chapter.The other three sections are:
Section 3: Leukodystrophies PRETEST: Answers can be found in the text of this section
PATHOLOGY METACHROMATIC LEUKODYSTROPHY Metachromatic leukodystrophy is characterized by deficient [in some cases] or dysfunctional [in other cases] laryl sulfatase. As a result, sulfatides are not broken down and are found in large amounts in astrocytes and macrophages. The sulfatide is metachromatic--that is, it causes a shift in the color of a dye--and this histologic characteristic has given the disease its name. In fully developed lesions, oligoglia are sparse or absent. Presumably they were adversely affected by the metabolic defect and/or storage of sulfatide. The injury to oligoglia is thought to account for the disappearance or absence of myelin, since these glial cells normally form the myelin. In addition to myelin loss, axon loss is often severe (presumably a secondary effect of myelin loss or glial injury) and astrocytosis is marked. KRABBE'S DISEASE OR GLOBOID LEUKODYSTROPHY Krabbe's disease is characterized by deficient galactosidase and accumulation of galactocerebroside in some cells. However, unlike typical storage diseases, overall tissue levels of the affected lipid are not increased, and this fact provides us with one additional reason for maintaining the leukodystrophies as a separate nosologic entity. Moreover, the accumulating cerebroside may not be the cause of tissue destruction. Instead, levels of psychosine, a toxin, are increased during the abnormal metabolism and may be responsible for the damage. As in other leukodystrophies, cases of Krabbe's disease display degenerated white matter, with absence or diminution in myelin, loss of axons, loss of oligodendroglia and astrocytosis. The galactocerebroside is stored in macrophages which may cluster together or fuse to form diagnostic "globoid" bodies (image below) which give the disease its name. Arrows delineate such a body on the image below. Injections of cerebroside into the brains of animals produce similar bodies. This effect is not produced by injections of other brain lipids. Recently doctors have successfully treated infants at risk for globoid leukodystrophy by intravascular injection of cord blood from normal newborns. Mononuclear cells from the cord blood enter the brain and produce sufficient cerebrosidase to ameliorate the symptoms. This technique--and presumably stem cells injected intravascularly-overcomes the difficulties of trying to treat enzyme deficiency diseases by injecting the patient with enzyme. In the latter situation enzyme may not pass the blood brain barrier and, moreover, the recipient may develop antibodies to the protein thereby nullifying its effect.
CANAVAN'S DISEASE The next disease we will discuss is Canavan's disease or spongiform leukodystrophy. This disease involves all the white matter, but particularly the "U" fibers or arcuate zone which lies immediately beneath the cortex. The affected area is demarcated by Xs in the image below. An enzyme defect has been uncovered in this very rare disease. The deficient enzyme , acetylaspartase, breaks down N-acetylaspartic acid. The latter is an important constituent of neurons. Since the enzyme which breaks it down is missing, the aspartate builds up in the neurons. However, the aspartase is not localized in the neurons. Instead it is found in the oligodendroglia. Hence the aspartate is normally transported down the axons, and in some way is made available for breakdown by the oligodendroglial enzyme. Why the absence of the enzyme in the latter should lead to myelin breakdown is not known. But it has been postulated that the accumulation of the aspartate in the white matter leads to increased osmotic pressure there with consequent drawing of water into the surrounding tissue. It has been further postulated that in some way this leads to the degeneration of the myelin. The disease is presented because it illustrates the fact that all leukodystrophies are not caused by intraneuronal or intraglial storage per se and because its pathology is illustrative of a very unusual type of ultrastructural lesion. When studied with the electron microscope, the myelin sheath appears to be "unraveling" the lamellae becoming widely separated. An electron microscopic picture of the large spaces between widely separated myelin lamellae is shown above. The large spaces appearing between the billowing lamellar sheets are the cause of the spongy appearance seen with the light microscope. It is the sponginess of the tissue that has given the disease one of its names. ALEXANDER'S DISEASE The last disease we will discuss is Alexander's disease. This rare leukodystrophy exists in several forms, depending upon the age of onset. In several forms abnormalities in the gene coding for glial fibrillary acidic protein have been found. This is the first disease in which the gene for GFAP has been implicated. This may explain a characteristic feature of the disease which is the accumulation in the degenerated white matter of large numbers of Rosenthal fibers and eosinophilic granular bodies. These structures are large accumulations of astrocytic processes "clumped" together. However, they are not specific for this disease and also accumulate in conditions where there has been prolonged proliferation of astrocytes--for example in slow growing or benign astrocytomas like pilocytic astrocytomas where they help the pathologist to make the diagnosis. In Alexander's disease the relationship, if any, of the astrocytic abnormality to the degeneration of myelin or its failure to form normally, or to the selection of white matter as the preferential target of the disease, has not been elucidated. PEROXISOMAL DISORDERS The peroxisome is another ultrastructural cytoplasmic organelle that contains catabolic enzymes. The deficiency of one of these enzymes leads to adrenoleukodsytrophy. This disorder is characterized by characteristic curvilinear bodies in affected adrenal cells and brain cells which are swollen contain stored very long chain fatty acids. TESTING PATIENTS AND PROSPECTIVE PARENTS Discovery of the enzymatic defect is extremely important. These defects are expressed in many cells, e.g., white blood cells or cells in amniotic fluid. Examination of these cells provides a rapid, definitive means of diagnosing the disease and often its carriers. These facts provide a basis for genetic counseling and for informed decisions concerning termination of pregnancy.
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