 
|
|
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 1 - Acute Disseminated Encephalomyelitis Section 4: Neuronal Lipidoses PRETEST: Answers can be found in the text of this section
PATHOLOGY OF LIPIDOSES The lipidoses are rare and complex diseases usually involving children which are characterized by progressive neurologic and mental deterioration, often with a fatal prognosis. Recent discoveries have provided understanding of the pathogenesis of these diseases and have also provided a means for detecting carriers or affected fetuses. Tables listing the various diseases and their enzyme defects can be found in standard texts. The same texts will have similar tables devoted to leukodystrophies and their enzyme defects or perhaps to lysosomal and also peroxisomal diseases with their enzyme defects. The latter method of classification emphasizes the fact that the missing or defective enzymes in lipidoses and in leukodystrophies are almost always in either the lysosomes or peroxisomes. This image below illustrates the appearance of neurons in a neuronal lipidosis. The cell bodies are ballooned or swollen by the poorly stained lipid. Sometimes they may appear to be almost empty. Special stains may sometimes distinguish one type of storage disease from another, but with ordinary hematoxylin and eosin staining as illustrated here, one neuronal lipidosis looks like another. Tay Sachs has been the most common of the neuronal lipidoses. This image is from such a case. Genetic testing of Jews of European origin has resulted in virtual disappearance of the disease in America due to the benefits of genetic counseling based upon diagnosis of carriers or of affected fetuses. The test looks for the enzyme hexoseaminidase A, whose deficiency results in storage of a GM2 ganglioside. Electron microscopy reveals lamellated bodies within the neuronal cytoplasm. These are formed by the stored lipid and vary somewhat in appearance depending upon the disease. In Tay-Sachs disease, they take the form of the concentric rings shown in this image. CHERRY RED SPOT One clinical sign of great notoriety is the "cherry red spot" in the retina of patients with Tay-Sachs disease and some other neuronal lipidoses. It is produced when ganglion cells, filled with lipid, degenerate, thereby exposing the vascular choroidal tissue behind these cells. The blindness ("amaurosis") produced by retinal involvement, together with the mental deterioration produced by destruction of other neurons, has given Tay-Sachs disease the name "amaurotic idiocy." MEDICAL GENETICS Most lipidoses appear to have a high familial incidence. Recent discoveries concerning the enzymatic basis of these diseases have provided a means not only for definitive diagnosis of symptomatic patients, but also for detecting carriers who are heterozygotes. Leukocytes, cultured fibroblasts, amniotic cells and choroid villus biopsies can all provide the material necessary for testing. This is true for all the lipidoses and leukodystrophies for which there is a defined enzyme deficiency. The enzymatic activity of heterozygote materials is intermediate between that of normal subjects and the very low levels of homozygotes, who are, of course, symptomatic, or in the case of affected fetuses, doomed to get the progressive lethal disease.
|
