14800-DvRappard

13 General introduction 1 the metabolic defect is the failure to catabolize sulfatide. 9 There is no, or insufficient ASA activity, and accumulation of sulfatides takes place in oligodendrocytes, Schwann cells, phagocytes, astrocytes, neurons and macrophages. 5 Why this accumulation leads to a loss of myelin and neuronal degeneration is not completely understood. A possibility is that lysosomes stop functioning because of the massive sulfatide accumulation, ensuing cell death. 10 Also, sulfatide loading triggers inflammatory cytokines, 11 thought to be involved in apoptosis. 12 Microglial activation, invasion of peripheral macrophages and astrogliosis, all indicating inflammation, are found in the CNS of MLD patients. This Ca 2+ increase leads to activation of intracellular proteases and subsequent injury. 8 The precise trigger for the inflammatory response is not yet understood, but of great importance to fully understand the pathomechanism of the disease. In chapter 6 , we study the inflammatory response in brain tissue of transplanted and non-transplanted MLD patients. PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM MLD owes its name to the pathological feature of metachromasia; 13 describing the accumulated sulfatides which are periodic acid-schiff (PAS)-positive (staining blue- violet) and pink or dull red/brown with the toluidine blue stain (Figure 2), in place of the orthochromatic blue staining for the latter. 13 This is caused by the shift of the absorption spectrumof anionic groups in sulfuric acid radicals when present in high concentrations. Macroscopically, the brain of MLDpatients appears initially normal, but with progression of the disease cerebral and cerebellar atrophy occurs. There is thinning of the corpus callosum and diffuse sclerosis of the frontal, parietal, temporal and occipital white matter. 14 The size of the thalamus can be markedly reduced . The brain stem and basal ganglia seem macroscopically unaffected. Histologically, MLD is characterized by reactive macrophages and astrocytes containing metachromatic granules (Figure 3A). 13 These macrophages are present throughout and at the edges of the lesions. Analytical histopathological studies of the brain of MLD patients showed that the white matter is most severely affected by metachromatic deposits, with a sulfatide content up to 8 times higher than normal, with relatively few gross chemical changes in gray matter. 9 Isolated myelin sheaths with granules as a result of demyelination are found in the corpus callosum, the internal capsule, centrum semiovale and frontal, parietal and temporal white matter. Oligodendroglia are practically absent in demyelinated areas. 14 The U-fibers tend to be spared. The pyramidal tracts are usually early affected, containing numerous metachromatic granules.