Myelin disease

FIGURE 38-1 Coronal slice of brain from a patient who died with MS. Demyelinated plaques are clearly visible in white matter (large arrows). Small plaques are also observed at the boundaries between gray and white matter (small arrows). (Reproduced with permission from Raine, C. S. The neuropathology of myelin diseases. In P. Morell (ed.) Myelin. New York Plenum Press, 1984, ch. 8.)... 

Myelin disorders can have a genetic, toxic, or infectious origin and some such as MS even an immunological component. For most of these diseases, there are animal models. Whatever the causes, the targets are structural or metabolic elements necessary for intact myelin. Diseases involving myelin are often related to specific myelin constituents whether common to CNS and PNS, or different. One can believe that these specialized compounds play significant roles in the pathology of myelin. Thus there are diseases or experimental models that involve only CNS or PNS, and others that involve both systems. 

A variety of pathogenic mechanisms has been shown to be at work in myelin diseases point mutations, recombination events leading to deletions, and duplication of genomic regions including myelin genes. The exquisite sensibility to gene... 

L.L. Sarlieve, Myelinogenesis in primary cultures, hi "A Multidisciplinary Approach to Myelin Diseases", G. Serlupi-Crescenzi, ed.. Proceedings of a NATO ARW, Plenum Press, New York, pp. 171-191 (1988). 

Spencer, P.S. et al, 1979, Neurotoxic fragrance produces ceroid and myelin disease. Science. 204 633 635, Spencer, P,S, et al, 1984. Neurotoxic properties of musk ambrette. 571 575. 

Spencer, P.S., et al., 1979. Neurotoxic fragrance produces ceroid and myelin disease. Science, 204 633-635. Spencer, P.S., et al., 1984. Neurotoxic properties of musk ambrette. Toxicol Appl Pharmacol, 75 571-575. Steinberg, R, et al., 1999. Acute hepatotoxicity of the polycyclic musk 7-acetyl-l,l,3,4,4,6-hexamethyll,2,3,4-tetrahydronaphthaline (AHTN. Toxicol. Lett, 111 151-160. 

For the pathogenesis of multiple sklerosis, autoimmune T-lymphocy tes play a predominant role, which are directed against components of the neural myelin sheath. T-lymphocy tes by secreting cytokines such as interferon y maintain the chronic inflammation which destructs the myelin sheath. Also cytotoxic T-lymphocytes may participate directly. The cause of multiple sklerosis is unknown. Significantly increased antibody titers against several vitusses, mostly the measles virus, point to a (latent) virus infection initiating the disease. 

Interferon beta-la (AVONEX , Rebif ), interferon beta-lb (Betaferon ), and interferon beta (Fiblaferon ) are applied in multiple sclerosis to reduce both frequency and severity of disease incidents and for the treatment of severe viral infections. In multiple sclerosis, DFN- 3 proteins modulate the destruction of myelin in the cause of the autoimmune reaction. 

Multiple scelerosis is an autoimmune disease mediated by T and B lymphocytes and macrophages. This is characterized by extensive inflammation and demyelination of the myelin sheath that surrounds the nerve fiber. The death of the nerve fiber results in a variety of symptoms that can lead to impairment of movement, paralysis, and death. 

Krabbe s disease P-Gaiactosidase Cer-i-Gai Gaiactosyiceramide Mental retardation myelin almost absent. 

MS, a chronic demyelinating disease of the CNS, is the most common cause of non-traumatic disability among young adults (Frohman et al. 2006). At the cellular level, MS is mediated by myelin-specific CD4h- T cells that destroy oligodendrocytes... 

DPDPB has been used to study the endocytosis of cadherin from intracellular junctions (Troyanovsky et al., 2006), the subunit arrangement in the flagellar rotor assembly (Lowder et al., 2005), and the disease-associated mutations in myelin proteolipid protein in the endoplasmic reticulum (ER) (Swanton et al., 2005). DPDPB can be used to conjugate reduced antibody molecules to p-D-galactosidase using essentially the same protocol as that described by O Sullivan et al. (1979). 

Swanton, E., Holland, A., High, S., and Woodman, P. (2005) Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. PNAS 102, 4342-4347. 

Myelin sheaths contain other proteins, some of which have only recently been established as myelin-related. The proteins described above represent most of the well-established myelin proteins that are myelin-specific or have been studied primarily in the context of myelin and demyelinating diseases. However, myelin sheaths contain numerous other proteins in smaller amounts that are also in many other cells and/or have only been identified relatively recently. Some of these are in compact myelin but others are enriched in specialized... 

Nave, K. A. and Griffiths, I. R. Models of Pelizeaus-Merzbacher disease. In R. A. Lazzarini (ed.), Myelin biology and disorders. San Diego, CA Elsevier Academic Press, 2004, 1125-1142. 

The importance of P0 in PNS myelin has been clearly demonstrated. In P0 gene knockout experiments in mice [40], severe hypomyelination and a virtual absence of compact myelin in the PNS is observed. In humans, there are two disease states associated with mutations in the P0 gene Charcot-Marie-Tooth type I disease (see Ch. 38) and Dejerine-Sottas disease, both dysmyelinating diseases that exhibit a spectrum of severity depending on the particular mutation. 

Table 36-1 lists some of the mechanisms important in governing the susceptibility of the PNS to disease and injury. Peripheral nerves, although toughened by their high content of collagen, are prone to injury to myelin by compression (e.g. carpal tunnel syndrome and tardy ulnar palsy) and to axons by excessive stretch (e.g. brachial plexopathy in newborn infants following a difficult delivery). Subcutaneous nerves, because of their exposed position, are also vulnerable to cold or heat injury. 

Schwann cells are responsible for PNS trophic functions that, in CNS, are carried out by both oligodendroglia and astroglia. Schwann cell diseases usually present as disorders of myelination. Axonal degeneration and diminution in axonal diameter may also occur in primary disorders of Schwann cells, as a consequence of loss of Schwann cell trophic support for axons. (See also Chs 4 and 38.)... 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

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