Myelination deficiency, models

The human leukodystrophies are inherited disorders of central nervous system white matter. These disorders are characterized by a diffuse deficiency of myelin caused by a variety of genetic lesions and often manifest before 10 years of age (Table 38-1). Some are caused by mutations in the PLP gene and resemble the PLP animal mutants described in Chapter 4 [ 1,23]. As with the animal models, depending on the nature of the mutation, they vary from a severe form in connatal Pelizaeus-Merzbacher disease (PMD) through an intermediate phenotype in classical PMD to a mild phenotype in spastic paraplegia. It is noteworthy that some mutations of the PLP gene also cause a peripheral neuropathy [24], very probably related to the expression of low levels of PLP in peripheral nerve (see Ch. 4). 

R, Toyka KV, Schaclrrrer M, Marfini R (2000) Immime deficiency in mouse models for irrherited peripheral neuropadiies leads to improved myelin maintenance. J Neui osci 20 729—735. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

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