Myelin genetic disorders

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). 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

TABLE B8-1 Genetically determined disorders affecting myelin in humans... 

Wrabetz, L., Feltri, M. L., Kleopa, K. A. etal. Inherited neuropathies clinical, genetic and biological features. In R. A. Lazzarini (ed.), Myelin Biology and Disorders. San Diego, CA Elsevier Academic Press, 2004, pp. 905-952. 

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. 

The influence of the immune system on disease progression in genetic myelin disorders. 

Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechert, P., Wevers, R., Grosso, S., and Gartner J., 2009. FDolate receptor alpha defect causes cerebral folate transport deficiency a treatable neuro-degenerative disorder associated with disturbed myelin metabolism. American Journal of Human Genetics. 85 354-363. 

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