Genetic lesions, nature

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). 

The nature of the genetic lesions produced by the test material should be identified, since certain types of lesions may imply greater risk than others. For example, a chemical that produced both gene mutations and chromosome damage at low concentrations would imply greater risk than a chemical that produced only chromosome damage at concentrations near a maximum tolerated test dose. 

Third, there is a need to determine the underlying cause since this may be on an inherited basis described as thrombophilia where all family members need to be investigated. Experience and access to a superior haemostasis laboratory is needed. Defects may extend from hyperhomocysteinaemia through sticky platelet syndrome to mutations of factors V and II or reduced levels of the naturally occurring anticoagulants. Treatments differ and more than one abnormality in what is known as genetic coexpression may co-exist. Correspondence acquired lesions may reflect environmental influences. 

Genetic and nutritional studies have illustrated the essential nature of copper for normal brain function. Deficiency of copper during the foetal or neonatal period will have adverse effects both on the formation and the maintenance of myelin (Kuo et al., 2001 Lee et al., 2001 Sun et al., 2007 Takeda and Tamana, 2010). In addition, various brain lesions will occur in many brain regions, including the cerebral cortex, olfactory bulb, and corpus striamm. Vascular changes have also been observed. It is also of paramount importance that excessive amounts of copper do not occur in cells, due to redox mediated reactions such that its level within cells must be carefully controlled by regulated transport mechanisms. Copper serves as an essential cofactor for a variety of proteins involved in neurotransmitter synthesis, e.g. dopamine P-hydroxylase, which transforms dopamine to nor-adrenahne, as well as in neuroprotection via the Cu/Zn superoxide dismutase present in the cytosol. Excess free copper is however deleterious for cell metabolism, and therefore intracellular copper concentration is maintained at very low levels, perhaps as low as 10 M. Brain copper homeostasis is still not well understood. 

Much work has sought to define a metabolic aetiology for obesity, but the comparison of lean and obese individuals does not, in general, allow differences to be identified as either causes or effects of the condition. The differences between genetically obese animals and their lean littermates have also been extensively studied in an attempt to clarify the potential metabolic predispositons that encourage obesity. However, most genetically obese animal models are complicated by the diverse nature of the metabolic lesions in the obese, some of which may not be related to the manifestation of excess adiposity (Bray and York, 1979). 

Two human genetic diseases are known which involve this disulphide amino acid. In one, cystinuria , there is a transport defect in the intestine and kidney. This results in abnormally high levels of cystine in the urine and can result in the precipitation of cystine crystals and kidney stone formation. In cystinosis, cystine crystals form within cells and eventually cause severe kidney damage. The nature of the primary biochemical lesion is unknown all known cystine reduction systems of the cell appear to be normal. 

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