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Advances in biochemistry and molecular genetics have led to the discovery of such a large number of metabolic diseases of the nervous system that it taxes the mind just to remember their names. As the causes and mechanisms of the diseases included in this chapter (and in several that follow) are increasingly being expressed in terms of molecular genetics, it seems appropriate, by way of introduction, to consider briefly some basic facts pertaining to the genetics of neurologic disease. A complete account of this subject may be found in the four-volume text edited by Scriver and colleagues. The reader is referred to the continuously updated Online Mendelian Inheritance in Man, a catalog of genetic disorders developed by V.A. McKusick and his colleagues and the National Center for Biotechnology Information (queried through: http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim).

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The biochemistry of every human organism is, of course, unique. Constitutional predispositions to disease lie in the variations of DNA of the chromosomes of each cell. Knowledge of the molecular basis of these diatheses may ultimately provide the means of diagnosis, prevention, and perhaps treatment of many human diseases.

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The diseases grouped in this chapter and the next represent four particular categories of genetic abnormality: (1) monogenic disorders determined by a single mutant gene that follow a mendelian pattern of inheritance; (2) multifactorial disorders, again following a mendelian pattern of inheritance but in which intrinsic (i.e., genetic) factors interact with exogenous environmental ones—susceptibility to these agents probably depend on single nucleotide polymorphisms within normal genes; (3) nonmendelian chromosomal aberrations, characterized by an excess, a lack, or a structural alteration of one or more of the 23 pairs of chromosomes (these are considered in the next chapter, with the developmental disorders); and (4) mitochondrial transmission of disease in a nonmendelian, mainly maternal pattern.

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As stated in the monograph of Scriver and colleagues, 6 to 8 percent of diseases in hospitalized children are attributable to single-gene defects and 0.4 to 2.5 percent to a chromosomal abnormality. Another 22 to 31 percent have a disease thought to be gene-influenced. In the general population, when multifactorial inheritance of late-onset diseases is included, the latter figure has been estimated to rise to approximately 60 percent. Mitochondrial inheritance of mutations is much less frequent.

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The nervous system is more frequently affected by a genetic abnormality than any other organ system, probably because of the large number of genes implicated in its development (an estimated one-third of the human genome). Approximately one-third of all inherited diseases are neurologic in some respect; if one adds the inherited diseases affecting the musculature, skeleton, eye, and ear, the number rises to 80 to 90 percent.

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Although only a minority of inherited diseases is identified as an enzymopathy, this group represents the most direct translation of mendelian disorders to primary defects in proteins. These constitute only one-third of the known recessive (autosomal and X-linked) disorders. Most of the enzymopathies ...

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