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 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. The reader is referred to the continuously updated database, Online Mendelian Inheritance in Man (OMIM)(http://www.ncbi.nlm.nih.gov/omim). This resource contains an overview on all known mendelian disorders and over 15,000 genes. It can be used to cross reference disorders, genes, and even single symptoms and the associated genetic variants.
The brain is more frequently affected by a genetic abnormality than any other organ, 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. Approximately 7 percent of diseases in hospitalized children are estimated to be attributable to single-gene defects and 0.4 to 2.5 percent to a chromosomal abnormality. Another 22 to 31 percent have a disease putatively due to polymorphisms, most of which are yet to be specified. Mitochondrial inheritance of mutations is much less frequent but gives rise to several distinctive diseases.
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 enzymopathies become manifest in infancy and childhood; only a few appear as late as adolescence or adult life. Many damage the nervous system so severely that survival to adult years and reproduction are impossible, and some cause death in utero. As a group, these diseases—along with congenital anomalies (see Chap. 37), birth injuries, epilepsy, disharmonies of development, and learning disabilities (see Chap. 27)—make up the bulk of the clinical problems with which the pediatric neurologist must contend.
The diseases grouped in this chapter, and many in the next, represent four particular categories of genetic abnormality: (1) monogenic disorders determined by a single mutation that follow a mendelian pattern of inheritance. These mutations can be of a single base pair (point mutation), an insertion or deletion of nucleotides, or structural rearrangements of a sequence of DNA, such as translocations or inversions; because the most important of these involve the protein coding (exonic) portion of DNA, they are likely to disrupt the structure and function of enzymes or cellular structural proteins; this “exome” constitutes 1 percent of the entire genome; (2) a type of monogenic mutation characterized by duplications or deletions of genes or parts of chromosomes, termed copy number variations; these account for some proportion the heritability of common diseases; (3) single nucleotide polymorphisms, which are variations from the most common, “wild type,” sequence of a gene and are by convention present with a frequency of greater than 1 percent in the population; these play a role in the genesis of disease but do not obligatorily result in a somatic aberration or alternatively, they interact with exogenous environmental factors; and (4) mitochondrial gene mutations that are inherited in a nonmendelian, mainly maternally inherited pattern. Furthermore, the expression of certain diseases may be modulated by epigenetic alterations in gene expression, which have not been fully explored.