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).
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.
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.
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.
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.
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 ...