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 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 (Chap.
38), birth injuries, epilepsy, disharmonies of development,
and learning disabilities (Chap. 28)—make
up the bulk of the clinical problems with which the pediatric neurologist
Traditionally, the recognition of the broad categories of genetically
determined diseases has rested on their pattern of occurrence in
families, segregated according to mendelian inheritance into autosomal
dominant, autosomal recessive, and sex-linked types. Mutations of
nuclear DNA account for the heritable autosomal and sex-linked diseases
described in this chapter, and they are remarkably diverse in nature.
Some are lethal and, as mentioned, are therefore not transmitted
to successive generations; others are less harmful and may conform
to one of the classic mendelian patterns. The mutation may be large
and result in duplication of a major part of a chromosome or even
of the entire gene (diploidy or triploidy) or a deletion (haploidy).
Other mutations are very small, involving only a single base pair
(“point mutation”). Between these two extremes
are deletions or duplications that include a portion of a gene,
an entire gene, or contiguous genes.
The factors conducive to mutations are poorly understood. The
parent’s increasing age is important in relation to some
mutations; the size, structure, and placement of the gene on the
chromosome are important in others. A mutation of the DNA of a germ
cell leaves unchanged the somatic phenotype of the individual in
whom it occurs, but it may have a devastating effect on the descendants.
Conversely, a DNA mutation of a somatic cell affecting only part
of the cell population may change the individual harboring it but
is not passed on to the descendants. Such an individual, with both
normal cells and cells containing the mutant gene, is referred to
as a mosaic. Mutations of somatic cells appear
to be most pertinent to cancer and aging.
In the monogenic inheritance of all three mendelian patterns,
the mutation usually causes an abnormality of a single protein.
It may involve an enzyme, peptide hormone, immunoglobulin, collagen,
or coagulation factor. Such abnormalities of single genes have been
isolated in several hundred diseases, but little is known of their
protein products. About one-quarter of these diseases are apparent
soon after birth and more than 90 percent by puberty. More than
half of them affect more than one organ. Of the 10 in every 1,000
live births with genetic diseases, 7 are dominant, 2.5 are recessive,
and the remainder are sex-linked.
Autosomal dominant mutations usually cause manifest disease in
heterozygotes, but variations in the size of the gene abnormality
can produce any one of several phenotypes. This poses a ...