Samenvatting Children with Disabilities
Chapter 1: Genetics underlying developmental disabilities
Introduction:
Disorders associated with developmental disabilities have a spectrum of genetic and environmental origins.
This chapter describes the human cell and explains chromosomes and genes. It also reviews and provides
illustrations and examples of the errors that can occur in the processes of meiosis (reductive cell division) and
mitosis (cell replication), summarizes inheritance patterns of single-gene disorders, and presents the concept of
epigenetics.
Genetic disorders:
All cells, with the exception of the red blood cell, are divided into two compartments:
1. Nucleus = a central, enclosed core
2. Cytoplasm = an outer area
The red blood cell differs insofar as it does not have a nucleus. The nucleus houses
chromosomes, structures that contain the genetic code, namely the DNA
(deoxyribonucleic acid), which is organized into hundreds of genes in each chromosome. There are 23 pairs of
chromosomes and about 20,000 proteincoding genes that collectively make up the human genome. These
genes are responsible for our physical attributes and for the biological functioning of our bodies. The nucleus
contains the blueprint for the organism’s growth and development, and the cytoplasm manufactures the
products needed to complete the task.
When there is a defect within this system, the result may be a genetic disorder, often causing
developmental disabilities. These disorders take many forms, for example the addition of an entire
chromosome in each cell, the loss of an entire chromosome in each cell, and the loss or deletion of a significant
portion of a chromosome. There can also be a microdeletion of a number of closely spaced or contiguous genes
within a chromosome. Microdeletions may have varied expression depending on stochastic (randomly
determined) and environmental processes, as well as on genetic effects, with these factors potentially acting
alone or in combination. Finally, there can be a defect within a single gene or altered expression of the gene.
Chromosomes:
Each organism has a fixed number of chromosomes that directs the cell’s activities. In each human cell, there
are normally 46 chromosomes which are organized into 23 pairs. Egg and sperm cells, unlike all other human
cells, each contains only 23 chromosomes. During conception, these germ cells (i.e., sperm and eggs) fuse to
produce a fertilized egg with the full complement of 46 chromosomes.
Among the 23 pairs of chromosomes, 22 are termed autosomes. The 23rd pair consists of the X and Y
chromosomes and are called the sex chromosomes. Two X chromosomes determine the child to be female; an
X and a Y chromosome determine the child to be male.
Cell division and its disorders:
Cells have the ability to divide into daughter cells that contain genetic information that is identical to the
information from the parent cell. The prenatal development of a human being is accomplished through cell
division, differentiation into different cell types, and movement of cells to different locations in the body. There
are two kinds of cell division:
1. Mitosis = nonreductive division where 2 daughter cells, each containing 46 chromosomes, are formed
from 1 parent cell. This occurs in all cells.
2. Meiosis = reductive division, 4 daughter cells, each containing only 23 chromosomes, are formed from
1 parent cell. This takes place only in the germ cells. A number of events that adversely affect a child’s
development can occur during meiosis:
a. Nondisjunction = when chromosomes divide unequally
The ability of cells to continue to undergo mitosis throughout the life span is essential for proper bodily
functioning.
, One of the primary differences between mitosis and meiosis is during the first of the two meiotic
divisions. During this cell division, the corresponding chromosomes line up beside each other in pairs (e.g., both
copies of chromosome 1 line up together). Unlike in mitosis, however, they intertwine and may “cross over,”
exchanging genetic material. This adds variability, reducing the chance that siblings end up as exact copies
(clones) of each other.
Throughout the life span of the male, meiosis of the immature sperm produces spermatocytes with 23
chromosomes each. These cells will lose most of their cytoplasm, sprout tails, and become mature sperm. This
process is termed spermatogenesis. In the female, meiosis forms oocytes that will ultimately become mature
eggs in a process called oogenesis. By the time a girl is born, her body has produced all of the eggs she will ever
have.
The majority of fetuses carrying chromosomal abnormalities are spontaneously aborted. Among those
children who survive these genetic missteps, intellectual disability, unusual (dysmorphic) facial appearances,
and various congenital organ malformations are common. As the woman ages, the risk of errors in meiosis
increases.
Chromosomal gain: Down Syndrome
The most frequent chromosomal abnormality is unequal division of non-sex chromosomes, and the most
common clinical consequence is trisomy 21, or Down syndrome. Nondisjunction can occur during either mitosis
or meiosis but is more common in meiosis. When nondisjunction occurs during the first meiotic division, both
copies of chromosome 21 end up in one cell. Instead of an equal distribution of chromosomes among cells (23
each), 1 daughter cell receives 24 chromosomes and the other receives only 22. The cell containing 22
chromosomes is unable to survive. However, the egg (or sperm) with 24 chromosomes occasionally can
survive. After fertilization with a sperm (or egg) containing 23 chromosomes, the resulting embryo contains 3
copies of chromosome 21, or trisomy 21. The child will be born with 47 rather than 46 chromosomes in each
cell and will thus have Down syndrome. Some individuals acquire Down syndrome as a result of translocation
and some acquire it from mosaicism (= some cells being affected and others not).
Chromosomal loss: Turner Syndrome
Turner syndrome is the only disorder in which a fetus can survive despite the loss of an entire chromosome.
Females with Turner syndrome have a single X chromosome and no second X or Y chromosome, for a total of
45, rather than 46, chromosomes. In contrast to Down syndrome, 80% of individuals with monosomy X
conditions are affected by meiotic errors in sperm production; these children usually receive an X chromosome
from their mothers but no sex chromosome from their fathers.
Girls with Turner syndrome typically have short stature, a webbed neck, a broad “shield-like” chest
with widely spaced nipples, and nonfunctional ovaries. Twenty percent have obstruction of the left side of the
heart, most commonly caused by a coarctation of the aorta. Most girls with Turner syndrome develop typically.
They do, however, have visual–perceptual impairments that predispose them to develop nonverbal learning
disabilities. Human growth hormone injections have been effective in increasing height in girls with Turner
syndrome, and estrogen supplementation can lead to the emergence of secondary sexual characteristics;
however, these girls remain infertile.
Mosaicism:
In mosaicism, cells in the same individual have different genetic makeups. For example, a child with the mosaic
form of Down syndrome may have trisomy 21 in skin cells but not in blood cells. Children with mosaicism often
appear as though they have a particular condition, however, the physical/organ and cognitive impairments may
be less severe. Usually mosaicism occurs when some cells in a trisomy conception lose the extra chromosome
via nondisjunction during mitosis. Mosaicism also can occur if some cells lose a chromosome after a normal
conception.
Translocations:
Translocation can occur during mitosis and meiosis when the chromosomes break and then exchange parts
with other chromosomes. Translocation involves the transfer of a portion of one chromosome to a completely
different chromosome.
,Deletions:
In deletion, part, but not all, of a chromosome is lost. Chromosomal deletions occur in two forms:
1. visible deletions = are large enough to be seen through the microscope
2. microdeletions = so small that they can only be detected at the molecular level and can be identified
by a test called chromosomal microarray
Frequency of chromosomal abnormalities:
In total, approximately 25% of eggs and 3%–4% of sperm have an extra or missing chromosome, and an
additional 1% and 5%, respectively, have a structural chromosomal abnormality. As a result, 10%–15% of all
conceptions have a chromosomal abnormality. It may therefore seem surprising that more children are not
born with chromosomal abnormalities. The explanation is that more than 95% of fetuses with chromosomal
abnormalities do not survive to term.
Genes and their disorders:
Genetic disorders can also result from an abnormality in a single gene. Single genes in humans code for
multiple proteins, giving humans the combinational diversity that lower organisms lack.
The mechanism by which genes act as blueprints for producing specific proteins needed for body
functions is as follows. Genes are composed of various lengths of DNA that, together with intervening DNA
sequences, form chromosomes. DNA is formed as a double helix, a structure that resembles a twisted ladder.
The sides of the ladder are composed of sugar and phosphate molecules, whereas the “rungs” are made up of
four chemicals called nucleotide bases: cytosine (C), guanine (G), adenine (A), and thymine (T). Pairs of
nucleotide bases interlock to form each rung (C-G and A-T). The sequence of nucleotide bases on a segment of
DNA make up an individual’s genetic code. It should also be noted that all genes are not “turned on” or
expressed at all times. The way gene expression is regulated involves a number of structural changes to the
DNA and its architecture without altering the actual nucleotide sequence of the DNA. This process is termed
epigenetics and is a cause of a number of genetic syndromes that are associated with developmental
disabilities.
Transcription:
The production of a specific protein begins when the DNA comprising that gene unwinds and the two strands
(the sides of the ladder) unzip to expose the genetic code. The exposed DNA sequence then serves as a
template for the formation, or transcription (the writing out), of a similar nucleotide sequence called
messenger ribonucleic acid (mRNA). In all RNA, the nucleotides are the same as in DNA except that uracil (U)
substitutes for thymine (T). In most genes, coding regions (exons) are interrupted by noncoding regions
(introns). During transcription, the entire gene is copied into a pre-mRNA, which includes exons and introns.
During the process of RNA splicing, introns are removed and exons are joined to form a contiguous coding
sequence. In its entirety, the part of the human genome formed by exons is called the exome. As might be
expected, errors or mutations may occur during transcription; however, a proofreading enzyme generally
catches and repairs these errors.
Translation:
Once transcribed, the single-stranded mRNA detaches and the double-stranded DNA zips back together. The
mRNA then moves out of the nucleus into the cytoplasm, where it provides instructions for the production of a
protein, a process termed translation. The mRNA attaches itself to a ribosome. The ribosome moves along the
mRNA strand, reading the message in three-letter “words,” or codons, such as GCU, CUA, and UAG. Most of
these triplets code for specific amino acids, the building blocks of proteins. As these triplets are read, another
type of RNA, transfer RNA (tRNA), carries the requisite amino acids to the ribosome, where
they are linked to form a protein. Certain triplets, termed stop codons, instruct the ribosome
to terminate the sequence by indicating that all of the correct amino acids are in place to form
the complete protein. Once the protein is complete, the mRNA, ribosome, and protein
separate. The protein is released into the cytoplasm and is either used by the cytoplasm or
prepared for secretion into the bloodstream. If the protein is to be secreted, it is transferred
to the Golgi apparatus, which packages it in a form that can be released through the cell
membrane and carried throughout the body.
, Mutations:
An abnormality at any step in the transcription or translation process can cause the body to produce a
structurally abnormal protein, reduced amounts of a protein, or no protein at all. When the error occurs in the
gene itself, thus disrupting the subsequent steps, that mistake is termed a mutation. Although most mutations
occur spontaneously, they can be induced by radiation, toxins, and viruses. Once they occur, mutations become
part of a person’s genetic code. If they are present in the germline, they can be passed on from one generation
to the next. Types of mutations are:
point mutations = most common type where there is a single base pair substitution. many point
mutations have no adverse consequences. Depending on where in the gene they occur, however,
point mutations are capable of causing a missense mutation or a nonsense mutation. A missense
mutation results in a change in the triplet code that substitutes a different amino acid in the protein
chain. In a nonsense mutation, the single base pair substitution produces a stop codon that
prematurely terminates the protein formation
Insertions and deletions = the insertion or deletion of one or more nucleotide bases. Base additions or
subtractions may also lead to a frame shift in which the three-base-pair reading frame is shifted. All
subsequent triplets are misread, often leading to the production of a stop codon and a nonfunctional
protein
Selective advantage:
The incidence of a genetic disease in a population depends on the difference between the rate of mutation
production and that of mutation removal. Typically, genetic diseases enter populations through mutation
errors. Natural selection, the process by which individuals with a selective advantage survive and pass on their
genes, works to remove these errors.
Single nucleotide polymorphisms:
The DNA sequence variations are called single nucleotide polymorphisms (SNPs). This genetic variation is the
basis of evolution, but it can also contribute to health, unique traits, or disease. Knowledge of SNPs, as well as
candidate disease genes, allows a better understanding of certain genetic conditions, which can lead to the
development of novel treatments.
Single-Gene (mendelian) disorders:
Gregor Mendel pioneered our understanding of single-gene defects. While cultivating pea plants, he noted that
when he bred two differently colored plants (yellow and green) the hybrid offspring all were green rather than
mixed in color. Mendel concluded that the green trait was dominant, whereas the yellow trait was recessive.
However, the yellow trait sometimes appeared in subsequent generations. Later, scientists determined that
many human traits, including some birth defects, are also inherited in this fashion. They are referred to as
Mendelian traits. Single-Gene disorders can be transmitted to offspring on the autosomes or on the X
chromosome. Mendelian traits may be either dominant or recessive. Thus, Mendelian disorders are
characterized as being autosomal recessive, autosomal dominant, or X-linked.
For a child to have a disorder that is autosomal recessive, he or she must carry an abnormal gene on
both copies of the relevant chromosome. In the vast majority of cases, this means that the child receives an
abnormal copy from both parents. The one exception is uniparental disomy. The different forms of a gene,
called alleles, include the normal gene (symbolized by a capital “A” and is dominant) and the mutated allele
(symbolized by the lowercase “a” and is recessive). Upon fertilization, the embryo receives two genes, one
from the father and one from the mother. The following combinations of alleles are possible: homozygous
(carrying the same allele) combinations, AA or aa, and heterozygous (carrying alternate alleles) combinations,
aA or Aa. Two abnormal recessive genes (aa) are needed to produce a child who has the disease. Therefore, a
child with aa would be homozygous for a mutation (i.e., have two copies of the mutated gene and manifest the
disease), a child with aA or Aa would be heterozygous and a healthy carrier of the mutation, and a child with AA
would be a healthy noncarrier. Siblings of affected children, even if they are carriers, are unlikely to produce
children with the disease because this can only occur if they have children with another carrier, which is an
unlikely occurrence in these rare diseases except in cases of intermarriage. Because it is unlikely for a carrier of
a rare condition to have children with another carrier of the same disease, autosomal recessive disorders are
