The majority of human
chromosomal abnormalities occur in the autosomes.
Most of these abnormalities are monosomies or trisomies.
In the case of a monosomy, there
is only one copy of each kind of chromosome instead of the usual pair of
homologous chromosomes. With trisomy, there are three of each type of chromosome.
All fetuses with autosomal monosomies spontaneously abort early in pregnancy.
Likewise, almost
all fetuses with trisomies die before birth. Those that survive usually have
multiple physical malformations, mental retardation, and relatively short
lives.
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The most well known and most common
autosomal abnormality is Down syndrome
. This is a mild to severe form of mental retardation accompanied by
distinctive physical traits. People with Down syndrome have an irregularity with autosome
pair 21. In most cases, there is an extra chromosome (i.e., trisomy). More
rarely (3-5%), there is a structural modification in this chromosome. Specifically,
there is a translocation of all or part of chromosome 21 to chromosome 14 or
15. The actual gene or genes on chromosome 21 that
are responsible for Down syndrome are now being identified in a critical region of 20-40
genes. About 2-4% of Down syndrome people are genetically mosaic. That is, some of their cells have chromosome 21
trisomy while others do not, resulting in generally milder symptoms.
The translocational type of Down syndrome also usually has less severe
symptoms.
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|
| Normal
Chinese child with epicanthic folds of her eyelids |
Down syndrome individuals
typically have short, stocky bodies with thick hands and feet.
Their hands commonly have a simian crease, which is a crease in the palm
that runs completely from one side of the hand to the other. In addition, they
usually have broad, short heads with small low-set ears, small concave saddle-shaped
or flattened noses, relatively large
ridged tongues that roll over a protruding lower lip, low muscle tone, and
loose joints. Frequently, their eyes have an
East Asian-like appearance due to an epicanthic fold
. This is a fold of skin over
the inner corner of each eyelid, which makes the eyes appear to slant upward. Because of this eye characteristic,
Down syndrome
was referred to as Mongoloidism
when it was first described in 1866 by the English physician John Langdon Down.
However, this term was misleading because Down syndrome can occur in any human group,
not just Asians. As a result, Mongoloidism has been rejected as a synonym for
Down syndrome. It wasn't until 1959 that it was
discovered that Down syndrome individuals have an irregular number of
chromosomes.
People with Down
syndrome
frequently have other medical problems. These include epilepsy
, hypothyroidism
,
crossed eyes, near-sightedness or far-sightedness, cataracts
,
hearing impairment, heart defects, intestinal malformations, hernias
,
and a marked susceptibility to respiratory infections, such as pneumonia. Childhood leukemia
is as much as 20 times more common than average. However, there is considerable
variability within the Down syndrome population in regards to susceptibility to these unpleasant
medical problems. This is likely due to variable penetrance.
That is,
the alleles for the Down syndrome genes may cause an effect in the phenotype of some individuals
but not others. It is likely that the abnormal traits characteristic of
Down syndrome are
at least in part a result of the over expression of the involved genes. This
over expression is a consequence of the presence of an extra chromosome 21.
Down syndrome individuals appear to
age at an accelerated rate. By age 35,
at least 25%
of those who have non-mosaic Down syndrome develop
Alzheimer syndrome
. This was not a problem
a century ago because most people with Down syndrome died in childhood. Today, however, they can expect to live into their
early or even mid 50's
in the United States and most other developed nations.
Unfortunately, this is not the case in poor countries with inadequate
medical care. About 55% of South American babies
who have Down syndrome die in their first year of life.
The most prominent and debilitating trait of people with Down syndrome is mental retardation. They usually only reach a mental age level of a 3-7 year old normal child. They are slow learners and their abstract reasoning is particularly limited. However, some high achieving individuals with Down syndrome have mental levels of 12 year olds, which is sufficient to function in society with little assistance. People with Down syndrome usually have gentle, shy, trusting personalities and are very warm and loving.
The
majority of Down syndrome fetuses are not sufficiently viable to
survive to birth--approximately 85% of them spontaneously abort.
It is likely that as many as 1/4 of all miscarriages are due to the trisomy form of
Down syndrome. However, about
350,000 people with Down syndrome in the
U.S. have survived birth and are alive today. While this is a large number, it is important to realize
that not all mentally retarded people have Down syndrome. In fact, the sex chromosome abnormality known as
fragile-X syndrome
may be responsible for more mental retardation.
The overall incidence of Down syndrome is only about 1 in 800 live births. However, the rate varies markedly with the age of the mother when conception occurs. This is the case for the common trisomy form of Down syndrome but not the rare translocational form. Women who are 20 years old apparently have the lowest chance (1 in 2000) of having a Down syndrome child. Women do not reach the average risk rate of 1 in 800 until they are about 30. Older mothers have a far higher frequency as indicated in the table below. As a result, amniocentesis is regularly recommended for women 35 and over. It is not routinely recommended for younger women because the diagnostic benefits do not outweigh the risk of miscarriage.
| Age of Mother | Frequency
of Down Syndrome |
Frequency of Any Chromosomal Disorder |
|---|---|---|
|
20 25 30 35 36 37 38 39 40 41 42 43 44 45 |
1 in 1667 |
1 in 526 |
Source: The American College of Obstetrics and Gynocology (based on data published in the Journal of the American Medical Association 1981;58:282-285 and 1983;249:2034-2038). Other published sources have somewhat different risk ratios, but the trend of increasing risk with the mother's age is the same. |
From these data, it would seem likely that most Down syndrome children are born to older mothers. However, this is not the case because older mothers are much less likely to have children. In the U.S., 75-80% of Down syndrome children are born to women under 35. The majority of mothers giving birth to Down syndrome children are still in their 20's.
There is some increase in the risk of Down syndrome children being conceived when the father is older. However, little data are available to support this. One study estimates that only about 5% of all Down syndrome children are the result of defective sperm. It has been suggested that defective sperm are less likely than ova to carry a Down syndrome related mutation because the entire male meiosis process resulting in the production of a sperm cell takes only 74 hours. In contrast, the female meiosis process resulting in ova actually begins before birth and is completed usually one or a few cells at a time later in life before each ovulation. An oöcyte can be stored in an ovary for 40-50 years or more before becoming an ovum. During that time, environmental contamination theoretically can render it defective. The very short life of sperm cells reduces the chance of such contamination. In addition, defective sperm are less likely to reach an ovum because they are more easily eliminated from competition in the process of traveling through a woman's reproductive tract.
Women who have already had a Down syndrome child are at a slightly higher risk of subsequent children also inheriting this problem. Women with Down syndrome are at a much higher risk of having children with this condition. Half of their offspring would be expected to inherit it. However, many affected fetuses are lost in miscarriages. Apparently, Down syndrome men can father a child though it is very rare--there has been only one documented instance of it.
While Down syndrome is the most common serious autosomal abnormality in humans, others are known to occur. Aberrations of chromosomes 8, 12, 13, 14, 15, and 18 have been reported. Most often, they are trisomies. Children with any of these abnormalities usually do not live as long as those with Down syndrome.
NEWS: In January 2007, the American College of Obstetricians and Gynecologists announced new guidelines for Down syndrome screening. They now recommend that all pregnant women, regardless of age, be tested with the triple or quad screening blood test and ultrasonography (described in the previous section of this tutorial). A combination of these two procedures can identify the presence of Down syndrome with 90% reliability during the first trimester of a pregnancy.
NOTE: Statistical data now show a connection between the age of a man and the likelihood that he will father a child with schizophrenia. The April 2001 issue of Archives of General Psychiatry published the results of a study indicating that men between 45-49 years of age have double the chance of fathering schizophrenic children as do men 25 or younger. For men who are 50 or over, the probability increases to three times. The age of the mother did not seem to matter. The reason that an older man is more likely to produce defective sperm may be because each of the sperm cell precursors (i.e., spermatogonia) divide about 23 times a year following puberty. In all of these divisions, there is a chance of an error in DNA replication. In addition, the DNA repair enzymes apparently are less effective in correcting errors in older men. A report in the September 2006 issue of Archives of General Psychiatry indicates that there is also a connection between the age of men and the likelihood of their fathering children with autism. The odds are 6 times higher for men who are 40 years of age or older. Other rare genetically inherited conditions have been linked to older fathers. These include dwarfism and a premature aging disease known as Hutchinson-Gilford progeria syndrome (March 29, 2008 Science News).