Trisomy 21

“Down Syndrome” Essay, Research Paper

Trisomy 21 is caused, as the name suggests, by the triplication of the 21st chromosome. Genes which, simplified, contain the blueprints for our cellular structure, are grouped along rod-like structures called chromosomes. Normally, the nucleus of each cell contains 23 pairs of chromosomes, half of which are inherited from each parent. In Down syndrome (DS), however, the cells usually contain not 46, but 47 chromosomes. This excess genetic material, in the form of additional genes along the 21st chromosome, results in DS. The estimated incidence of Down syndrome is between 1 in 1,000 to 1 in 1,100 live births. Each year approximately 3,000 to 5,000 children are born with this chromosome disorder. It is believed there are about 250,000 families in the United States who are affected by DS. (Berg, 614) Discussed in this paper will be a more detailed description of the pathophysiology of Down syndrome, as well as the discovery, possible causes, physical features, associated conditions, possible treatment, electroneurodiagnostic corollaries, and psychosocial issues.

Down syndrome or Trisomy 21 has been alluded to in art, literature and science for centuries. One of the more interesting of these is the “Changeling” in Gaelic myth. It was believed that when a child was born with the dysmorphic characteristics now associated with DS i.e. epicanthal folds, simian creases, small ears etc., an elf or evil spirit had replaced the infant that was meant to be theirs with the offspring of a mischievous creature. However, it wasn’t until 1866, that a physician named John Langdon Down published an essay in England in which he described a set of children with common features who were distinct from other children with mental retardation. Down was superintendent of an asylum for children with mental retardation in Surrey, England when he made the first distinction between children who were cretins (later to be found to have hypothyroidism) and what he referred to as “Mongoloids.” Down based this unfortunate name on his notion that these children looked like people from Mongolia, who were thought then to have an arrested development. This ethnic insult came under fire in the 1960s from Asian genetic researchers, and the term was dropped from scientific use. Instead, the condition became called “Down’s syndrome.” In the 1970s, an American revision of scientific terms changed it simply to “Down syndrome,” due to the insinuation of ownership caused by the possessive apostrophe, although it is still called “Down’s” in Europe. The causes of DS were much speculated over during the first part of the twentieth century. The first to speculate that Down syndrome might be chromosomal in nature were Waardenberg and Bleyer during the 1930’s. However it wasn’t until 1959 that Jerome Lejeune and Patricia Jacobs, working independently, first determined the cause to be trisomy (triplication) of the 21st chromosome.

To understand the pathophyisology of Trisomy 21 you must first understand the basic structure of chromosomes. Chromosomes are thread-like structures composed of DNA and other proteins. They are present in every cell of the body and carry the genetic information needed for that cell to develop. Genes, which are units of information, are “encoded” in the DNA. Human cells normally have 46 chromosomes, which can be arranged in 23 pairs. Of these 23, 22 are alike in males and females; these are called the “autosomes.” The 23rd pair are the sex chromosomes (’X’ and ‘Y’). Each member of a pair of chromosomes carries the same information, in that the same genes are in the same spots on the chromosome. However, variations of that gene (”alleles”) may be present. (Example: the genetic information for eye color is a “gene;” the variations for blue, green, etc. are the “alleles.”)

Human cells divide in two ways. The first is ordinary cell division (”mitosis”), by which the body grows. In this method, one cell becomes two cells, which have the exact same number and type of chromosomes as the parent cell. The second method of cell division occurs in the ovaries and testicles (”meiosis”) and consists of one cell splitting into two, with the resulting cells having half the number of chromosomes of the parent cell. So, normal eggs and sperm cells only have 23 chromosomes instead of 46. Many errors can occur during cell division. In meiosis, the pairs of chromosomes are supposed to split up and go to different spots in the dividing cell; this event is called “disjunction.” However, occasionally one pair doesn’t divide, and the whole pair goes to one spot. This means that in the resulting cells, one will have 24 chromosomes and the other will have 22 chromosomes. This accident is called “nondisjunction.” If a sperm or egg with an abnormal number of chromosomes merges with a normal mate, the resulting fertilized egg will have an abnormal number of chromosomes. In DS, 95% of all cases are caused by this event: one cell has two 21st chromosomes instead of one, so the resulting fertilized egg has three 21st chromosomes. Hence the scientific name, trisomy 21. Recent research has shown that in these cases, approximately 90% of the abnormal cells are the eggs. The cause of the nondisjunction error isn’t known, but there is definitely connection with maternal age. Research is currently aimed at trying to determine the cause and timing of the nondisjunction event. Three to four percent of all cases of trisomy 21 are due to Robertsonian Translocation. (Leshin, www.ds-health.com, 2000) In this case, two breaks occur in separate chromosomes, usually the 14th and 21st chromosomes. There is rearrangement of the genetic material so that some of the 14th chromosome is replaced by extra 21st chromosome. So while the number of chromosomes remain normal, there is a triplication of the 21st chromosome material. Some of these children may only have triplication of part of the 21st chromosome instead of the whole chromosome, which is called a partial trisomy 21. Translocations resulting in trisomy 21 may be inherited, so it’s important to check the chromosomes of the parents in these cases to see if either may be a “carrier.” The remainder of cases of trisomy 21 are due to mosaicism. These people have a mixture of cell lines, some of which have a normal set of chromosomes and others which have trisomy 21. In cellular mosaicism, the mixture is seen in different cells of the same type. In tissue mosaicism, one set of cells, such as all blood cells, may have normal chromosomes, and another type, such as all skin cells, may have trisomy 21.

The chromosomes are holders of the genes, those bits of DNA that direct the production of a wide array of materials the body needs. This direction by the gene is called the gene’s “expression.” In trisomy 21, the presence of an extra set of genes leads to overexpression of the involved genes, leading to increased production of certain products. For most genes, their overexpression has little effect due to the body’s regulating mechanisms of genes and their products. But the genes that cause Down syndrome appear to be exceptions.

Which genes are involved? That’s been the question researchers have asked ever since the third 21st chromosome was found. From years of research, it has been found that only a small portion of the 21st chromosome actually needs to be triplicated to get the effects seen in DS; this is called the Down syndrome Critical Region. However, this region is not one small isolated spot, but most likely several areas that are not necessarily side by side. The 21st chromosome may actually hold 200 to 250 genes (being the smallest chromosome in the body in terms of total number of genes); but it’s estimated that only 20 to 50 genes may eventually be included in the Down syndrome Critical Region. (Berg 615) Right now, the question of which genes do what is highly speculative. However, there are some suspects; Superoxide Dismutase (SOD1)- overexpression may cause premature aging and decreased function of the immune system; its role in Senile Dementia of the Alzheimer’s type or decreased cognition is still speculative., COL6A1- overexpression may be the cause of heart defects. ETS2 -overexpression may be the cause of skeletal abnormalities and/or leukemia. CAF1A-overexpression may be detrimental to DNA synthesis. Cystathione Beta Synthase (CBS)– overexpression may disrupt metabolism and DNA repair. DYRK-overexpression may be the cause of mental retardation. CRYA1- overexpression may be the cause of cataracts. GART- overexpression may disrupt DNA synthesis and repair. INFAR- the gene for expression of Interferon, (Leshin) overexpression may interfere with the immune system as well as other organ systems. Other genes that are also suspects include APP, GLUR5, S100B, TAM, PFKL, and a few others. (Vosatka, 185) Again, it is important to note that no gene has yet been fully linked to any feature associated with DS.

One of the more notable aspects of Down syndrome is the wide variety of features and characteristics of people with trisomy 21: there is a wide range of mental retardation and developmental delay noted among children with DS. Some babies are born with heart defects and others aren’t. Some children have associated illnesses such as epilepsy, hypothyroidism or celiac disease, and others don’t. The first possible reason is the difference in the genes that are triplicated. As I mentioned above, genes can come in different alternate forms, called “alleles.” The effect of overexpression of genes may depend on which allele is present in the person with trisomy 21. The second reason that might be involved is called “penetrance.” If one allele causes a condition to be present in some people but not others, that is called “variable penetrance,” and that appears to be what happens with trisomy 21: the alleles don’t do the same thing to every person who has it. Both reasons may be why there is such variation in children and adults with Down syndrome.

The actual causative factors of Downs are still unknown. Although many theories have been developed. Some professionals believe that hormonal abnormalities, X-rays, viral infections, immunologic problems, or genetic predisposition may be the cause of the improper cell division resulting in DS. It has been known for some time that the risk of having a child with Down syndrome increases with advancing age of the mother; i.e., the older the mother, the greater the possibility that she may have a child with DS. However, most babies with Down syndrome (more than 85 percent) (Vosatka, 213) are born to mothers younger than 35 years. Some investigators reported that older fathers might also be at an increased risk of having a child with DS.

An interesting note about this is that this is only the case for Down syndrome caused by the triplication of chromosome 21, the risk of DS through Robertsonian translocation actually decreases with age. Again the causes of this are not fully realized, only that the risks for triplication of chromosome 21 seem to be variable and increase exponentially with age, while Robertsonian translocation is a constant variable and seems to be hereditary. Approximately 40% to 50% are familial in that they are inherited from a cytogenetically balanced parent. (Epstien 57)

Diagnosis of Down syndrome can be done either prenatally through screening and diagnostic tests, or through physical examination of the newborn. The most commonly used screening tests are the Triple Screen and the Alpha-fetoprotein Plus. (National DS Society) These tests measure quantities of various substances in the blood (alpha-fetoprotein, human chorionic gonadotropin and unconjugated estriol) and together with the woman’s age, estimate her risk of having a child with DS. These screening tests are typically offered between fifteen and twenty weeks of gestation. Screening tests are of limited value and are often performed in conjunction with a detailed sonogram. These tests are only able to accurately detect about sixty percent of fetuses with Down syndrome. (National Down Syndrome Society) Many women who undergo these tests will be given false-positive readings, and some women will be given false-negative readings. The procedures available for prenatal diagnosis of DS are chorionic villus sampling (CVS), amniocentesis and percutaneous umbilical blood sampling (PUBS). Each one of these procedures carries a small risk of miscarriage as tissue is extracted from the placenta or the umbilical cord to examine the fetus’ chromosomes. The procedures are about 98 to 99 percent accurate in the detection of Down syndrome. (National Down Syndrome Society) Amniocentesis is usually performed between 12 and 20 weeks of gestation, CVS between eight and 12 weeks and PUBS after 20 weeks. The diagnosis of DS is usually suspected after birth as a result of the baby’s appearance. It is a particularly difficult time, coupled with the natural stresses of childbirth. Although there is no easy way to be informed, most families agree that having the baby present, being together and being told as soon as possible is the best way to proceed. There are many physical characteristics which form the basis for suspecting an infant has Down syndrome. Many of these characteristics are found, to some extent, in the general population of individuals who do not have DS. Hence, if Down syndrome is suspected, a karyotype will be performed to ascertain the diagnosis. Some infants with DS have only a few of these traits, while others have many. Among the most common traits (with corresponding percentage of frequency) are; oblique (upslanting) palpebral fissures (82%), loose skin on nape of neck (81%), narrow palate (76%), brachyclephaly (75%), flat nasal bridge (68%), gap between first and second toes (68%), short, broad hands (64%), short neck (61%), abnormal teeth (61%), epicanthic folds (59%), short fifth finger (58%), open mouth (57%), Incurved fifth finger (57%), Brushfield spots (56%), Furrowed tongue (55%), transverse palmer crease (53%), folded or displastic ear (50%), protruding tongue (47%). (Berg, 614)

Along with the dysmorphic features, Down syndrome also has many more serious associated conditions. Again not all conditions appear in all patients with DS, but the risk is generally much higher than those without Down syndrome.

The most characteristic feature of DS in newborns and infants is hypotonia, which is weak or absent muscle tone. In a longitudinal study, the muscle tone of Down syndrome newborns was rated as 1.6 plus or minus .84 for males and 1.5 plus or minus .70 for females at two years of age (with 0=extremely hypotonic, 1= moderate, 2= mild, 3= normal).(Epstein 50)

Mental retardation occurs to some degree in all individuals with DS. The degree of mental retardation varies from mild (IQ: 50 – 70) to moderate (IQ: 35 – 50), and only occasionally to severe (IQ: 20 – 35). The greatest problem being language development, and the ability to handle more advance cognitive strategies and processes. Such as the inability to comprehend instructions, to plan alternative approaches to the problem, to attend to several variable at one time, or to express oneself clearly to another to receive help. Patients with Down syndrome are highly receptive of their environment and respond well to early intervention with an average of 10 points higher IQ (intelligence quotient) and 15 points higher DQ (developmental quotient). (Berg, 615) With the exception of the profound hypotonia, the behavior of infants with DS is generally normal at birth. Developmental retardation usually becomes obvious during the first few months of life, and the mean age at which developmental landmarks are attained becomes increasingly more delayed as time goes on. Thus although the average delay may be of the order of two months for the very early landmarks (e.g. rolling over, transferring objects), it gradually lengthens and reaches one to two years for function that ordinarily appear at about two years of age. For example an average two year old would be expected to speak in three word sentences, and feed themselves, while a child with Down syndrome might not be able to accomplish this until they were four.

Patients with DS also have a higher occurrence of Alzheimer’s disease. The exact percentage is currently under debate, with estimates ranging from twenty-five percent to as high as seventy five percent depending on age. This controversy stems from the fact that nearly all Down syndrome patients (upwards of 97%) (Leshin, www.ds-health.com), exhibit a pathology characteristic of Senile dementia. Namely neuronal tangles, and plaque deposits which exhibit themselves approximately fifteen years earlier (some as early as 35 years of age) than in patients without Down’s. However recent evidence suggests that there isn’t the mental decline in later years as had originally been assumed. Based both on cross-sectional and relatively short-term longitudinal studies, it is claimed that only one-third of persons with DS over 35 years of age show intellectual deterioration. (Leshin, www.ds-health.com) Although the relationship between the numbers of tangle and plaques and degree of dementia in Down syndrome is not known, the most likely theory deal with the threshold level for the number of plaques and tangles necessary to cause dementia. It has been theorized that patients with DS have a higher threshold level for these abnormalities than in non-Down syndrome patients.

Sixty to eighty percent of children with DS also have hearing deficits. Brain-stem auditory evoked potentials were examined in 37 adult patients with Down syndrome and in 37 age-matched normal subjects. All absolute and interpeak latencies except for the interpeak latency IV-V were shorter in the patients with DS than in normal subjects. The amplitude of wave V and the amplitude ratio of V/I were smaller in patients than in normal subjects. Short latencies in patients were considered to be due to the smaller size of the brain-stem or to faster conduction velocity. The prolonged interpeak latency IV-V and smaller wave V may indicate physiological dysfunctions between the upper pons and lower midbrain. (National DS Society)

Forty to forty-five percent of children with Down syndrome have congenital heart disease. Thirty three percent of these are endocardial cushion defects, and the remainder are verntricular septal defects. Tetralogy of Fallot and atrial septal defects also occur. (Epstein, 58)

Malformations of the gastrointestinal tract, including intestinal atresia and iperforate anus, occur in about five to ten percent of patients, and there is a reported increased incidence of Hirschsprung’s disease, as well as a higher incidence of gastro-esophogeal reflux. (Epstein, 58)

Seizure activity is also a risk although if you look at the population of all children with mental retardation, there is a very large number (from 20 to 40%) that have epilepsy. The number is quite lower in DS, but it’s still a larger number than in the general population. Studies in the last two decades have estimated the number of people with DS who have seizures to be from 5 to 10%. (Epstein 56)

There appears to be two “peaks” in ages at which the onset of epilepsy is more common in DS. The first peak occurs in the first two years of life. The type of seizure most often seen in this age range is the “infantile spasm.” This type of seizure involves what looks like a spasm of the body, lasting a few seconds, and sometimes not affecting the infant’s state of consciousness. It can also look like a quick drop of the head and/or shoulders if the baby is sitting or standing up. Another type of seizure seen is the generalized “tonic-clonic” seizure (also called “grand mal”); this type of seizure involves the whole body, with stiffening of the trunk and jerking of the extremities, followed by a period of sleepiness. Other types of seizures have been described, including atonic (head-drop) seizures and reflex (myoclonic, “startle”) seizures.

When the second peak occurs is more debatable, with some researchers putting it at 15-25 years, and others putting it in the third decade of life. The most common seizure in this age range is the tonic-clonic seizure, but other types are also seen.

Other associated abnormalities include pulmonary hypertension, upper airway obstruction, obstructive sleep apnea, and an increased incidence of thyroid dysfunction, diabetes mellitus, cataracts, and leukemia.

Electroencephalography has not been shown to have any conclusive diagnostic value for Down syndrome, aside from the diagnosis of associated conditions such as seizure disorders and to some degree Alzheimer’s. However according to Ellingson et al (1970) EEG abnormalities occur in twenty to thirty percent of Down’s patients and are more common in childhood than in adulthood. Gibbs and Gibbs (1964) described bilateral “spike-like” activity over parietal areas in sleep records of DS children and also noted widespread monorhythmic 4/sec waves (chiefly frontal and parietal in the waking state. Prominent occipital high voltage 1-2/sec waves with a sharp component in the terminal phase were also reported (Gibbs and Gibbs, 1964). There are no correlations between EEG abnormalities and special clinical features.(Neidermeyer 373-374)

Currently there is no specific treatment for Down Syndrome, and therapy is focused on treating the associated conditions as well as early intervention for educational needs. Research on Down syndrome is making great strides in identifying the genes on chromosome 21 that cause the characteristics of Down syndrome. Scientists now feel strongly that it will be possible to improve, correct or prevent many of the problems associated with Down syndrome in the future.

In the past it was assumed that due to the nature of the developmental delay with Down syndrome patients, their emotional growth was somehow also stunted. This has been proved to be most untrue. In an emotional and psychological context the adult DS patient goes through the same developmental stages that a non-Down’s syndrome person might. They experience puberty at the same time, with the intimacy needs that are inclusive with that stage in development. Women with Down syndrome are capable of reproduction, however there is a thirty-five to fifty percent chance that their child will also have DS. Males with Down syndrome are generally accepted to be sterile, although there was one documented case in England of a male patient fathering a child. Today people with DS live at home with their families and are active participants in the educational, vocational, social and recreational activities of the community. They are integrated into the regular education system, and take part in sports, camping, music, art programs and all the other activities of their communities. In addition, they are socializing with people with and without disabilities, and as adults are obtaining employment and living in group homes and other independent housing arrangements.

In conclusion, while living with Down syndrome is difficult, and carries with it inherent challenges and unfortunately many health risks, it is possible for the DS patient to live a full and productive life. Social stigmas abound, and the ability to for many people with DS to fully realize their potential is often stunted by well meaning, but poorly educated parents, schools, and health care providers. However, it is only through the collective efforts of parents, professionals and concerned citizens that acceptance is becoming widespread. Individuals with Down syndrome are being employed in small and medium sized offices: by banks, corporations, nursing homes, hotels and restaurants. They work in the music and entertainment industry, in clerical positions and in the computer industry. Like any patient that we see, they should be treated with dignity and respect.

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Charles J. Epstein “Down Syndrome” Pediatric Neurology. Ed. K.L. Briggs New York

Tellman & Geriwitz publishing, 1998. 49-58

Ernst Niedermeyer, Electroencephalography, Basic principles, Clinical Applications, and

Related Fields. Baltimore. Williams & Wilkins, 1998. 373-374

Rober J. Vosatka “Techniques of Molecular Diagnosis” Avery’s Diseases of the

Newborn. Ed. H William Taeusch. Philadelphia W.B. Saunders Company, 1995. 184-185, 210-213.

Len Leshin, M.D., F.A.A.P. “Trisomy 21: The Story of Down Syndrome” Down Syndrome: Health Issues. www.ds-health.com, 2000

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