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Down syndrome and Epilepsy

Definition

Down syndrome, also known as trisomy 21 syndrome, is a chromosomal disorder that is caused by the presence of extra chromosome 21 material in the "blueprint" of the body. The combination of birth defects present in individuals with DS include heart defects, infection, vision and hearing problems, and many other health problems (10). It also causes delays and limitations in physical and intellectual development (6).

Brief History

Down syndrome is named after an English physician, John Langdon Down. In 1862, he first reported a specific group of patients with unique physical characteristics (4). Four years later, he published a scholarly essay in which he described a set of children with common features that were distinct from those in mental retardation (8). He also described the ethnic classification of idiots, where he used the term "Mongoloids" to refer to these children. However, in the early 1960s, when Asian genetic researchers protested the ethnic insult that came from the use of such term, the condition became known as Down's syndrome (11). During the 1970s, an American revision of scientific terms simplified it to "Down Syndrome" (11). Down's clinical description of the condition roughly remained the same up to now, except for the addition of descriptions of single transverse crease in the palm (noted by Reginald in 1908) and the characteristic grey spots on the iris of the eye (noted by Brushfield in 1924) (4).

Starting at the early 20th century, researchers began to look into the causes of Down syndrome. In the 1930s, Waardenberg and Bleyer first speculated that Down syndrome is due to chromosomal abnormalities (11). However, it was not until 1959 that Jerome Lejeune and Patricia Jacobs individually determined the cause to be the trisomy (triplication) of the 21st chromosome (11). In the next three years, translocation and mosaicism were also described (11).

Prevalence

Down syndrome occurs in approximately 1 in 700 to 900 live births in Canada (around 35,000 – 45,000 persons with Down syndrome) (3).
Over 350,000 in the United States have Down syndrome (8).
Down syndrome is the most common cause of mental retardation and malformation in newborns (14).
The prevalence of Down syndrome does not correlate with race, religion, nationality, or socioeconomic status (5).
About 88% of the time, the mother provides the extra chromosome 21. In about 8% of the cases, it is derived from the father. In the remaining cases, Down syndrome is caused by mitotic errors – errors in cell division shortly after fertilization (9).

Risk of DS increases dramatically with the mother's age (9):

Mother's age	Incidence of Down Syndrome
under 30 30 35 36 37 38 39 40 42 44 46 48 49	Less than 1 in 1,000 1 in 900 1 in 400 1 in 300 1 in 230 1 in 180 1 in 135 1 in 105 1 in 60 1 in 35 1 in 20 1 in 16 1 in 12

Cause

Down syndrome is a genetic disorder that is caused by the presence of an extra set of genes, on chromosome 21. Thus, it is often referred to as Trisomy 21, meaning the triplication of the 21st chromosome. The extra information on the genes leads to over-expression, which also leads to increased production of certain proteins. Usually, over-expression can be compensated by the body's regulating mechanisms, but the genes involved in Down syndrome appear to be exceptions (11). There are generally three possible causes of Down syndrome: 1) non-disjunction (95% of all cases); 2) mosaicism (1-2% of all cases); and 3) translocation (3-4% of all cases).

Non-disjunction is the most common cause of Down syndrome. It occurs prior to, or at, conception, when a pair of the 21st chromosomes, in either the sperm or the egg, fail to separate (8). This results in the baby having a total of 47 chromosomes instead of the normal 46, and the three 21st chromosomes are labelled as trisomy 21 (14). As the embryo develops, the extra chromosome is replicated in every cell of the body, causing the symptoms that are seen in Down syndrome. Recent researches have shown that in approximately 90% of all non-disjunction cases, the abnormal cells come from the mother (11). This is due to the fact that error in cell division is more likely to occur in the egg prior to conception. It has also been hypothesized that some environmental factors are implicated with non-disjunction (8). However, it is important to note that currently there is no known connection between any types of Down syndrome and the mother's activities before or during pregnancy (8). What causes non-disjunction
is still unknown, but there is definitely a correlation with maternal age.

Mosaicism is very similar to non-disjunction. The only difference is that the error occurs shortly after fertilization – the phase where cells are dividing rapidly. Therefore, individuals with mosaic Down syndrome possess two types of cells: normal cells that have 46 chromosomes and trisomy 21 cells with 47 chromosomes (14). Some researchers suggest that the symptoms in mosaic Down syndrome are somewhat less severe than those associated with non-disjunction (14). However, the physical symptoms of mosaic Down syndrome may vary, depending on the proportion of abnormal cells that the person carries (9). There are two types of mosaicism: in cellular mosaicism, the mixture is seen in the same type of cells; in tissue mosaicism, one set of cells (e.g. blood cells) may have normal chromosomes, while another set of cells (e.g. skin cells) may have trisomy 21.

Translocation occurs when, during cell division, a section of chromosome 21 breaks off and attaches to another chromosome, usually number 14. In this case, each cell still has 46 chromosomes, but the extra piece of genetic information results in the signs and symptoms of Down syndrome (14). Like non-disjunction, translocation occurs either before or at conception. However, unlike non-disjunction, risk of translocation is not connected with maternal age (8). In addition, in about 1/3 of cases, one parent is a carrier of translocated chromosome, meaning that the chance of having another child with translocation Down syndrome may increase significantly. In other cases, translocation occurs spontaneously (3).

Common Symptoms

Some facial features that could be seen in individuals with Down syndrome are: (6), (7), (14)

Flattened and small nose (low nasal bridge)
Upward slanting eyes
Flat face
Small mouth, which causes the tongue to protrude and to appear overly large
Epicanthal folds – extra rounded folds of skin located at the inside corner of each eye
Small, misshapen ears
Iris lesion, Brushfield spots – an abnormality of the coloured part of the eye

Other symptoms include: (7), (10), (14)

Low muscle tone, somewhat "floppy"
Simian crease – an unusual, deep crease across the center of the palm
Small and wide hands (microcephaly), with short fingers
A malformed fifth finger
A wide gap between the big and the second toes
Unusual creases on the soles of the feet
Double-jointed – overly-flexible joints
Shorter than normal height
Short necks
Delayed mental and social skills development
Mental retardation

In addition, many other health problems may be implicated in Down syndrome: (7), (13), (14)

Congenital heart defects
Cardiac abnormalities
Gastrointestinal abnormalities such as esophageal atresia (obstruction of the esophagus) and duodenal atresia (obstruction of the duodenum)
Higher than average incidence of acute lymphocytic leukemia
Low levels of thyroid hormone
Skeletal problems such as joint instability
Poor weight gain in infants
Increased risk of infections
Skin disorders
Visual problems
Poor hearing
Seizures

Seizures

Studies have estimated that the prevalence of seizures in the Down syndrome population is from 5 to 10% (1). The reason for such high incidence lies in the balance between the excitatory and inhibitory pathways in the brain. A seizure could occur when there is (1):

However, other factors may also be involved, since not all children with Down syndrome have seizures, these factors include: (2)

Microscopic CNS abnormalities that are associated with chromosomal disorders may increase the vulnerability to seizure disorders.
Down syndrome may cause abnormalities of neurotransmitters, which in turn affect serotoninergic systems.
Additional congenital abnormalities are associated with seizures in early infancy
Recently, a gene on the number 21 chromosome has been found to be related to progressive myoclonic epilepsy

The most common type of seizure found in patients with Down syndrome is generalized tonic-clonic seizure (2).

Diagnosis

There are generally four tests that could be performed prior to birth to determine the risks of chromosomal disorders in the babies. These include amniocentesis, chorionic villus sampling (CVS), ultrasound, and percutaneous umbilical cord blood sampling (PUBS).

Among these, the most commonly used test is amniocentesis. It is performed at around 15-20 weeks of pregnancy, and the results are usually available within two weeks (12). Amniocentesis is the safest diagnostic method, as the risk of miscarriage is only between 0.25 to 0.5%, and that less than 0.001% women develop a uterine infection after the procedure (15). The procedure for amniocentesis is as follows (15):

Amniocentesis is recommended only to women who (15):

Are 35 years or older
Have a screening test or exam result that indicates a possible birth defect or problem
Had birth defects in previous pregnancies
Have family history of genetic disorders

Chorionic Villus Sampling (CVS) involves removing a tiny piece of tissue from placenta. It could be performed earlier than amniocentesis, at around 10-12 weeks into pregnancy, and the results are also available within 2 weeks (12). However, CVS does carry a higher risk of miscarriage (1 to 2%) than amniocentesis, but the degree of risk is often related to the skill and experience of the doctor performing the procedure (15). Other risks involved with CVS may include: birth defects, rupture of amniotic sac, uterine infection, and vaginal bleeding (15). CVS is accurate 99% of the time; in cases of uncertainty, amniocentesis may be performed later in pregnancy (15). There are two ways CVS could be carried out: transabdominal (through the abdomen) and transcervical (through the cervix). Often if the woman has a tipped uterus, the doctor would choose the transabdominal procedure to minimize the risk of fetal harm.

Transabdominal CVS (15):

Transcervical CVS (15):

Percutaneous Umbilical Cord Blood Sampling (PUBS) is the most accurate method out of all, but carries the greatest risk of miscarriage (around 2%) (15). It cannot be done until the 18-22 week of pregnancy, and is usually recommended when other tests do not provide any conclusive results on the fetus' condition (9). Results from PUBS come out in as soon as 48 hours (15). The procedure of PUBS is very similar to that of amniocentesis, but instead of analyzing the fetal cells from the amniotic fluid, fetal blood is drawn: under ultrasound guidance, the doctor inserts a fine needle through the mother's abdomen into the fetal vein in the umbilical cord. The fetal blood is then analyzed to detect chromosomal defects, other abnormalities, certain infections, and blood disorders (15).

Another generally used diagnostic procedure is ultrasound. Its purpose is to determine the status of a pregnancy. There is no known health risks associated with ultrasound, although long-term effects may exist. The procedure for ultrasound is as follows (15):

It is important to note that these diagnostic tests do not provide definite conclusions about your child; it only suggests a risk of having a disorder.

Diagnosis could also be performed after the birth of the child. The attending physician will most likely notice the physical features while the baby is still in the delivery. However, further tests must be performed to ensure the accuracy of the diagnosis. A very commonly used blood test is called chromosomal karyotype. It involves "growing" the baby's blood cells for about two weeks, followed by a microscopic visualization of the chromosomes to determine if extra material from chromosome 21 is present (9). Additional tests may include chest and gastrointestinal x-rays, echocardiography, and electrocardiogram (13).

Classification

There is currently no classification for Down syndrome. However, some professionals describe different types of Down syndrome according to the causes. Please refer to the causes section.

References:

Down Syndrome and Epilepsy

http://www.ds-health.com/epilepsy.htm

Epilepsy: A Comprehensive Textbook

What is Down Syndrome and Types of Down Syndrome

http://www.cdss.ca/medicalguidechildren.html

John Langdon Down and Down's Syndrome

http://www.intellectualdisability.info/changing-values/history_cw.htm

What is Down Syndrome?

http://www.dsamt.toronto.on.ca

Alzheimer Disease and Down Syndrome

http://www.alzheimer.ca/english/disease/causes-down.htm

Down Syndrome