Introduction

Down syndrome (the most common term in US English),

Down's syndrome (standard in the rest of the English-

speaking world), trisomy 21, or trisomy G is a

chromosomal disorder caused by the presence of all or

part of an extra 21st chromosome. It is named after John

Langdon Down, the British doctor who described the

syndrome in 1866. The disorder was identified as a

chromosome 21 trisomy by Jérôme Lejeune in 1959. The

condition is characterized by a combination of major and

minor differences in structure. Often Down syndrome is

associated with some impairment of cognitive ability and

physical growth as well as facial appearance. Down

syndrome in a baby can be identified with amniocentesis

during pregnancy or at birth.

Individuals with Down syndrome tend to have a lower

than average cognitive ability, often ranging from mild

to moderate developmental disabilities. A small number

have severe to profound mental disability. The incidence

of Down syndrome is estimated at 1 per 800 to 1,000

births, although these statistics are heavily influenced

by older mothers. Other factors may also play a role.

Many of the common physical features of Down syndrome

may also appear in people with a standard set of

chromosomes, including microgenia (an abnormally small

chin)[1], an unusually round face, macroglossia[2]

(protruding or oversized tongue), an almond shape to the

1

eyes caused by an epicanthic fold of the eyelid,

upslanting palpebral fissures (the separation between the

upper and lower eyelids), shorter limbs, a single

transverse palmar crease (a single instead of a double

crease across one or both palms, also called the Simian

crease), poor muscle tone, and a larger than normal space

between the big and second toes. Health concerns for

individuals with Down syndrome include a higher risk for

congenital heart defects, gastroesophageal reflux

disease, recurrent ear infections, obstructive sleep

apnea, and thyroid dysfunctions.

Early childhood intervention, screening for common

problems, medical treatment where indicated, a conducive

family environment, and vocational training can improve

the overall development of children with Down syndrome.

Although some of the physical genetic limitations of Down

syndrome cannot be overcome, education and proper care

will improve quality of life.[3]

2

Chapter 1

Characteristics

Individuals with Down syndrome may have some or all

of the following physical characteristics: microgenia

(abnormally small chin)[1], oblique eye fissures with

epicanthic skin folds on the inner corner of the eyes

(formerly known as a mongoloid fold[2]), muscle hypotonia

(poor muscle tone), a flat nasal bridge, a single palmar

fold, a protruding tongue (due to small oral cavity, and

an enlarged tongue near the tonsils) or macroglossia[2], a

short neck, white spots on the iris known as Brushfield

spots,[4] excessive joint laxity including atlanto-axial

instability, congenital heart defects, excessive space

between large toe and second toe, a single flexion furrow

of the fifth finger, and a higher number of ulnar loop

dermatoglyphs. Most individuals with Down syndrome have

mental retardation in the mild (IQ 50–70) to moderate (IQ

35–50) range,[5] with individuals having Mosaic Down

syndrome typically 10–30 points higher.[6] In addition,

individuals with Down syndrome can have serious

abnormalities affecting any body system. They also may

have a broad head and a very round face.

The medical consequences of the extra genetic

material in Down syndrome are highly variable and may

affect the function of any organ system or bodily

process. The health aspects of Down syndrome encompass

anticipating and preventing effects of the condition,

3

recognizing complications of the disorder, managing

individual symptoms, and assisting the individual and

his/her family in coping and thriving with any related

disability or illnesses.[5]

Down syndrome can result from several different

genetic mechanisms. This results in a wide variability in

individual symptoms due to complex gene and environment

interactions. Prior to birth, it is not possible to

predict the symptoms that an individual with Down

syndrome will develop. Some problems are present at

birth, such as certain heart malformations. Others become

apparent over time, such as epilepsy.

The most common manifestations of Down syndrome are

the characteristic facial features, cognitive impairment,

congenital heart disease (typically a ventricular septal

defect), hearing deficits (maybe due to sensory-neural

factors, or chronic serous otitis media, also known as

Glue-ear), short stature, thyroid disorders, and

Alzheimer's disease. Other less common serious illnesses

include leukemia, immune deficiencies, and epilepsy.

However, health benefits of Down syndrome include

greatly reduced incidence of many common malignancies

except leukemia and testicular cancer[7] — although it is,

as yet, unclear whether the reduced incidence of various

fatal cancers among people with Down syndrome is as a

direct result of tumor-suppressor genes on chromosome 21

(such as Ets2),[8] because of reduced exposure to

4

environmental factors that contribute to cancer risk, or

some other as-yet unspecified factor. In addition to a

reduced risk of most kinds of cancer, people with Down

syndrome also have a much lower risk of hardening of the

arteries and diabetic retinopathy.[8]

5

Chapter 1.1

Cognitive development

Cognitive development in children with Down syndrome

is quite variable. It is not currently possible at birth

to predict the capabilities of any individual reliably,

nor are the number or appearance of physical features

predictive of future ability. The identification of the

best methods of teaching each particular child ideally

begins soon after birth through early intervention

programs.[9] Since children with Down syndrome have a wide

range of abilities, success at school can vary greatly,

which underlines the importance of evaluating children

individually. The cognitive problems that are found among

children with Down syndrome can also be found among

typical children. Therefore, parents can use general

programs that are offered through the schools or other

means.

Language skills show a difference between

understanding speech and expressing speech, and commonly

individuals with Down syndrome have a speech delay,

requiring speech therapy to improve expressive language.[10] Fine motor skills are delayed[11] and often lag behind

gross motor skills and can interfere with cognitive

development. Effects of the disorder on the development

of gross motor skills are quite variable. Some children

will begin walking at around 2 years of age, while others

will not walk until age 4. Physical therapy, and/or

6

participation in a program of adapted physical education

(APE), may promote enhanced development of gross motor

skills in Down syndrome children.[12]

Individuals with Down syndrome differ considerably in

their language and communication skills. It is routine to

screen for middle ear problems and hearing loss; low gain

hearing aids or other amplification devices can be useful

for language learning. Early communication intervention

fosters linguistic skills. Language assessments can help

profile strengths and weaknesses; for example, it is

common for receptive language skills to exceed expressive

skills. Individualized speech therapy can target specific

speech errors, increase speech intelligibility, and in

some cases encourage advanced language and literacy.

Augmentative and alternative communication (AAC) methods,

such as pointing, body language, objects, or graphics are

often used to aid communication. Relatively little

research has focused on the effectiveness of

communications intervention strategies.[13]

In education, mainstreaming of children with Down

syndrome is becoming less controversial in many

countries. For example, there is a presumption of

mainstream in many parts of the UK. Mainstreaming is the

process whereby students of differing abilities are

placed in classes with their chronological peers.

Children with Down syndrome may not age

emotionally/socially and intellectually at the same rates

as children without Down syndrome, so over time the

7

intellectual and emotional gap between children with and

without Down syndrome may widen. Complex thinking as

required in sciences but also in history, the arts, and

other subjects can often be beyond the abilities of some,

or achieved much later than in other children. Therefore,

children with Down syndrome may benefit from

mainstreaming provided that some adjustments are made to

the curriculum.[14]

Some European countries such as Germany and Denmark

advise a two-teacher system, whereby the second teacher

takes over a group of children with disabilities within

the class. A popular alternative is cooperation between

special schools and mainstream schools. In cooperation,

the core subjects are taught in separate classes, which

neither slows down the typical students nor neglects the

students with disabilities. Social activities, outings,

and many sports and arts activities are performed

together, as are all breaks and meals.[15]

8

Chapter 1.2

Fertility

Fertility amongst both males and females is reduced;

males are usually unable to father children, while

females demonstrate significantly lower rates of

conception relative to unaffected individuals.[citation needed]

Approximately half of the offspring of someone with Down

syndrome also have the syndrome themselves.[16] There have

been only three recorded instances of males with Down

syndrome fathering children.[17][18]

9

Chapter 2

Genetics

Down syndrome is a chromosomal abnormality

characterized by the presence of an extra copy of genetic

material on the 21st chromosome, either in whole (trisomy

21) or part (such as due to translocations). The effects

of the extra copy vary greatly among people, depending on

the extent of the extra copy, genetic history, and pure

chance. Down syndrome occurs in all human populations,

and analogous effects have been found in other species

such as chimpanzees[19] and mice. Recently, researchers

have created transgenic mice with most of human

chromosome 21 (in addition to the normal mouse

chromosomes).[20] The extra chromosomal material can come

about in several distinct ways. A typical human karyotype

is designated as 46,XX or 46,XY, indicating 46

chromosomes with an XX arrangement typical of females and

46 chromosomes with an XY arrangement typical of males.[21]

Karyotype for trisomy Down syndrome. Notice the three

copies of chromosome 21

10

Chapter 2.1

Trisomy 21

Trisomy 21 (47,XX,+21) is caused by a meiotic

nondisjunction event. With nondisjunction, a gamete

(i.e., a sperm or egg cell) is produced with an extra

copy of chromosome 21; the gamete thus has 24

11

chromosomes. When combined with a normal gamete from the

other parent, the embryo now has 47 chromosomes, with

three copies of chromosome 21. Trisomy 21 is the cause of

approximately 95% of observed Down syndromes, with 88%

coming from nondisjunction in the maternal gamete and 8%

coming from nondisjunction in the paternal gamete.[22]

Chapter 2.2

Mosaicism

Trisomy 21 is usually caused by nondisjunction in the

gametes prior to conception, and all cells in the body

are affected. However, when some of the cells in the body

are normal and other cells have trisomy 21, it is called

mosaic Down syndrome (46,XX/47,XX,+21).[23][24] This can

occur in one of two ways: a nondisjunction event during

an early cell division in a normal embryo leads to a

fraction of the cells with trisomy 21; or a Down syndrome

embryo undergoes nondisjunction and some of the cells in

the embryo revert to the normal chromosomal arrangement.

There is considerable variability in the fraction of

12

trisomy 21, both as a whole and among tissues. This is

the cause of 1–2% of the observed Down syndromes.[22]

Chapter 2.3

Robertsonian translocation

The extra chromosome 21 material that causes Down

syndrome may be due to a Robertsonian translocation in

the karyotype of one of the parents. In this case, the

long arm of chromosome 21 is attached to another

chromosome, often chromosome 14 (45,XX, t(14;21q)) or

itself (called an isochromosome, 45,XX, t(21q;21q)). A

person with such a translocation is phenotypically

normal. During reproduction, normal disjunctions leading

to gametes have a significant chance of creating a gamete

with an extra chromosome 21, producing a child with Down

syndrome. Translocation Down syndrome is often referred

to as familial Down syndrome. It is the cause of 2–3% of

observed cases of Down syndrome.[22] It does not show the

maternal age effect, and is just as likely to have come

from fathers as mothers.

13

Chapter 2.4

Duplication of a portion of chromosome 21

Rarely, a region of chromosome 21 will undergo a

duplication event. This will lead to extra copies of

some, but not all, of the genes on chromosome 21 (46,XX,

dup(21q)).[25] If the duplicated region has genes that are

responsible for Down syndrome physical and mental

characteristics, such individuals will show those

characteristics. This cause is very rare and no rate

estimates are available.

14

Chapter 3

Screening

Ultrasound of fetus with Down syndrome and megacystis

15

Pregnant women can be screened for various

complications during pregnancy. Many standard prenatal

screens can discover Down syndrome. Genetic counseling

along with genetic testing, such as amniocentesis,

chorionic villus sampling (CVS), or percutaneous

umbilical cord blood sampling (PUBS) are usually offered

to families who may have an increased chance of having a

child with Down syndrome, or where normal prenatal exams

indicate possible problems. In the United States, ACOG

guidelines recommend that non-invasive screening and

invasive testing be offered to all women, regardless of

their age, and most likely all physicians currently

follow these guidelines. However, some insurance plans

will only reimburse invasive testing if a woman is >34

years old or if she has received a high-risk score from a

non-invasive screening test.

Amniocentesis and CVS are considered invasive

procedures, in that they involve inserting instruments

into the uterus, and therefore carry a small risk of

causing fetal injury or miscarriage. The risks of

miscarriage for CVS and amniocentesis are often quoted as

1% and 0.5% respectively. There are several common non-

invasive screens that can indicate a fetus with Down

syndrome. These are normally performed in the late first

trimester or early second trimester. Due to the nature of

screens, each has a significant chance of a false

positive, suggesting a fetus with Down syndrome when, in

fact, the fetus does not have this genetic abnormality.

Screen positives must be verified before a Down syndrome

16

diagnosis is made. Common screening procedures for Down

syndrome are given in Table 1.

Table 1: First and second trimester Down syndrome screens

Screen

When

performed

(weeks

gestation)

Detection

rate

False

positive

rate

Description

Quad screen 15–20 81%[8] 5% This test

measures the

maternal

serum alpha

feto protein

(a fetal

liver

protein),

estriol (a

pregnancy

hormone),

human

chorionic

17

gonadotropin

(hCG, a

pregnancy

hormone),

and inhibin-

Alpha

(INHA).[26]

Nuchal

translucency/free

beta/PAPPA screen

(aka "1st

Trimester

Combined Test")

10–13.5 85%[27] 5% Uses

ultrasound

to measure

Nuchal

Translucency

in addition

to the

freeBeta hCG

and PAPPA

(pregnancy-

associated

plasma

protein A).

NIH has

confirmed

that this

first

trimester

test is more

accurate

than second

trimester

18

screening

methods.[28]

Performing

an NT

ultrasound

requires

considerable

skill; a

Combined

test may be

less

accurate if

there is

operator

error,

resulting in

a lower-

than-

advertised

sensitivity

and higher

false-

positive

rate,

possibly in

the 5-10%

range.

Integrated Test 10-13.5

and 15–20

95%[29] 5% The

Integrated

19

test uses

measurements

from both

the 1st

Trimester

Combined

test and the

2nd

trimester

Quad test to

yield a more

accurate

screening

result.

Because all

of these

tests are

dependent on

accurate

calculation

of the

gestational

age of the

fetus, the

real-world

false-

positive

rate is >5%

and maybe be

20

closer to

7.5%.

Even with the best non-invasive screens, the

detection rate is 90%–95% and the rate of false positive

is 2%–5%. Inaccuracies can be caused by undetected

multiple fetuses (very rare with the ultrasound tests),

incorrect date of pregnancy, or normal variation in the

proteins.

Confirmation of screen positive is normally

accomplished with amniocentesis or chorionic villus

sampling (CVS). Amniocentesis is an invasive procedure

and involves taking amniotic fluid from the amniotic sac

and identifying fetal cells. The lab work can take

several weeks but will detect over 99.8% of all numerical

chromosomal problems with a very low false positive rate.[30]

21

Chapter 3.1

Ethical issues

A 2002 literature review of elective abortion rates

found that 91–93% of pregnancies in the United States

with a diagnosis of Down syndrome were terminated.[31] Data

from the National Down Syndrome Cytogenetic Register in

the United Kingdom indicates that from 1989 to 2006 the

proportion of women choosing to terminate a pregnancy

following prenatal diagnosis of Down Syndrome has

remained constant at around 92%.[32][33] Physicians and

ethicists are concerned about the ethical ramifications

of this.[34] Conservative commentator George Will called it

"eugenics by abortion".[35] British peer Lord Rix stated

that "alas, the birth of a child with Down's syndrome is

still considered by many to be an utter tragedy" and that

the "ghost of the biologist Sir Francis Galton, who

founded the eugenics movement in 1885, still stalks the

corridors of many a teaching hospital".[36] Doctor David

Mortimer has argued in Ethics & Medicine that "Down's

syndrome infants have long been disparaged by some

doctors and government bean counters."[37] Some members of

the disability rights movement "believe that public

support for prenatal diagnosis and abortion based on

disability contravenes the movement's basic philosophy

and goals."[38]

22

Chapter 4

Management

Treatment of individuals with Down Syndrome depends

on the particular manifestations of the disease. For

instance, individuals with congenital heart disease may

need to undergo major corrective surgery soon after

birth. Other individuals may have relatively minor health

problems requiring no therapy.

Chapter 4.1

Plastic surgery

Plastic surgery has sometimes been advocated and

performed on children with Down syndrome, based on the

assumption that surgery can reduce the facial features

associated with Down syndrome, therefore decreasing

social stigma, and leading to a better quality of life.[39]

Plastic surgery on children with Down syndrome is

uncommon,[40] and continues to be controversial.

Researchers have found that for facial reconstruction,

"...although most patients reported improvements in their

child's speech and appearance, independent raters could

not readily discern improvement...."[41] For partial

glossectomy (tongue reduction), one researcher found that

1 out of 3 patients "achieved oral competence," with 2

out of 3 showing speech improvement.[42] Len Leshin,

23

physician and author of the ds-health website, has

stated, "Despite being in use for over twenty years,

there is still not a lot of solid evidence in favor of

the use of plastic surgery in children with Down

syndrome."[43] The National Down Syndrome Society has

issued a "Position Statement on Cosmetic Surgery for

Children with Down Syndrome"[44] which states that "The

goal of inclusion and acceptance is mutual respect based

on who we are as individuals, not how we look."

Chapter 4.2

Alternative treatment

See also: Alternative therapies for developmental and

learning disabilities

The Institutes for the Achievement of Human Potential

is a non-profit organization which treats children who

have, as the IAHP terms it, "some form of brain injury,"

including children with Down syndrome. The approach of

"Psychomotor Patterning" is not proven,[45] and is

considered alternative medicine.

24

Chapter 5

Prognosis

These factors can contribute to a shorter life

expectancy for people with Down syndrome. One study,

carried out in the United States in 2002, showed an

average lifespan of 49 years, with considerable

variations between different ethnic and socio-economic

groups.[46] However, in recent decades, the life expectancy

among persons with Down syndrome has increased

significantly up from 25 years in 1980. The causes of

death have also changed, with chronic neurodegenerative

diseases becoming more common as the population ages.

Most people with Down Syndrome who survive into their 40s

and 50s begin to suffer from an alzheimer's-like

dementia.[47]

25

Chapter 6

Epidemiology

Graph showing probability of Down syndrome as a

function of maternal age.

The incidence of Down syndrome is estimated at one

per 800 to one per 1000 births.[48] In 2006, the Centers

for Disease Control and Prevention estimated the rate as

one per 733 live births in the United States (5429 new

cases per year).[49] Approximately 95% of these are trisomy

21. Down syndrome occurs in all ethnic groups and among

all economic classes.

Maternal age influences the chances of conceiving a

baby with Down syndrome. At maternal age 20 to 24, the

probability is one in 1562; at age 35 to 39 the

probability is one in 214, and above age 45 the

probability is one in 19.[50] Although the probability

increases with maternal age, 80% of children with Down

syndrome are born to women under the age of 35,[51]

reflecting the overall fertility of that age group.

Recent data also suggest that paternal age, especially

beyond 42,[52] also increases the risk of Down Syndrome

manifesting in pregnancies in older mothers.[53]

26

Current research (as of 2008) has shown that Down

syndrome is due to a random event during the formation of

sex cells or pregnancy. There has been no evidence that

it is due to parental behavior (other than age) or

environmental factors.

27

Chapter 7

History

English physician John Langdon Down first

characterized Down syndrome as a distinct form of mental

disability in 1862, and in a more widely published report

in 1866.[54] Due to his perception that children with Down

syndrome shared physical facial similarities (epicanthal

folds) with those of Blumenbach's Mongolian race, Down

used the term mongoloid, derived from prevailing ethnic

theory.[55] Attitudes to Down's syndrome were very much

tied to racism until as recently as the 1970s.

By the 20th century, Down syndrome had become the

most recognizable form of mental disability. Most

individuals with Down syndrome were institutionalized;

few of the associated medical problems were treated, and

most died in infancy or early adult life. With the rise

of the eugenics movement, 33 of the (then) 48 U.S. states

and several countries began programs of forced

sterilization of individuals with Down syndrome and

comparable degrees of disability. The ultimate expression

of this type of public policy was "Action T4" in Nazi

Germany, a program of systematic murder. Court

challenges, scientific advances and public revulsion led

to discontinuation or repeal of such sterilization

programs during the decades after World War II.

Until the middle of the 20th century, the cause of

Down syndrome remained unknown. However, the presence in

28

all races, the association with older maternal age, and

the rarity of recurrence had been noticed. Standard

medical texts assumed it was caused by a combination of

inheritable factors which had not been identified. Other

theories focused on injuries sustained during birth.[56]

With the discovery of karyotype techniques in the

1950s, it became possible to identify abnormalities of

chromosomal number or shape. In 1959, Jérôme Lejeune

discovered that Down syndrome resulted from an extra

chromosome.[57][58] The extra chromosome was subsequently

labeled as the 21st, and the condition as trisomy 21.

In 1961, eighteen geneticists wrote to the editor of

The Lancet suggesting that Mongolian idiocy had

"misleading connotations," had become "an embarrassing

term," and should be changed.[59] The Lancet supported

Down's Syndrome. The World Health Organization (WHO)

officially dropped references to mongolism in 1965 after

a request by the Mongolian delegate.[60] However, almost 40

years later, the term ‘mongolism’ still appears in

leading medical texts such as General and Systematic

Pathology, 4th Edition, 2004, edited by Professor Sir

James Underwood.

In 1975, the United States National Institutes of

Health convened a conference to standardize the

nomenclature of malformations. They recommended

eliminating the possessive form: "The possessive use of

an eponym should be discontinued, since the author

29

neither had nor owned the disorder."[61] Although both the

possessive and non-possessive forms are used in the

general population, Down syndrome is the accepted term

among professionals in the USA, Canada and other

countries; Down's syndrome is still used in the United

Kingdom and other areas.[62]

Chapter 8

Society and culture

Advocates for people with Down syndrome point to

various factors, such as additional educational support

and parental support groups to improve parenting

knowledge and skills. There are also strides being made

in education, housing, and social settings to create

30

environments which are accessible and supportive to

people with Down syndrome. In most developed countries,

since the early twentieth century many people with Down

syndrome were housed in institutions or colonies and

excluded from society. However, since the early 1960s

parents and their organizations (such as MENCAP),

educators and other professionals have generally

advocated a policy of inclusion,[63] bringing people with

any form of mental or physical disability into general

society as much as possible. In many countries, people

with Down syndrome are educated in the normal school

system; there are increasingly higher-quality

opportunities to move from special (segregated) education

to regular education settings.

Despite these changes, the additional support needs

of people with Down syndrome can still pose a challenge

to parents and families. Although living with family is

preferable to institutionalization, people with Down

syndrome often encounter patronizing attitudes and

discrimination in the wider community.

The first World Down Syndrome Day was held on 21

March 2006. The day and month were chosen to correspond

with 21 and trisomy respectively. It was proclaimed by

European Down Syndrome Association during their European

congress in Palma de Mallorca (febr. 2005). In the United

States, the National Down Syndrome Society observes Down

Syndrome Month every October as "a forum for dispelling

stereotypes, providing accurate information, and raising

31

awareness of the potential of individuals with Down

syndrome."[64] In South Africa, Down Syndrome Awareness Day

is held every October 20.[65] Organizations such as Special

Olympics Hawaii provide year-round sports training for

individuals with intellectual disabilities such as down

syndrome.

Chapter 8.1

Notable individuals

Scottish award-winning film and TV actress Paula Sage

receives her BAFTA award with Brian Cox.

Stephane Ginnsz, actor (Duo)—In 1996 was first actor

with Down syndrome in the lead part of a motion

picture.[66]

Joey Moss, Edmonton Oilers locker room attendant.[67]

Isabella Pujols, adopted daughter of St. Louis

Cardinals first baseman Albert Pujols and inspiration

for the Pujols Family Foundation.[68]

Paula Sage, Scottish film actress and Special

Olympics netball athlete.[69] Her role in the 2003

film AfterLife brought her a BAFTA Scotland award for

best first time performance and Best Actress in the

Bratislava International Film Festival, 2004.[70]

Chris Burke, American actor who portrayed "Corky

Thatcher" on the television series Life Goes On and

"Taylor" on Touched By An Angel.

Edward Barbanell, played Billy in 2005's The Ringer.

32

Danny Alsabbagh, Australian actor who played Toby in

the Australian mockumentary series Summer Heights

High

Tommy Jessop, British actor who played Ben in Coming

Down the Mountain, opposite Nicholas Hoult

Rene Moreno, subject of "Up Syndrome" - a documentary

film about life with Down syndrome.[71][72]

Nigel Hunt, British author (The World Of Nigel Hunt;

The Diary Of A Mongoloid Youth—this book was

published in 1967, when "mongoloid" was still quite

commonly used to refer to people with Down's

Syndrome).

Portrayal in fiction

Bret Lott: Jewel

Bernice Rubens: A Solitary Grief

Paul M Belous & Robert Wolterstorff: Quantum Leap:

Jimmy

Emily Perl Kingsley: Welcome to Holland

The Kingdom and its American counterpart, Kingdom

Hospital

Stephen King: Dreamcatcher

Dean Koontz: The Bad Place

Jeffrey Eugenides: The Virgin Suicides

Theodore Sturgeon: More Than Human

Janet Mitchell, character in EastEnders

Kim Edwards: The Memory Keeper's Daughter

June Rae Wood: The Man Who Loved Clowns

Jaco van Dormael: Le huitième jour

33

Mark Haddon: Coming Down the Mountain (BBC Radio play

and BBC TV Drama)

Theodore "T-Bag" Bagwell's mother: Prison Break

Chris Burke as Charles "Corky" Thatcher in Life Goes

On

"Toby": Summer Heights High

Chapter 9

Research

Down syndrome is “a developmental abnormality

characterized by trisomy of human chromosome 21" (Nelson

619). The extra copy of chromosome-21 leads to an over

expression of certain genes located on chromosome-21.

34

Research by Arron et al. shows that some of the

phenotypes associated with Down syndrome can be related

to the disregulation of transcription factors (596), and

in particular, NFAT. NFAT is controlled in part by two

proteins, DSCR1 and DYRK1A; these genes are located on

chromosome-21 (Epstein 582). In people with Down

syndrome, these proteins have 1.5 times greater

concentration than normal (Arron et al. 597). The

elevated levels of DSCR1 and DYRK1A keep NFAT primarily

located in the cytoplasm rather than in the nucleus,

preventing NFATc from activating the transcription of

target genes and thus the production of certain proteins

(Epstein 583).

This dysregulation was discovered by testing in

transgenic mice that had segments of their chromosomes

duplicated to simulate a human chromosome-21 trisomy

(Arron et al. 597). A test involving grip strength showed

that the genetically modified mice had a significantly

weaker grip, much like the characteristically poor muscle

tone of an individual with Down syndrome (Arron et al.

596). The mice squeezed a probe with a paw and displayed

a .2 newton weaker grip (Arron et al. 596). Down syndrome

is also characterized by increased socialization. When

modified and unmodified mice were observed for social

interaction, the modified mice showed as much as 25% more

interactions as compared to the unmodified mice (Arron et

al. 596).

35

The genes that may be responsible for the phenotypes

associated may be located proximal to 21q22.3. Testing by

Olson et al. in transgenic mice show the duplicated genes

presumed to cause the phenotypes are not enough to cause

the exact features. While the mice had sections of

multiple genes duplicated to approximate a human

chromosome-21 triplication, they only showed slight

craniofacial abnormalities (688-690). The transgenic mice

were compared to mice that had no gene duplication by

measuring distances on various points on their skeletal

structure and comparing them to the normal mice (Olson et

al. 687). The exact characteristics of Down syndrome were

not observed, so more genes involved for Down Syndrome

phenotypes have to be located elsewhere.

Reeves et al., using 250 clones of chromosome-21 and

specific gene markers, were able to map the gene in

mutated bacteria. The testing had 99.7% coverage of the

gene with 99.9995% accuracy due to multiple redundancies

in the mapping techniques. In the study 225 genes were

identified (311-313).

The search for major genes that may be involved in

Down syndrome symptoms is normally in the region 21q21–

21q22.3. However, studies by Reeves et al. show that 41%

of the genes on chromosome-21 have no functional purpose,

and only 54% of functional genes have a known protein

sequence. Functionality of genes was determined by a

computer using exon prediction analysis (312). Exon

36

sequence was obtained by the same procedures of the

chromosome-21 mapping.

Research has led to an understanding that two genes

located on chromosome-21, that code for proteins that

control gene regulators, DSCR1 and DYRK1A can be

responsible for some of the phenotypes associated with

Down syndrome. DSCR1 and DYRK1A cannot be blamed outright

for the symptoms; there are a lot of genes that have no

known purpose. Much more research would be needed to

produce any appropriate or ethically acceptable treatment

options.

Recent use of transgenic mice to study specific genes

in the Down syndrome critical region has yielded some

results. APP[73] is an Amyloid beta A4 precursor protein.

It is suspected to have a major role in cognitive

difficulties.[74] Another gene, ETS2[75] is Avian

Erythroblastosis Virus E26 Oncogene Homolog 2.

Researchers have "demonstrated that over-expression of

ETS2 results in apoptosis. Transgenic mice over-

expressing ETS2 developed a smaller thymus and lymphocyte

abnormalities, similar to features observed in Down

syndrome."[75]

Vitamin supplements, in particular supplemental

antioxidants and folinic acid, have been shown to be

ineffective in the treatment of Down syndrome.[76]

37

Footnotes

1. ^ a b Meira Weiss. "Conditional love: parents' attitudes toward

handicapped children". p. page 94. http://books.google.com/books?

id=a62J5GPHd3cC&pg=PA94&lpg=PA94&dq=%22down%27s+syndrome

%22+chin+face&source=bl&ots=hVCgwMgpKi&sig=dZ3TYZnWjWMEnTioJY9WQcLP_4

E&hl=en&ei=0Q9nSsegJYOZjAe6ypmmAQ&sa=X&oi=book_result&ct=result&resnu

m=5. Retrieved 2009-07-22.

38

2. ^ a b c This discussion by Myron Belfer, M.D., book by Gottfried

Lemperie, M.D., and Dorin Radu, M.D. (1980). "Facial Plastic Surgery

in Children with Down's Syndrome (preview page, with link to full

content on plasreconsurg.com)". p. page 343.

http://scholar.google.com/scholar?

q=info:Nt6asksVAiYJ:scholar.google.com/&hl=en&output=viewport.

Retrieved 2009-07-22.

3. ^ Roizen NJ, Patterson D.Down's syndrome. Lancet. 2003 12

April;361(9365):1281–9. Review. PMID 12699967

4. ^ "Definition of Brushfield's Spots".

http://www.medterms.com/script/main/art.asp?articlekey=6570.

5. ^ a b American Academy of Pediatrics Committee on Genetics (February

2001). "American Academy of Pediatrics: Health supervision for

children with Down syndrome". Pediatrics 107 (2): 442–449.

doi:10.1542/peds.107.2.442. PMID 11158488.

6. ^ Strom, C. "FAQ from Mosaic Down Syndrome Society".

http://www.mosaicdownsyndrome.com/faqs.htm. Retrieved 2006-06-03.

7. ^ Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down's

syndrome in the USA from 1983 to 1997: a population-based study.

Lancet 2002 23 March;359(9311):1019–25. PMID 11937181

8. ^ a b c [1][dead link]

9. ^ "Dear New or Expectant Parents". National Down Syndrome Society.

http://www.ndss.org/index.php?

option=com_content&task=view&id=2015&Itemid=198. Retrieved 2006-05-

12. Also "Research projects - Early intervention and education".

http://www.downsed.org/topics/early-intervention/. Retrieved 2006-06-

02.

10. ^ Bird, G. and S. Thomas (2002). "Providing effective speech

and language therapy for children with Down syndrome in mainstream

settings: A case example". Down Syndrome News and Update 2 (1): 30–

31. Also, Kumin, Libby (1998). "Comprehensive speech and language

treatment for infants, toddlers, and children with Down syndrome". in

Hassold, T.J.and D. Patterson. Down Syndrome: A Promising Future,

Together. New York: Wiley-Liss.

11. ^ "Development of Fine Motor Skills in Down Syndrome".

http://www.about-down-syndrome.com/fine-motor-skills-in-down-

syndrome.html. Retrieved 2006-07-03.

39

12. ^ M. Bruni. "Occupational Therapy and the Child with Down

Syndrome". http://www.ds-health.com/occther.htm. Retrieved 2006-06-

02.

13. ^ Roberts JE, Price J, Malkin C (2007). "Language and

communication development in Down syndrome". Ment Retard Dev Disabil

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14. ^ S.E.Armstrong. "Inclusion: Educating Students with Down

Syndrome with Their Non-Disabled Peers".

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Retrieved 2006-06-12. Finally, see a survey by NDSS on inclusion,

Gloria Wolpert (1996). "The Educational Challenges Inclusion Study".

National Down Syndrome Society.

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15. ^ There are many such programs. One is described by Action

Alliance for Children, K. Flores. "Special needs, "mainstream"

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2006-05-13. Also, see Flores, K.. "Special needs, "mainstream"

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16. ^ Hsiang YH, Berkovitz GD, Bland GL, Migeon CJ, Warren AC

(1987). "Gonadal function in patients with Down syndrome". Am. J.

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2955699.

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19. ^ McClure HM, Belden KH, Pieper WA, Jacobson CB. Autosomal

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21. ^ For a description of human karyotype see Mittleman, A.

(editor) (1995). "An International System for Human Cytogenetic

Nomeclature". http://www.iscn1995.org/. Retrieved 2006-06-04.

22. ^ a b c "Down syndrome occurrence rates (NIH)".

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23. ^ Mosaic Down syndrome on the Web

24. ^ International Mosaic Down syndrome Association

25. ^ Petersen MB, Tranebjaerg L, McCormick MK, Michelsen N,

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genetic characterization of two unrelated patients with different

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26. ^ For a current estimate of rates, see Benn, PA, J Ying, T

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27. ^ ACOG Guidelines Bulletin #77 state that the sensitivity of

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28. ^ NIH FASTER study (NEJM 2005 (353):2001). See also J.L.

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