Down syndrome: A literature review of the genetics, diagnosis, and

management of Down syndrome, including an overview of current

research and emerging therapies

by: A. R. Barredo, M.M. Antenor, P.J. Jongco, G.R. Roldan, A.R. Tababa

Down syndrome (DS) is a chromosomal disorder that occurs when there

is an extra whole or partial copy of chromosome 21. This error during cell

division alters how their body and brain grow. In addition, they may experience

difficulties with their mental and physical development. DS can affect several

major body systems, including the central nervous system, cardiovascular

system, respiratory system, gastrointestinal system, immune system,

musculoskeletal system, and endocrine system. Each of these systems can be

affected to varying degrees, and individuals with DS have a higher risk for

various medical issues associated with each system. Furthermore, in this

literature review, we will discuss the latest research on the genetics, diagnosis,

and management of down syndrome, including current research and emerging

therapies.

Genetics

According to Lejeune, Gautier, and Turpin (1959) in their study “Study of

somatic chromosomes from 9 mongoloid children”, was among the first to

identify the chromosomal abnormality that underpins DS, the researchers

suggest that the additional chromosome 21 may have a role in modifying the

usual genetic composition, and that the development of DS is most likely

influenced by a combination of multiple genetic and environmental factors.

Chromosomes 21 may be a factor of some medical issues and cognitive

disorders. In addition, DS is a genetic condition, but it is only hereditary in 1%

of cases. The two other types of DS, trisomy 21 (nondisjunction) and

mosaicism, do not have a hereditary component. Translocation, which is the

third type of DS, may have a hereditary component in approximately one-third

of cases, accounting for 1% of all cases of DS (National Center on Birth

Defects and Developmental Disabilities, & Centers for Disease Control and

Prevention, 2021).

Moreover, the reason behind the occurrence of an extra chromosome,

whether it is a complete or partial one, is yet to be identified. However, research

has shown that advanced maternal age is the only known factor that increases

the likelihood of having a baby with DS as a result of either nondisjunction or

mosaicism. Despite this, more than half of all children with DS are born to

women who are younger than 35 years old, likely due to higher birth rates in

this age group (De Graaf, Buckley, & Skotko, 2021).

On the other hand, the genetic abnormality involves the increased

production of products from genes on chromosome 21 that have been

overexpressed in cells and tissues of DS patients, resulting in phenotypic

abnormalities. Given that half of all DS patients have a normal heart, this aspect
suggests that genetic modifiers interact with dosage sensitive genes on

chromosome 21 to cause congenital heart disease (Plaiasu, 2017).

Diagnosis

DS can be identified prior to delivery using prenatal diagnostic tests such

as chorionic villus sampling (CVS) or amniocentesis, or after birth using clinical

features and genetic testing. Moreover, Natoli et al. (2012), who studied a

systematic review of termination rates from 1995-2011 have found out that

prenatal diagnosis of DS in the United States presents the largest synthesis of

data on termination rates. Termination rates for pregnancies affected by DS are

influenced by factors such as maternal age, race, and ethnicity. However, there

are indications that rates have decreased over time, potentially due to

advancements in medical and societal support. It is important to recognize that

a uniform termination rate may not accurately reflect the diverse experiences of

pregnant women across different regions and demographics in the United

States.

Furthermore, a definitive prenatal diagnosis of DS necessitates the use

of invasive techniques, which are associated with a 0.3-1% risk of miscarriage,

based on the kind of procedure (Tabor & Alfiveric, 2010). In addition, a meta-

analysis of Gil et al. (2019), prenatal down syndrome diagnosis is critical for

managing affected pregnancies and informing parents about their options. The

accuracy of screening tests for DS varies, and the decision to undergo invasive

diagnostic testing should be made after careful consideration of the risks and
benefits. The non-invasive prenatal testing (NIPT) is a highly accurate Down

syndrome screening test that may be useful in the prenatal diagnosis of this

condition.

Management of Down Syndrome

Physiotherapy has been identified as an important management strategy

for people with Down syndrome in order to improve their physical and functional

abilities. According to (Shields, 2021), exercise improves physical function and

may improve cognitive function. Exercise interventions can improve muscle

strength, cardiovascular fitness, and motor function in children and adults with

Down syndrome. Exercise interventions outperform control conditions in terms

of improving static and static-dynamic balance in children with Down syndrome.

Furthermore, findings in adolescents with Down syndrome indicate that

exercise interventions are more effective than control conditions in improving

static-dynamic balance. However, results on dynamic balance in children and

static balance in adolescents are

inconclusive (Maïano et al., 2019).

Current Research and Emerging Therapies

Recent research clearly shows that prenatal treatment can save overall

brain development and behaviour, and that this effect outlasts treatment

discontinuation. In order to improve the DS-linked brain phenotype, a number

of therapies have been tested in mouse models of DS. Recent findings that
show brain irregularities in mice with Down syndrome can be avoided through

early intervention offer hope that prenatal therapies could potentially save brain

development in human foetuses with the condition (Stagni et al., 2015).

According to Baggot and Baggot (2014), there are three documented instances

of infants with DS whose mothers were administered high doses of vitamin B

and other substances during pregnancy. These cases indicate that early

interventions for DS could potentially have a meaningful effect on

intellectual disability.

Though preliminary, the research could be a step toward achieving a goal

that has eluded scientists for decades. As well as a small human trial, raises the

possibility of treatments to improve learning difficulties in people with Down

syndrome. Since its inception, the National Institute of Child Health

and Human Development (NICHD) has conducted and supported DS

research. The investigation of specific genes and gene groups that may play a

role in the syndrome, understanding how maternal age influences the disorder,

and the development of new prenatal and postnatal diagnostic methods. While

most research into DS has focused on understanding the mechanisms

underlying its symptoms (Underwood, 2022).

In conclusion, DS is a genetic condition caused by the presence of an

extra copy of chromosome 21. The additional chromosome can lead to

phenotypic abnormalities, including medical issues and cognitive disorders. The

exact cause of the extra chromosome is unknown, but advanced

maternal age is a known risk factor. Prenatal diagnostic tests can identify DS,

and termination rates vary based on factors such as maternal age and ethnicity.

Physiotherapy and exercise interventions are important management strategies

for people with DS, and recent research has shown promise for prenatal

therapies to improve brain development in foetuses with the condition.

References:

Baggot, P., & Baggot, R. (2017). Fetal therapy for Down syndrome: report of

three cases and a review of the literature. PubMed.

https://pubmed.ncbi.nlm.nih.gov/29108162/

De Graaf, G., Buckley, F., & Skotko, F. (2021, April 6). Facts about Down

syndrome. Centers for Disease Control and Prevention.

https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html

Gil, M., Quezada, R., Revello, R., Akolekar, K., & Nicolaides, H. (2015,

February 1). Analysis of cell-free DNA in maternal blood in screening

for fetal aneuploidies: Updated meta-analysis. PubMed.

https://pubmed.ncbi.nlm.nih.gov/25639627/

Maïano, C., Hue, O., Lepage, G., Morin, A., Tracey, D., & Moullec, G. (2019,

April 30). Do exercise interventions improve balance for children and

adolescents with Down syndrome? A systematic review. OUP

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for Disease Control and Prevention. (2021, April 6). Facts about Down

syndrome. Centers for Disease Control and Prevention.

https://www.cdc.gov/ncbddd/birthdefects/downsyndrome.html

National Down Syndrome Society. (n.d.). About Down syndrome. Front page |

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Natoli, J., Ackerman, D., McDermott, S., & Edwards, J. (2012, March 14).

Prenatal diagnosis of Down syndrome: a systematic review of

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diagnosis techniques. PubMed.

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Underwood, E. (2022, September 1). Restoring a key hormone could help

people with Down syndrome. Science | AAAS.

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couldhelp-people-down-syndrome