Lecture 6: Down Syndrome

Question 1

What is Down syndrome?

Answer 1

• • Down Syndrome (DS) is a life-long genetic disorder, that is caused by the presence of three copies of chromosome 21 – it is a chromosomal abnormality
• • Also referred to as trisomy 21;

Question 2

What is the life expectancy of a Down syndrome patient?

Answer 2

Average life expectancy of Down Syndrome patients is ~60 years

Question 3

Who is Down syndrome named after?

Answer 3

Down Syndrome (DS) is named after John Langdon Down, a British doctor who described the syndrome in 1866.

Question 4

What is the epidemiology of Down syndrome?

Answer 4

• • The most frequent form of intellectual disability;
• • The most common chromosomal abnormality amongst liveborn babies; most babies with chromosomal abnormalities don’t make it and die before birth

Question 5

What increases the risk of Down syndrome?

Answer 5

• • Age of mother can increase probability of trisomy 21;
• • age of mom has increased throughout the years (between 2005 and 2013) yet the rates of down syndrome has stayed the same (and increasing age of mother is one of the biggest factors in down syndrome). This is because we are better at screening down syndrome at birth

Question 6

What are the clinical presentations of Down syndrome?

Answer 6

• • The impact of DS for each person is individual and is regarded as a spectrum disorder (phenotype will vary quite largely depending on the individual)
• • Typically associated with physical disabilities (growth delays), characteristic facial features, and mild-to-moderate intellectual disability;
• • Typically have poor immune function and generally hit developmental milestones at a much later age (in FXS, missing those developmental milestones are one of the biggest red flags whereas in down syndrome, because the physical characteristics are so pronounced and obvious, we don’t have to wait for the developmental milestones to be missed to notice anything)
• • Increased risk of several other health conditions:
    1) Congenital heart defect; can lead to premature death so if we can fix this issue than the low life expectancy of people with DS can be increased
    2) Epilepsy;
    3) Leukemia;
    4) Thyroid diseases;
    5) Mental health disorders

Question 7

What are the physical characteristics of down syndrome?

Answer 7

1) Small chin;
2) Slanted eyes;
3) Poor muscle tone;
4) Flat Nasal bridge;* can see pre-birth
5) Single crease of the palm;* can see pre-birth
6) Protruding tongue;
7) Slowed growth in height.
- -Flat and wide face, short neck, excessive joint flexibility, extra space between big toe and second toe (too much apoptosis), abnormal pattern on fingertips, etc.

Question 8

What are the neurological characteristics of Down syndrome?

Answer 8

Mild to moderate intellectual disability
– IQ ranges from 35 – 69, can be lower than 35 in severe cases;
– Speech abnormalities (Stutter, rapid or irregular speech)
– Typically language comprehension is much more advanced than ability to speak;
but these are easy things we can help with through speech-language pathologists

Question 9

What are comorbodies of Down syndrome?

Answer 9

Mental illness can occur in ~30% of DS patients
– Autism occurs in 5-10% of patients;
– Depression and anxiety are more prevalent in early adulthood.
Epileptic seizures occur in 5-10% of children and up to 50% of adults living with DS
–extra copy of the chromosome leads to an over expression of the sodium channels (mutant sodium channels that open up when it shouldn’t and when it does open in millions of neurons it leads to an epileptic seizure
– in non-down syndrome patients, the rate of epileptic seizures decreases in adults because the brain gets rid of the mutant sodium channels but this doesn’t happen in DS
Dementia/Alzheimer disease
– Adults with DS demonstrate neuropathological and functional changes reminiscent of Alzheimer disease; however in DS these changes start at a much younger age (ex 30) rather than 70/80 in dementia/alzheimer

Question 10

How can you diagnose DS?

Answer 10

–prenatal screening, confirmed with a clinical genetic test.
– Screening testscan indicate the likelihood that a mother is carrying a baby with DS. But these tests cannot tell for sure (i.e. diagnose) whether the baby has DS.
1) Chorionic villus sampling (CVS)
Cells are taken from the placenta and used to analyze the fetal chromosomes;
Typically performed in the first trimester;
The risk of pregnancy loss (miscarriage) from a CVS is very low.
sometimes mom doesn’t know she’s pregnant or she misses this period to get checked so there are other tests
2) Amniocentesis
A sample of the amniotic fluid (similar to the protective CSF that surrounds the brain) surrounding the fetus is withdrawn through a needle inserted into the mother’s uterus;
This sample is then used to analyze the chromosomes of the fetus;
Doctors usually perform this test in the second trimester;
This test also carries a very low risk of miscarriage.

–Otherwise, DS can be recognized from the characteristic phenotypic features present in a newborn.

Question 11

What is mosaic Down syndrome?

Answer 11

• • Occurs in a very small percentage of cases;
• • Some of the cells in the body are normal, while others have trisomy 21.
• • phenotype is much more mild

Question 12

What causes Down syndrome?

Answer 12

• • Failure of the 21st chromosome to separate during egg or sperm development;
• • Sperm or egg cell is produced with an extra copy of chromosome 21;
• • Therefore, this cell has 24 chromosomes, and 47 chromosomes when combined with cell from the other parent;
• • 88% of cases of trisomy 21 result from the nonseparation of the chromosomes in the mother, 8% result from nonseparation of the chromosomes in the father, and 3% after the egg and sperm have merged.

Question 13

Why does an extra chromosome cause problems?

Answer 13

• -Extra chromosomes sets off homeostasis because you get an over expression of genes that results in too much of something
• • research suggest that genes for beta amyloid and superoxide dismutase (SOD) are overexpressed.
• • – Too much is associated with alzheimers and normally this happens at a very old age because it takes time for these proteins to be made but because there’s an extra chromosome in DS the production of these proteins are massively increased so you get these dementia-like cognitive deficits much earlier (age 30 compared to 70/80)
    1) accumulation of beta-amyloid in pancreas –> diabetes
    2) accumulation of beta-amyloid in temporal lobe
• -> Alzheimer’s
  3) accumulation of beta-amyloid all over brain –> CTE (chronic traumatic encephaly)

Question 14

What is beta-amyloid and what does it do?

Answer 14

• • b-amyloid is a protein derived from the amyloid precursor protein (APP),located on Chromosome 21, whose normal function is poorly understood
• • Involved in activation of kinase enzymes, protection against oxidative stress, and regulation of cholesterol & iron transportation;
• • main component of amyloid plaques (Extracellular deposits found in the brain (and periphery) of patients with Alzheimer’s Disease)
• • These amyloid plaques are a collection of misfolded proteins that are able to stick together (become sticky and grab other proteins)
• • Deposits can physically disrupt tissue architecture;
• • They can also form ion channels in lipid membranes (physically poke holes in the membrane ), which are permeable to calcium
• • Calcium dysregulation is associated with mitochondrial damage and apoptosis.
• • Plaques & neurofibrillary tangles are present in nearly all DS patients by age 35 and associated with cognitive dysfunction (the more plaques the more cognitive deficits)

Question 15

What is oxidative stress?

Answer 15

• • the imbalance between production and removal of oxygen-derived free radicals
• • when a cell uses oxygen to get ATP so it can function, it forms oxygen-derived free radicals (unpaired valence electron) which are extremely reactive. This means that they can interact with your proteins, DNA, cell membrane, and start messing things up. Producing the oxygen-derived free radicals is normal, but we can also get rid of them too to neutralize them. When there’s an imbalance between the production/removal of these free radicals, then that is a problem

Question 16

How does oxidative stress contribute to Down syndrome?

Answer 16

Oxidative stress may contribute to some clinical features of DS, such as:

• • Decreased immune function (lipid peroxidation);
• • Premature aging (DNA oxidation);
• • Impaired mental function (Protein oxidation); cells need proteins to do work so if they are messing up the proteins it is messing up how the cell functions

Question 17

What is superoxide dismutase and how does it contribute to oxidative stress?

Answer 17

• • superoxide dismutase is an enzyme that will break down the harmful oxygen free radical and convert it to hydrogen peroxide (less harmful than –O2)
• • The gene for superoxide dismutase is located on chromosome 21, and it’s activity seems to be increased in DS patients (massively overproducing superoxide dismutase).
• • However, in the presence of ferrous iron (Fe2+), hydrogen peroxide forms the highly toxic hydroxyl radical (OH), which can result in profound cellular damage
• • Beta-amyloid has something to do with iron transport in and out of the cell, and there’s too much beta-amyloid in patients with DS so they have lots of ferrous iron inside the cell. Too much ferrous iron with the overproduction of hydrogen peroxide causes detrimental effects because it produces the highly toxic hydroxyl radical
• • Hydroxide radical leads to cellular damage which leads to Lipid peroxidation, DNA oxidation, Protein oxidation

Question 18

How can Down syndrome be managed?

Answer 18

–Preventing cellular damage from oxidative stress is one approach to managing DS.
–Supplementation with antioxidant nutrients has been proposed as a potential therapy for DS.
Zinc, selenium, megavitamins, minerals, etc.
– Education and proper patient care have been shown to drastically improve quality of life.
– Some DS patients are educated in typical schools, other require more specialized education;
– Some DS patients graduate high-school, some attend post-secondary education;