Down Syndrome Flashcards
What is Down Syndrome?
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.
Associated with growth delays, characteristic facial features, and mild-to-moderate intellectual disability.
What is the average life expectancy of someone with Down Syndrome?
~60 years.
What is the epidemiology of Down Syndrome?
Most common chromosomal abnormality amongst liveborn babies.
What is the incidence rate?
In Canada, ~15.8 per 10,000 babies were born with DS between 2005 and 2013.
Most frequent form of intellectual disability.
Age of mother can increase probability of DS: 0.1% in 20-year old mothers vs. 3% in those aged 45+
Clinical Presentation of DS
It’s regarded as a spectrum disorder.
Those with DS nearly always have physical and intellectual disability.
Typically have poor immune function and generally hit developmental milestones at a much later age.
Comorbidity:
Congenital heart defect, epilepsy, leukemia, thyroid diseases, and mental health disorders.
Physical Characteristics
Small chin, slanted eyes, poor muscle tone, flat nasal bridge, single crease of the palm, protruding tongue, and slowed growth in height.
Other common features include:
Flat and wide face, short neck, excessive joint flexibility, extra space between big toe and second toe, abnormal pattern on fingertips, etc.
Neurological Characteristics
Mild to moderate intellectual disability - IQ ranges from 35 to 69 and can be lower than 35 in severe cases. DS accounts for 1/3 of all intellectual disabilities worldwide.
Speech abnormalities - stutter, rapid, or irregular speech. Typically, language comprehension is more advanced than ability to speak.
Mental illness can occur in ~30% of DS patients. Autism occurs 5-10% of patients. Depression and anxiety are more prevalent in early adulthood. Epileptic seizures in 5-10% of children and up to 50% of adults living with DS.
Dementia/Alzheimer disease - Adults with DS demonstrate neuropathological and functional changes reminiscent of Alzheimer disease.
Diagnosing DS
Prenatal screening, confirmed with a clinical genetic test.
Otherwise, DS can be recognized from the characteristics phenotypic features present in a newborn.
Etiology of Down Syndrome
Trisomy 21:
Overexpression of each of the 300-500 genes carried on chromosome 21.
Extra chromosome occurs by chance.
To date, there are no known behavioural activities or environmental factors that influence the probability of this.
Advanced maternal age is the most significant risk factors associated with it.
Mosaic Down Syndrome:
Occurs in a very small percentage of cases.
What causes Trisomy 21?
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 result from the nonseparation o the chromosomes in the mother, 8% result from the nonseparation in the father, and 3% after the egg and sperm have merged.
Why does an extra copy of Chromosome 21 cause problems?
Extra genetical material -> Overexpression of genes.
Some research suggest that genes for amyloid, superoxide dismutase, a proto oncogene, and possible some microRNAs are overexpressed.
Beta Amyloid overproduction is associated with what?
Dementia-like symptoms.
Plaques and neurofibrillary tangles are present in nearly all DS patients by age 35 and associated with cognitive dysfunction.
B Amyloid
This is a protein derived from the amyloid precursor protein located on Chromosome 21, whose normal function is poorly understood:
APP KO mice do not show any obvious loss of physiological function. Impaired LTP and memory function.
Perhaps involved in activation of kinase enzymes, protection against oxidative stress, and regulation of cholesterol and iron transportation.
What is component of amyloid plaques?
Extracellular deposits found in the brain of patients with Alzheimer’s Disease.
These plaques are aggregates of misfolded proteins that are able to stick together.
Deposits can physically disrupt tissue architecture.
They can also form ion channels in lipid membranes, which are permeable to calcium (Calcium dysregulation is associated with mitochondrial damage and apoptosis).
Etiology of Down Syndrome - SOD
Oxidative stress = the imbalance between production and removal of oxygen-derived free radicals.
Oxidative stress may contribute to some clinical features of DS, such as:
Decreased immune function (lipid peroxidation), premature aging (DNA oxidation), and impaired mental function (protein oxidation).
The gene for superoxide dismutase is located on chromosome 21, and its activity seems to be increased in DS patients:
The hyperactivity of superoxide dismutase produces hydrogen peroxide.
In the presence of ferrous iron, hydrogen peroxide forms the highly toxic hydroxyl radical, which can result in profound cellular damage.
