Neurodevelopmental Disorders Down Syndrome Flashcards
What is Down Syndrome?
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;
- Typically associated with physical growth delays, characteristic facial features, and mild-to-moderate intellectual disability;
- Average life expectancy of Down Syndrome patients is ~60 years*
Epidemiology of Down Syndrome
• The most common chromosomal abnormality amongst liveborn babies (in Canada and worldwide);
- In Canada (excluding QC), ~15.8 per 10,000 babies were born with DS, between 2005 and 2013 (Health Canada);
• The most frequent form of intellectual disability;
• Age of mother can increase probability of trisomy 21
Clinical Presentation of DS
The impact of DS for each person is individual and is regarded as a spectrum disorder.
Those with DS nearly always have physical and intellectual disabilities.
Typically have poor immune function and generally hit developmental milestones at a much later age.
Increased risk of several other health conditions: - Congenital heart defect;
- Epilepsy;
- Leukemia;
- Thyroid diseases;
- Mental health disorders.
Clinical Presentation: Physical Characteristics
Patients with DS may have some or all the following: - Small chin;
- Slanted eyes;
- Poor muscle tone;
- Flat Nasal bridge;
- Single crease of the palm; - Protruding tongue;
- Slowed growth in height.
Other common features may include:
- Flat and wide face, short neck, excessive joint flexibility, extra space between big toe and second toe, abnormal pattern on fingertips, etc.
Clinical Presentation: Neurological Characteristics
Mild to moderate intellectual disability
- IQ ranges from 35 – 69, 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 much more advanced than ability to speak.
Clinical Presentation: Comorbidities
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.
Dementia/Alzheimer disease
- Adults with DS demonstrate neuropathological and functional changes reminiscent of Alzheimer disease;
Diagnosing DS
The diagnosis of DS is often made by prenatal screening, confirmed with a clinical genetic test. Screening tests can 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. Diagnostic tests that can identify Down syndrome include:
1.
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- -
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.
2. Amniocentesis
- A sample of the amniotic fluid 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
Etiology of Down Syndrome
Trisomy 21
- Overexpressionofeachofthe300-500genescarried on chromosome 21;
- Extrachromosomeoccursbychance;
- Todate,therearenoknownbehavioralactivitiesor environmental factors that influence the probability of trisomy 21;
- Advanced maternal age is the most significant (and best understood) risk factors associated with DS.
Mosaic Down Syndrome
- Occursinaverysmallpercentageofcases;
- Someofthecellsinthebodyarenormal,whileothers have trisomy 21.
Etiology of Down Syndrome
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.
Etiology of Down Syndrome
Why does an extra copy of Chromosome 21 cause problems? - Extra genetic materialàoverexpression of genes;
- While it is not entirely clear which genes are overexpressed, some research suggest that genes for beta amyloid and superoxide dismutase (SOD) are overexpressed.
Similarly to Alzheimer’s Disease (AD), beta amyloid overproduction in DS patients is associated with dementia-like symptoms.
- Plaques & neurofibrillary tangles are present in nearly all DS patients by age 35 and associated with cognitive dysfunction.
Etiology of Down Syndrome – b Amyloid
-amyloid is a protein derived from the amyloid precursor protein (APP),located on Chromosome 21, whose normal function is poorly understood:
APP KO mice do not show any obvious loss of physiological function;
Impaired LTP & memory formation;
Perhaps involved in activation of kinase enzymes, protection against oxidative stress, and regulation of cholesterol & iron transportation;
b amyloid is the main component of amyloid plaques:
Extracellular deposits found in the brain (and periphery) 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);
- Impaired mental function (Protein oxidation);
The gene for superoxide dismutase is located on chromosome 21, and it’s activity seems to be increased in DS patients.
What is hyperactivity
The hyperactivity of superoxide dismutase
produces hydrogen peroxide (less harmful than –O2);
However, in the presence of ferrous iron (Fe2+), hydrogen
peroxide forms the highly toxic hydroxyl radical (OH),
which can result in profound cellular damage.
DS patients typically show deficits in iron transport across membranes and are therefore at risk of experience oxidative stress.
Managing Down Syndrome Patients
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;
As of May 2013, ~20% of Americans with a diagnosis of DS have paid jobs in some capacity
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.
