Week 2 Flashcards
What is aneuploidy
Abnormal number of chromosomes in a haploid set
Clinical features in the newborn period
Hypotonia
Sleepiness
Excess nuchal skin
Craniofacial clinical features of DS
Brachycephaly - shorter skull
Epicanthic folds - skin fold of the upper eye covering the inner eye corner
Protruding tongue
Small ears
Upward sloping palpebral fissures
Strabismus - eyes point in diff directions
Clinical features of DS in limbs
Single palmer crease
Small middle phalanx on the fifth finger
Wide gap between first and second toes
Clinical features of DS - cardiac
Atrial and ventricular septal wall defects
Common AV canal
Patent ductus arteriosus - persistent opening between two blood vessels leading from the heart
What is atresia in DS
narrowing
Anal atresia and duodenal atresia are clinical features of DS
What is hirschsprung disease
Stool stuck in bowels
A clinical feature of DS
IQ in DS children
Have a broad range
25-75
Normal - 40-45
Social skills in DS children compared to normal
Relatively happy, advanced and affectionate
Average height in DS patients
150 cm
Life expectancy in DS patients
50-60 years
15-20% of heart affected DS patients have an early death
Alzheimer’s relation to DS
Early onset Alzheimer’s is common in DS patients - 2-3 decades earlier
Development of Alzheimer’s
- Shrinkage of cerebral cortex + enlarged ventricles
- Amyloid beta plaques
- Tau neurofibrillary tangles
- Amyloid precursor protein
How does amyloid precursor protein contribute to Alzheimer’s
Beta and gamma- secretase abnormally cleave onto APP
Which generates beta amyloid peptides
Which accumulate into neurotoxic amyloid plaques in the brain tissues
What is the main chromosomal cause of DS
Meitotic non-disjunction (90%)
- error in cell division meiosis 1
- causes trisomy in chromosome 21
- mechanism = one chromosome pair fails to split into two
Other chromosomal causes of DS
- mitotic non-disjunction
- robertsonian translocation
What is screening
Test applied to a whole population
Identifies those at high risk
What is a diagnostic test
More specific test that identifies those who have the disease
How does screening in DS work
Pregnant women are offered a screening test
Using an algorithm a probability is calculated
If P > 1/150, a diagnostic test is offered
What are the methods of screening used for DS
- Ultrasound
- Serum markers
- Cell free foetal DNA
- Non invasive prenatal testing
How is ultrasound used for DS
Identifies the nuchal translucency feature
What bio markers are used for serum marker screening test used for DS screening
2 bio markers are used
- low pregnancy associated plasma A
- high human chorionic gonadotropin hCG
How are serum markers used to screen DS
Quadruple test
1. Decreased alpha fetoprotein
2. Decreased unconjugated estriol
3. Elevated hCG
4. elevated inhibit A
Triple test - inhibit A is not included
P>1/150 - diagnostic test is offered
mitotic non-disjunction
failure of two chromosomes to separate during mitosis
so both go to one daughter cell
robertsonian translocation
an acrocentric chromosome joins end to end with another
why non disjunction increases with maternal age
cohesion between sister chromatids deteriorate
missegragation of recombinant chromosomes
meitotic spindle aberrations
efficiency of kinetochore
shortening of telomeres
reduced blood flow to oocytes
what is mosaicism in DS
when a person has two or more genetically different sets of cells in their body
so in DS not all cells have the extra chromosome 21
what is the presentation of mosaic DS
fewer DS features
what is an acrocentric chromosome
the centromere is pushed toward the end of the chromosome
what is a satellite structure
the remaining short arms after a robertsonian translocation
HSA21 gene relation to DS
genes on the long arm of chromosome 21
15% functional
DS caused by over-expression of HSA21 in trisomic cells
how is DS disordered gene expression
HSA21 is over-expressed
other genes have dysregulation
so whole genome is affected
what is XIST
X inactive specific transcript
a non coding RNA transcript on the X chromosome
what is the barr body
an inactivated X chromosome
what does XIST do
it induces heterochromatin changes
= compaction/condensation
into the Barr body
method to use XIST to inactivate chromosome 21
- fibroblasts treated back into induced pluripotent stem cells
- then XIST gene is introduced
- they are turned on by the Doc mechanism
- XIST is then produced which inactivates the chromosome
biological implications of using XIST to inactivate chromosome 21
positively impacts intellectual disability
silencing leads to faster differentiation of neural progenitor cells
what is dup-app
chromosomal region on APP gene that is duplicated
dup-app individuals tend to develop alzeimers early
how is dup-app related to down syndrome
in comparison to DS, dup-APP individuals develop dementia earlier
this suggests that the extra chromosome is not the only contributing factor
leads to the neuroprotective hypothesis
what is the neuroprotective element hypothesis
BACE2 is another gene
a homolog of beta secretase
it is suggested that BACE2 acts antagonistically to beta secretase
which results in less formation of beta amyloid
what chromosome are tau tangles on
17
not 21
