Huntington Disease Flashcards
Describe Genetic Anticipation.
Future generations may be affected earlier because polyQ can expand and get bigger. A parent with incomplete penetrance (36-40 repeats) may pass on a copy with increased number of repeats, resulting in a child with fully penetrant HD and since instability is greater in spermatogenesis, it is more likely a paternally inherited HD.
Which sex is more affected by HD?
Both equally affected
What chromosome contains the Htt gene?
4p
Where do you see neuronal loss in Huntington disease?
Basal ganglia and cerebral cortex
What is the polymorphic trinucleotide repeat that causes large polyglutamine repeats?
CAG
What is the relationship between time of onset and number of repeats?
More repeats = Earlier onset
If less than 35 repeats, what is your risk of transmission to offspring?
No risk
If 35-40 repeats, 40 to 60 repeats, or over 60 repeats, what is your risk of transfer to offspring?
50 % risk
What is the most common age of onset?
35-50
What are the neurodegenerative symptoms of Huntington disease?
Chorea, psychiatric disturbances, cognitive impairment.
You have to have more than what number of repeats to have full HD penetrance?
40
Over exposure to Glutamate in HD patients causes what receptor to be lost in the putamen?
NMDA receptor
What makes up the striatum?
Caudate, putamen, nucleus accumbens
What does the poly Q repeat do to the Huntingtin protein?
Makes it insoluble and it aggregates
What do you stain for to find the Huntingtin protein?
Ubiquitin
Why can other pathways be altered because of the aggregation of Huntingtin protein?
Things like transcription factors can get stuck in the aggregates!
What pathway is hyperactive in hyperkinetic disorders (HD)?
Direct pathway
What pathway is hyperactive in hypokinetic disorders (PD)?
Indirect pathway
What neurons are lost in HD and what happens because of it?
Nigrostriatal GABA projection neurons (spiny stiratal neurons). So the striatum is very active and it inhibits the Gpi. This means the thalamus is more active to excite the cortex so we get increased movement.
What are two drugs commonly used to improve HD symptoms and how do they work?
Haloperidol. It is a D2 antagonist.
Tetrabenzine. It is a dopamine depleter (inhibits transport into presynaptic vesicles) and it has its highest binding density in the striatum.
What are the extrapyramidal side effects of Tetrabenzine?
Anxiety, depression, sedation, insomnia
Is there a treatment to stop, delay, slow, or reverse HD?
No
What is “Pre-symptomatic testing?” Can it be prenatal?
Tests for variants causing or associated with diseases or disorders known to be inherited in the family, often with adult onset of symptoms.
Yes, it can be prenatal to assure a non-affected child.
What is an exclusion test?
When a parent does not want to know personally but wants to assure/know if offspring is at high risk for the disease.
What do you call the increase in motor output in response to a loss of spiny striatal neurons?
Choreoathetosis
What are the grades of atrophy in HD?
0 and 1. No atrophy.
- Some atrophy, caudate still convex.
- More atrophy, caudate flat.
- Tons of atrophy, caudate concave.
What do you see microscopically happening with the astrocytes in HD?
Proliferation! Fibrillary gliosis (because astrocytes have fibrillary processes)
What do the Huntington-Protein aggregates look like?
basket-like
What causes cognitive changes in HD?
Neuronal loss in the cortex.
Grossly, 2 major things are noticeable in the brains of HD patients, what are they?
Atrophy and hydrocephalus ex vacuo.
What is the relationship between number of neurons lost and clinical symptoms?
more neurons lost = more clinical symptoms.
