Huntington's Disease Flashcards
Who discovered Huntington’s disease?
George Huntington - 1872. He was 22.
What is the incidence of Huntington’s?
5-10/100,000
What is the age of onset?
About 40 years old.
3 main involuntary movements of HD.
- Chorea: ‘dancelike’ (comes back to centre line)
- Athetosis: No return to midline. To the side.
- Extrapyramidal: reflexes, coordination.
How long is the progression to incapacitation?
15 years.
What do sufferers often succumb to if they have HD?
Aspiration Pneumonia (inflammation of the lungs caused by inhaling or choking on vomitus; may occur during unconsciousness)
Is HD autosomal recessive?
No, it is autosomal dominant. There is dominant inheritance.
What is the name of the gene coding for HD and where is it located?
IT15 on the short arm of chromosome 4.
Is there a region of expansion and if so, what is it? How many repeats for a normal individual vs an HD patient?
Yes, CAG (coding for glutamine).
Up to 35 repeats in a normal individual.
35-40 repeats in a carrier.
40 + repeats in effected individual.
What is the ratio of males to females on obtaining HD?
1:1
How many cases arise as a result of a new mutation?
Less than 1%
If there is a long CAG expansion, when will the onset of symptoms for HD be?
Early. Vice versa for a short expansion of CAG.
What is HD generally associated with?
Genetic anticipation.
Increasing severity or earlier age of onset of a genetic trait in succeeding generations. Gene positive patients may experience genetic anticipation. They are likely to receive a longer CAG repeat if they inherited the gene from their father.
What does the IT15 gene code for? How much does it weigh?
htt protein (huge protein). It weighs about 350kDa
htt has what type of function?
Antiapoptotic. It increases the levels of some neurotrophins.
What are inclusions? What cells have them?
Accumulations of the htt protein. They are heavily ubiquitinated. Most cells, even dying ones, do not have inclusions. You must look for them.
What does the brain of a diseased patient look like?
Cerebral atrophy (mainly basal ganglia):
- caudate nucleus
- putamen
- globus pallidus
What makes up the striatum?
Caudate nucleus + Putamen
Which neurons are preferentially affected?
GABA neurons. They are called MSNs (medium-spiny neurons).
How much of the striatum do MSNs make up? How much is lost in HD?
95% make up striatum.
More than 80% are lost!
Non-GABAergic neurons are affected?
No, they are relatively spared.
What is the current scale to describe cell loss in the basal ganglia?
Vonsattel Pathology Grading system.
- allows comparison between the severity of diff. cases
- grading is given after the death of a patient.
What does each grade stand for?
0 = minimal overt change 1 = 50% loss of MSNs in the CN (shrinkage is very obvious to the eye) 2-3 = major loss of MSNs 4 = more than 80% loss of neurons in the CN (major shrinkage of CN and loss of cortical tissue)
MSNs contain 2 main things. What are they?
Enkephalin and CB1 receptor
substance P and CB1 receptor-IR
What happens in the normal brain in terms of MSNs and proteins present?
GABA + ENK -> GB externa is ok
GABA + SP -> GB interna is ok
GABA + SP -> SNr is ok
What happens in a grade 0 brain in terms of MSNs and proteins present?
GABA + ENK -> GB externa is diminishing
GABA + SP -> GB interna is ok
GABA + SP -> SNr is ok
What happens in a grade 1 brain in terms of MSNs and proteins present?
GABA + ENK -> GB externa is diminishing
GABA + SP -> GB interna is ok
GABA + SP -> SNr is diminishing
Remember: Only 1 good pathway is left.
What happens in a grade 3 brain in terms of MSNs and proteins present?
GABA + ENK -> GB externa is diminishing
GABA + SP -> GB interna is diminishing
GABA + SP -> SNr is diminishing
Remember: All 3 paths are diminishing
Is the subthalamic nucleus GABAergic?
No.
What is the mechanism of chorea development?
No more ENK from Putamen -> G.P. externa so can no longer inhibit G.P. externa -> SUT, so this will fire more.
SUT -> G.P. interna decreases (so no excitation)
G.P. interna -> VA-VL fires LESS
VA-VL -> cortex fires MORE; LESS CONTROL.
Hyprerkinetic movement (Chorea)
What are treatment options for HD?
Minocycline (antibiotic) - possible neuroprotective and anti-inflam effects
Coenzyme Q10: Proposed, but medical use is controversial. Not approved by the FDA.
Creatine monohydrate (natural energy source) - need a lot, no major break through.
GABA agonists - need to preserve cells in order for this to work
Antidepressants - can alleviate mood symptoms
What are alternative therapies for HD?
Stem cell transplantation to replace dying MSNs
-in theory, a fantastic idea, but the cells don’t form the
right connections yet – lots of interest in this area
Deep Brain Stimulation
-Putting electrodes to mimic normal cell firing
responses, works for some patients to alleviate chorea symptoms, but not others! We don’t know how it works
Knock out htt but leave wild type alone.
