Huntington's

Question 0

Where is degeneration in HD?

Answer 0

BG and cortex

Impacts many pathways biochemically

Question 1

What is the inheritance of huntingtons?

Answer 1

• Autosomal dominant
• 100% penetrance
• 4p
• HTT, 67 exons, 3144 A.A.s

Question 2

What is the genetic defect responsible for HD?

Answer 2

CAG –> Q –> glutamine 36-122 –> destabilizes the DNA and proteins

Question 3

What number of CAG repeats is associated with HD?

Answer 3

36-41 May or may not have

40-60 adult onset

60 or greater juvenile onset

Question 4

Can a parent who does not have the disease make a child that does?

Answer 4

Yes, a copy of 36-40 may make more repeats, genetic anticipation

Question 5

What modifies HD severity?

Answer 5

Variants in the NMDA receptor influence disease severity

Question 6

What causes Huntington protein agreagtion?

Answer 6

The glutamine repeat makes it insoluble and stuff gets stuck in the aggregates

Question 7

What is the excitotoxicity hypothesis in HD pathology?

Answer 7

Over exposure to glutamate causes - pathological change in neurons, ion influx,energy depletion –> cell death

NMDARs are a subclass of receptors relevant to neuronal cell death

• relatively high permeability to Ca and slow activation/deactivation
• loss of NMDARs in HD patients

Question 8

What is the most common inherited neurodegenerative disorder?

Answer 8

HD

Question 9

What is the age of onset and bias of HD?

Answer 9

35-50. Earliest is 2

Life expectancy is 20yrs after onset

Effects all races and sexes equally

Question 10

What is the pathogenesis of HD?

Answer 10

• Loss of neurons in BG –> less motor control
  (BG also in prefrontal loops and limbic loops)
• Lose spiny striatal neurons that dampen motor activity –> increased motor output (choreoathetosis) crazy movements

Question 11

What are gross features of HD?

Answer 11

• small brain
• atrophic striatum (caudate) and frontal lobe
• dilated lateral and third ventricle

Question 12

What are the grades of HD?

Answer 12

0-1: only microscopic changes

2: some atrophy but caudate still convex
3: more atrophy, caudate is flat
4: so much caudate atrophy that it becomes concave

Question 13

What are microscopic changes of HD?

Answer 13

• loss of striatal neurons, especially medium spiny neurons
• tons of fibrillation gliosis
• degeneration = severity of clinical
• Huntington aggreation
• caudate has no neurons, lots of astrocytes

Question 14

What does the huntington protein stained with and look like?

Answer 14

• ubiquitin stain in caudate (brown)

- basket like structure - long sticky proteins that catch other proteins

Question 15

What is ELSI?

Answer 15

Ethical, legal, and social implications

Question 16

What is the treatment for HD?

Answer 16

None, cannot slow or cure

Only treat symptoms

Question 17

What is the exclusion test?

Answer 17

Px does not want to know but wants to know if offspring will have it

Question 18

What makes up the striatum?

Answer 18

Caudate + putamen + nucleus accumbens

Question 19

What is the lenticular nucleus?

Answer 19

Putamen and globus pallidus

Question 20

What pathway is out of control in HD?

Answer 20

BG - direct pathway

Hyperactive

Question 21

What pathway is out of control in PD?

Answer 21

BG - indirect

Hyperacitve

Question 22

What happens in the BG pathway in HD?

Answer 22

Loss in caudate and putamen with gliosis –> loss of Nigrostriatal GABA projection neurons –> decreased GPi inhibition of thalamus –> increased movement

Question 23

What are treatments of HD?

Answer 23

Dopamine blockers and depleters

1. Haloperidol - D2 antagonist (FGA)
2. Risperidone - SGA motor and psychiatric
3. Clozaril - DA antagonist, risk of agranulocytosis
4. Tetrabenazine - Monoamine depleting agent stopping transport into vesicles (best in striatum)
5. Valproic acid - enhances GABA effects
6. Lithium - serotonin reuptake, NE, D2
7. Benzos - chorea, but increase sedation