Huntington's Disease (Week 4--Chesselet and Bordelon)

Question 1

Pathology of Huntington’s Disease vs. Parkinson’s Disease

Answer 1

HD: neurons in striatum itself (caudate) die (see atrophy of caudate)

PD: dopamine neurons that project to striatum (from SNc) die

Question 2

Which neurons are affected early in HD?

Answer 2

Neurons from striatum to GPe (containing enkephalin) affected early in HD –> those neurons usually inhibit GPe –> increased activity of GPe (indirect pathway) –> increased inhibition of subthalamic nucleus –> decreased activity of subthalamic nucleus –> decreased stimulation of GPi/SNr –> decreased inhibition of VA/VL of thalamus –> increased movement

Neurons from striatum to GPi (substance P) relatively unaffected in HD

Question 3

In HD, what movement disorder occurs?

Answer 3

Hyperkinetic disorder (too MUCH movement) due to imbalance in striatal outputs

Note: in contrast to PD where you get too LITTLE movement

Question 4

General reason why you get too much movement in HD

Answer 4

Loss of “brake” (loss of indirect pathway) because loss of those initial neurons projecting from striatum to GPe

Question 5

2 clinical situations that cause abnormal movements similar to those seen in HD

Answer 5

1) Lesion of subthalamic nucleus (due to stroke): hemiballismus; less stimulation of GPi/SNr (via indirect pathway) so more activity of thalamocortical
2) Long-term treatment with L-DOPA (treatment for PD): causes dyskinesia; increased effect of dopamine on D1 receptors so more inhibition of GPi/SNr so more activity of thalamocortical

Question 6

Triad of clinical signs of Huntington Disease

Answer 6

1) Motor
2) Cognitive
3) Psychiatric

Question 7

General info on HD

Answer 7

Adult onset neurodegenerative disorder characterized by uncontrolled movements (chorea and dystonia), behavioral changes (depression, anxiety, psychosis, obsessive-compulsive traits), cognitive dysfunction (executive dysfunction and dementia)

Typical onset is 30s or 40s and have 15-25 year progression

Caused by CAG repeat in IT-15 gene endocing ubiquitously expressed huntingtin protein

Question 8

Mechanisms of toxicity in HD

Answer 8

Mitochondrial dysfunction

Excitotoxicity

Proteasomal/lysosomal/autophagy dysfunction

Transcriptional dysregulation

Protein aggregates

Axonal transport disruption

Cell death pathway perturbation

Question 9

Juvenile onset form of HD

Answer 9

Only 6% present before age 20

More rapid progression

Seizures common

Dystonia, rigidity, bradykinesia

Paternal inheritance due to anticipation (expansion of CAG repeat)

Question 10

Is there a gene test for HD?

Answer 10

Yes!

Remember “Thirteen” (Olivia Wilde) from the show House

Can get a gene test to see if you have the huntingtin gene even before you’re symptomatic

Question 11

What is the “huntingtin” gene?

Answer 11

The gene is IT-15 on short arm of chromosome 4 and encodes the huntingtin protein

Question 12

What is the mutation of IT-15 that causes HD?

Answer 12

Expanded CAG repeat in exon 1 is the mutation that causes HD

Normal: <26 repeats

Intermediate: 26-39 repeats

Pathologenic: >39 repeats

Question 13

If you have more CAG repeats (> 39) what does that mean?

Answer 13

Means you are more likely to have earlier age of onset of HD

However, CAG repeat length accounts for only 50-60% of onset age variability (other factors contribute too)

Question 14

Other expanded CAG repeat disorders

Answer 14

Spinal bulbar muscular atrophy (Kennedy’s disease)

Spinocerebellar ataxias (SCA2?!)

Dentatorubropallidoluysian atrophy

Question 15

Why is the mutant huntingtin so bad?

Answer 15

Cleaved to generate N-terminal polyQ fragments which aggregate

Aggregates form in cytoplasm and in nucleus (amyloid-like conformation)

Controversy over whether aggregates are toxic or protective

Gain of toxic function and/or loss of protective function

Question 16

What might be transcriptionally dysregulated in HD?

Answer 16

Tx dysregulation of neurotrophic factors

Question 17

Symptoms of HD

Answer 17

Motor: chorea, dystonia, abnormal eye movement, gait/balance problems, rigidity, bradykinesia, dysarthria, dysphagia

Cognitive: executive dysfunction (concentration, attention, multi-tasking), visuospatial dysfunction, memory problems

Psychiatric: depression, anxiety, obsessions, compulsions, hallucinations, delusions, apathy, impulsivity, suicidality

Question 18

What are the first symptoms to appear in a person with HD?

Answer 18

Behavioral problems (remember “Thirteen” from show House!)

Then cognitive problems, then last motor problems

Question 19

Treatment for HD

Answer 19

Symptom-based

Must be individualized

Data lacking to show which treatments best

For chorea: amantadine, neuroleptics or antipsychotics (dopamine receptor blockers), reserpine (irreversible inhibitor of VMAT1 and 2 so no dopamine released from pre-synaptic terminal), tetrabenazine (reversible inhibitor of VMAT2)

For dystonia: baclofen, BoTox, DBS

For rigidity, bradykinesia: levodopa, pridopidine, baclofen, tizanidine

For gait and balance: PT, exercise, consider amantadine

For dysarthria, dysphagia: speech and swallowing therapy

For depression, anxiety, etc: SSRIs (fluoxetine), tricyclics, benzodiazepines, cognitive-behavioral therapy, counseling

For cognitive impairment: cholinesterase inhibitors, memantine, atomoxetine

Question 20

How do we use tetrabenazine to treat HD

Answer 20

Give tetrabenazine until patient becomes a bit Parkinsonian (because you’ve blocked so much dopamine) then back off

Remember, tetrabenazine is a reversible inhibitor of VMAT2

Question 21

In the future, how might we prevent onset or slow progression of HD?

Answer 21

Gene silencing to reduce amount of mutant protein produced