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

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Flashcards in Huntington's Disease (Week 4--Chesselet and Bordelon) Deck (21)

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

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

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


Which neurons are affected early in HD?

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


In HD, what movement disorder occurs?

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

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


General reason why you get too much movement in HD

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


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

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


Triad of clinical signs of Huntington Disease

1) Motor

2) Cognitive

3) Psychiatric


General info on HD

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


Mechanisms of toxicity in HD

Mitochondrial dysfunction


Proteasomal/lysosomal/autophagy dysfunction

Transcriptional dysregulation

Protein aggregates

Axonal transport disruption

Cell death pathway perturbation


Juvenile onset form of HD

Only 6% present before age 20

More rapid progression

Seizures common

Dystonia, rigidity, bradykinesia

Paternal inheritance due to anticipation (expansion of CAG repeat)



Is there a gene test for HD?


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


What is the "huntingtin" gene?

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


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

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

Normal: <26 repeats

Intermediate: 26-39 repeats

Pathologenic: >39 repeats


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

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)


Other expanded CAG repeat disorders

Spinal bulbar muscular atrophy (Kennedy's disease)

Spinocerebellar ataxias (SCA2?!)

Dentatorubropallidoluysian atrophy


Why is the mutant huntingtin so bad?

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


What might be transcriptionally dysregulated in HD?

Tx dysregulation of neurotrophic factors


Symptoms of HD

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


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

Behavioral problems (remember "Thirteen" from show House!)

Then cognitive problems, then last motor problems


Treatment for HD


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



How do we use tetrabenazine to treat HD

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


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

Gene silencing to reduce amount of mutant protein produced

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