Huntington's Disease Flashcards
In what year was the Huntington Disease gene identified?
1993
What are some of the motor symptoms seen in HD?
Chorea, dystonia, dysarthria, dysphagia, poor posture, in coordination, impaired gait and balance, delayed initiation of voluntary saccades
What are some cognitive symptoms associated with HD?
Loss of executive functions, difficulty in multitasking, inflexible thoughts, poor concentration, impaired spatial perception, disinhibition, poor insight, short term memory loss
What are some of the psychiatric symptoms associated with HD?
Depression, anhedonia, decreased libido, suicidal ideation, social isolation, disrupted sleep pattern, delusions, hallucinations, paranoia, irritability
When was the first genetic mouse model of HD made?
1996
What comprises the clinical triad of HD symptoms?
Cognitive, motor and psychiatric
How is HD diagnosed?
- Neurological exam, family history
- Patients with symptoms of HD will now undergo genetic testing to confirm diagnosis
- Children of HD parents can be tested at 18
What occurs during the prodromal phase of Huntington’s disease?
No motor symptoms but there are psychiatric and cognitive symptoms
In which disease phase does quality of life start to decline?
Prodromal phase
By which stage of HD progression does treatment need to occur and why?
Treatment needs to occur during prodromal phase because after the neurons die there is little that can be done
Which structures in the brain start to atrophy in HD?
Basal ganglia
What does the indirect dopamine pathway normally do?
Inhibit involuntary motor activity
What happens to the external globus pallidus as a result of degeneration of dopamine D2 neurons in the striatum?
The EGP receives less inhibition
What happens as a result of decreased inhibition of the EGP?
More neurotransmitters are released to the subthalamic nucleus, resulting in higher STN inhibition
What happens as a result of increased inhibition of the STN?
Less excitatory neurotransmitters are released to the internal globus pallidus (IGP)
What happens as a result of fewer excitatory NTs being released to the IGP?
The IGP neurons become less excited, which in turn reduces inhibitory neurotransmission to the thalamus
The thalamus receives less inhibition from the IGP which results in what?
- Increased transmission from the thalamus to the motor cortex, causing over-stimulation
- This indirect pathway may account for the chorea seen early in HD
What does the direct dopamine pathway normally do?
Stimulates voluntary motor activity
What happens as a result of degeneration of D1 dopamine neurons?
Less inhibition of the IGP which results in increased transmission to the thalamus from the IGP
What happens as a result of increased transmission to the thalamus?
A net increase in thalamic inhibition, causing less stimulation of the motor cortex
How does less stimulation of the motor cortex as a result of damage to the direct pathway present clinically in HD?
The direct pathway may account for the slower than usual movement seen later on in HD
What is believed to be the reason for the time course of chorea and involuntary movement vs bradykinesia/rigitdity of voluntary movement?
It is believed that striatal cells that project to the EGP (indirect pathway, dopamine D2) die before cells that project to the IGP (direct pathway, dopamine D1)
What treatments are available for HD?
- Drugs are used to manage early psychiatric symptoms such as depression and anxiety
- Physiotherapy and occupational therapy
- Early motor symptoms (chorea) are treated by tetrabenazine
What is tetrabenazine?
- A reversible monoamine (e.g. DA) uptake and storage inhibitor - reduces dopamine activity in the brain, therefore reducing the effects of chorea in HD
- Developed as an antipsychotic for schizophrenia in the 1950s
