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Neuroanatomy and neurodegenerative disorders > Huntington's Disease > Flashcards

Huntington's Disease Flashcards

1
Q

In what year was the Huntington Disease gene identified?

A

1993

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2
Q

What are some of the motor symptoms seen in HD?

A

Chorea, dystonia, dysarthria, dysphagia, poor posture, in coordination, impaired gait and balance, delayed initiation of voluntary saccades

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3
Q

What are some cognitive symptoms associated with HD?

A

Loss of executive functions, difficulty in multitasking, inflexible thoughts, poor concentration, impaired spatial perception, disinhibition, poor insight, short term memory loss

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4
Q

What are some of the psychiatric symptoms associated with HD?

A

Depression, anhedonia, decreased libido, suicidal ideation, social isolation, disrupted sleep pattern, delusions, hallucinations, paranoia, irritability

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5
Q

When was the first genetic mouse model of HD made?

A

1996

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6
Q

What comprises the clinical triad of HD symptoms?

A

Cognitive, motor and psychiatric

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7
Q

How is HD diagnosed?

A
  • 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
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8
Q

What occurs during the prodromal phase of Huntington’s disease?

A

No motor symptoms but there are psychiatric and cognitive symptoms

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9
Q

In which disease phase does quality of life start to decline?

A

Prodromal phase

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10
Q

By which stage of HD progression does treatment need to occur and why?

A

Treatment needs to occur during prodromal phase because after the neurons die there is little that can be done

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11
Q

Which structures in the brain start to atrophy in HD?

A

Basal ganglia

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12
Q

What does the indirect dopamine pathway normally do?

A

Inhibit involuntary motor activity

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13
Q

What happens to the external globus pallidus as a result of degeneration of dopamine D2 neurons in the striatum?

A

The EGP receives less inhibition

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14
Q

What happens as a result of decreased inhibition of the EGP?

A

More neurotransmitters are released to the subthalamic nucleus, resulting in higher STN inhibition

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15
Q

What happens as a result of increased inhibition of the STN?

A

Less excitatory neurotransmitters are released to the internal globus pallidus (IGP)

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16
Q

What happens as a result of fewer excitatory NTs being released to the IGP?

A

The IGP neurons become less excited, which in turn reduces inhibitory neurotransmission to the thalamus

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17
Q

The thalamus receives less inhibition from the IGP which results in what?

A
  • Increased transmission from the thalamus to the motor cortex, causing over-stimulation
  • This indirect pathway may account for the chorea seen early in HD
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18
Q

What does the direct dopamine pathway normally do?

A

Stimulates voluntary motor activity

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19
Q

What happens as a result of degeneration of D1 dopamine neurons?

A

Less inhibition of the IGP which results in increased transmission to the thalamus from the IGP

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20
Q

What happens as a result of increased transmission to the thalamus?

A

A net increase in thalamic inhibition, causing less stimulation of the motor cortex

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21
Q

How does less stimulation of the motor cortex as a result of damage to the direct pathway present clinically in HD?

A

The direct pathway may account for the slower than usual movement seen later on in HD

22
Q

What is believed to be the reason for the time course of chorea and involuntary movement vs bradykinesia/rigitdity of voluntary movement?

A

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)

23
Q

What treatments are available for HD?

A
  • 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
24
Q

What is tetrabenazine?

A
  • 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
25
Q

What is the mechanism of action of tetrabenazine involving VMATs?

A
  • Proteins called vesicular mono-amine transporters (VMATs) normally put the neurotransmitter dopamine into vesicles
  • Tetrabenazine binds to VMATs, preventing them from allowing DA particles into vesicles, thereby reducing the amount of DA in the brain
26
Q

What is the mechanism of action of tetrabenazine involving dopamine receptors?

A
  • Dopamine binds to the receptors, causing the signal to be sent down the receiving nerve cell
  • Tetrabenazine competes with dopamine by binding to receptors on the surface of the receiving nerve cell, blocking DA from binding and passing on electrical signals
27
Q

Where is DA released from and what is its function in the striatum?

A

Released from the substantia nigra and inhibits the striatum via D1 and D2 receptors, therefore modulating activation of the direct and indirect pathways

28
Q

Where is the primary reported site of neurodegeneration in HD?

A

Striatum

29
Q

Which pathway and dopamine receptor are thought to be responsible for the early chorea symptoms?

A

Indirect pathway and striatal D2 dopamine receptors

30
Q

Which pathway and dopamine receptor are thought to be responsible for the later slow movement symptoms?

A

Direct pathway and striatal D1 receptors

31
Q

Where is the Htt gene found?

A

Chromosome 4

32
Q

How is HD inherited?

A
  • Autosomal dominant inheritance - only one copy needs to be inherited for HD to develop
  • Each child has 50% chance of inheriting the mutant gene
  • 100% penetrance
33
Q

What is the characteristic repeat seen in HD?

A
  • CAG repeat expansion disorder
  • CAG codes for glutamine
34
Q

What is produced as a result of CAG repeat expansion disorder?

A

CAG trinucleotide repeat expansions in exon 1 of Htt gene (>36 repeats) are translated into abnormally long polyglutamine tracts in Huntingtin protein

35
Q

How do the length of the CAG repeat tract and severity and age of onset of disease correlate?

A

As the CAG repeat tract increases in length the severity of the disease increases and the age of onset decreases

36
Q

What would give a positive test result for CAG repeat count?

A

>40 CAG repeats

37
Q

How many counts is classed as an uninformative test result?

A

36-39 CAG repeats

38
Q

What is a negative CAG test result?

A

<36 CAG repeats

39
Q

What happens as a result of extended polyglutamine protein?

A

Misfolding occurs, leading to aggregation which causes neuronal cell death

40
Q

What is the function of the Huntingtin protein?

A
  • Main function in humans is unclear but is known to interact with a plethora of proteins
  • Vital for embryonic development
41
Q

Where are the highest levels of Htt detected?

A

Brain and testes - but expressed in all cells

42
Q

Why is HD referred to as a polyQ disease?

A

Q=glutamine and there are multiple CAG repeats so multiple glutamines

43
Q

What chance does each child of a HD parent have of being a gene carrier?

A

50%

44
Q

What chance does each child of a HD parent have of developing the disease?

A

50%

45
Q

Was ASO silencing of Htt successful in animal models?

A

Yes for 4 months

46
Q

How is ASO treatment delivered?

A

Patients will have a Huntingtin holiday with intermittent ASO delivery through epidural injections

47
Q

What are some considerations that need be taken into account for gene silencing treatment?

A
  • Getting ASO into the brain - direct injection into the brain? brain shuttle? - first clinical trial used spinal injection
  • Distribution - does it need to reach the striatum? rodent studies show it doesn’t reach deep structures efficiently
  • Switch off one or both - no difference in HD symptom reversal when both WT and mutant alleles were switched off in mice
  • Choosing the right target
  • Side effects - ASO may bind to other mRNA, immune response
48
Q

What are the 3 main classes of genetic mouse model?

A

N-terminal transgenics, full length transgenics, knock-ins

49
Q

How many CAG repeats occur in the endogenous mouse gene?

A

7

50
Q

Which class of genetic mouse model has the most severe phenotype?

A

N-terminal transgenics

Neuroanatomy and neurodegenerative disorders (7 decks)

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