Huntington's Disease Flashcards

1
Q

What is the incidence of Huntington’s disease?

A

5.6/100,000 in NZ

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2
Q

When does onset usually occur?

A

midlife 35-45 years, approx 40yrs

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3
Q

What are the symptoms?

A

Symptoms are VARIABLE but can include:

  1. Hyperkinesia/Rigidity
  2. Behavioural (emotional) and cognitive changes- often before motor symptoms, often not picked up as indicative of HD
  3. Involuntary movements:
    3. 1 Chorea (dance-like, return to midline)
    3. 2 Athetosis (slow,convoluted, writhing movements to one side, don’t return to midline)
    3. 3 Extrapyramidal movements (reflexes and movement, movement modulation i.e. coordination) - not crucial, important for fine-tuning
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4
Q

How long do patients have to live after onset?

A

15 year progression to incapacitation, sufferers often die from aspiration pneumonia (become rigid, can’t lift chest to breathe)

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5
Q

What is the genetic basis of HD?

A

HD is an autosomal dominant neurological disorder i.e. abnormal gene dominates

Expanded CAG (glutamine coding) region in the gene IT15 on the short arm of chromosome 4

        - -> up to 35 CAG repeats = normal
        - ->35-40 CAG repeats = Gene carrier
        - ->above 40 CAG repeats = HD
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6
Q

What is the ratio of HD in men and women?

A

1:1

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7
Q

How much do new mutations contribute to HD incidence?

A

Cause less than 1% of new cases

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8
Q

How does the length of the CAG repeat relate to the onset and severity of HD?

A

Longer CAG repeat lengths –> earlier onset, increased severity of symptoms and pathology

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9
Q

What does it mean to say that HD is associated with genetic anticipation?

A

There is increasing severity or earlier age of onset of a genetic trait in succeeding generations

Gene positive patients may experience genetic anticipation

More likely to receive a longer CAG repeat if gene is inherited from father.

No apparent symptoms early in life despite genetic injury

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10
Q

What does the HD gene encode?

A

The htt protein, a protein of ~350kDa

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11
Q

What is the htt protein involved in?

A
  1. Protein transport
  2. Antiapoptotic function
  3. Increases the levels of some neurotrophins (like BDNF)
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12
Q

What are inclusions?

A

Heavily ubiquinated accumulations of the htt protein that like to clump around the nuclei of cells, however most cells even dying ones don’t have inclusions

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13
Q

What is the macroscopic pathology of HD?

A
  1. Marked cerebral atrophy

2. Atrophy of caudate nuclues, putamen (caudate nuclues + putamen = striatum)and globus pallidus

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14
Q

What is the microscopic pathology of HD?

A
  1. Neurons that use GABA (Gamma-aminobutyric acid) as their neurotransmitter are preferentially lost
    These neurons are called Medium-spiny neurons (MSNs)
  2. MSNs make up 95% of the striatum and are lost early on in the disease. There is a greater than 80% loss of MSNs
    3.Non-GABAergic interneurons are relatively spared
    4.Differential pattern of receptor loss in the basal ganglia as the disease progresses
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15
Q

How is cell loss in the basal ganglia described?

A

Using the Vonsattel Pathology Grading system

                  - only current system
                  - allows comparison between the severity of different HD cases
                  - grading given by pathologist after death of patient
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16
Q

What are the grades of the Vonsattel Pathology Grading system?

A

Grade 0 - minimal overt change

Grade 1 - 50% loss of MSNs in caudate nucleus (shrinkage is obvious to the eye)

Grades 2-3 - major loss of MSNs

Grade 4 - >80% loss of neurons in caudate nucleus (up to 95% loss of MSNs)
-major shrinkage of caudate nucleus and loss of cortical tissue

17
Q

A dramatic and early loss occurs of GABAergic MSNs that also contain what?

A

The peptide enkephalin and the CB1 receptor

18
Q

In later grades, there is a major loss of GABAergic MSNs that also contain what?

A

Substance P and CB1 receptor