Huntington's Disease

Question 1

What is the incidence of Huntington’s disease?

Answer 1

5.6/100,000 in NZ

Question 2

When does onset usually occur?

Answer 2

midlife 35-45 years, approx 40yrs

Question 3

What are the symptoms?

Answer 3

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

Question 4

How long do patients have to live after onset?

Answer 4

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

Question 5

What is the genetic basis of HD?

Answer 5

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

Question 6

What is the ratio of HD in men and women?

Answer 6

1:1

Question 7

How much do new mutations contribute to HD incidence?

Answer 7

Cause less than 1% of new cases

Question 8

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

Answer 8

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

Question 9

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

Answer 9

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

Question 10

What does the HD gene encode?

Answer 10

The htt protein, a protein of ~350kDa

Question 11

What is the htt protein involved in?

Answer 11

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

Question 12

What are inclusions?

Answer 12

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

Question 13

What is the macroscopic pathology of HD?

Answer 13

1. Marked cerebral atrophy

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

Question 14

What is the microscopic pathology of HD?

Answer 14

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

Question 15

How is cell loss in the basal ganglia described?

Answer 15

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

Question 16

What are the grades of the Vonsattel Pathology Grading system?

Answer 16

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

Question 17

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

Answer 17

The peptide enkephalin and the CB1 receptor

Question 18

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

Answer 18

Substance P and CB1 receptor