Huntington's disease

Question 1

What is Huntington’s disease?

Answer 1

• Neurodegenerative
• Autosomal dominant-complete penetrance
• Prevalence around 4-10 per 100,000 (might be 2x as common though)
• Most commonly presents in mid-life
• Slow progressive over 20-30 years
• Cognitive, motor and psychiatric symptoms

Question 2

What is the cause of Huntingtons disease?

Answer 2

• Huntingtin gene (HTT) is located on short arm chr 4
• 5’ end-CAG repeat sequence
• Protein-extended polyhutamine tail
• • Caused by a mutation of a gene called huntingtin – the disease is when you have >40 repeats of CAG (normal people have 17-21)

Question 3

How to predict and recognise early onset?

Answer 3

• Onset determined by clinical onset of motor symptoms
• Relationship between CAG repeat length and age of onset
• Not predictive on individual basis
• Other genes that modify onset and phenotype
• 1.Estimated 50% of variability in onset

Question 4

What is Huntingtin?

Answer 4

• HD gene identified in 1993
• Chromosome 4
• Codes for huntingtin protein, it is ubiquitously expressed
• Cytoplasmic
• Essential for embryonic dev

Question 5

What is Huntingtin involved in?

Answer 5

• Intracellular transport
• Intracellular signalling
• Metabolism
• Neurogenesis and formation of CNS
• Synaptic activity
• Transcription regulation
• Anti-apoptopic

Question 6

What happens to mutant Huntingtin?

Answer 6

• Mutant Huntingtin aggregates (clumps together) and some stages of the aggregation are toxic, and some are protective.
• Issues arise when mutation either gains or loses a function.

Question 7

Explain the pathology of Huntingtons Disease.

Answer 7

• 10-20% reduction in brain weight
• Decreased striatal volume and cell death
• Decreased cortical volume and cell death
• Increased ventricle size
• Proteinous inclusions throughout brain

Question 8

What does the disease target predominantly?

Answer 8

• Selective loss of GABA cont medium spiny neurons (MSN) in striatum
• 1st enkephalin cont MSN (indirect pathway)
• Later stage: Substance P sont (direct pathway)
• Cholinrgic interneurones of striatum are spared

Question 9

Where does the indirect pathway lead?

Answer 9

• Terminals release GABA onto external Globus Pallidus

Question 10

Where does the direct pathway lead?

Answer 10

• Terminals release GABA onto internal Globus Pallidus

Question 11

Explain the direct pathway.

Answer 11

(dopamine turns on direct)

Question 12

Explain the indirect pathway.

Answer 12

(Dop turns off indirect)
(Losing Dop=No Movt)

Question 13

Explain the huntington’s pathway.(Diag)

Answer 13

Question 14

Explain Huntington’s Pathway. (Words)

Answer 14

• Thalamus releasing more glutamate causing overactivity in cortex.
• Inability to stop movts happening due to the loss of a single cell type in circuit casue shit fuck
• Overactivity in SNc, therfore compunding the effect
• Direct pathway further stimulated and Indirect lost
  So even more movement experienced

Question 15

What is the circuitry of 1 motor circuit and what is it responsible for?

Answer 15

• 1 motor supplementary->Putamen->GP/SN->Thalamus
• Resonsible for motor symptoms

Question 16

What is the circuitry of Dorsolat prefrontal circuit and what is it responsible for?

Answer 16

• Dorsalat prefrontal->Caudate->GP/SN->Thalamus
• Cognition symptoms

Question 17

What is the circuitry of Lat orbito-frontal circuit and what is it responsible for?

Answer 17

• Lat orbito-frontal->Caudate->GP/SN->Thalamus
• Cognition symptoms

Question 18

What is the circuitry of Med orbito-frontal circuit and what is it responsible for?

Answer 18

• Med orbito-frontal->Nuc acc->GP/SN->Thalamus
• Psychiatric symptoms
• (Nuc acc is v.imp in reward behaviour, so if lost leads to be less inclined to do things as dont get rewards from things you used to.)

Question 19

What are the early motor symptoms?

Answer 19

• Abnormal eye movts
• Inapp hand and toe movts
• General restlessness

Question 20

What are the Midcourse motor symptoms?

Answer 20

• Onset of involuntary movts (Chorea)
• Hypertonic rigidity and dystonia (slow abnormal movts with inc muscle tone)

Question 21

What are the late stage motor symptoms?

Answer 21

Impaired voluntary movts:
* Rigidity
* Bradykinesia
* Dystonia
* Convulsions
* Weight loss
* LEADS to death via pneumonia, choking, chronic skin ulcers or nutritional deficits

Question 22

What are the cognitive symptoms?

Answer 22

May procede motor onset by a decade or more.
* Dysexecutive syndrome
* Attention deficits, difficulty switching attention from one task to another
* Impaired insight and judgement
* Forgetfulness
* Language deficits

Question 23

What are the psychiatric symptoms?

Answer 23

• Highly variable over time and between patients
• May precede motor symptoms by a decade or more
• Core features:
  1. Anxiety
  2. Depression
  3. Obsessive/compulsive
• Less common:
• Hallucinations and delusions

Question 24

What are other significant symptoms?

Answer 24

• Weight loss:
  1. Invol movts, loss app and motiv, dysphagia, metabolic dysf
• Sleep disturbance
  1. Circadian rhythm disturb, depression, loss of routine,’break through’ inv movts, caffeine intake.
• Muscle weakness
  1. Primary muscle involvement (inc, mitochondrial dysf), disuse atrophy, nutritional deficiencies

Question 25

How to treat Huntington’s?

Answer 25

• Block dopaminergic transmission-dopamine antagonists (tetrabenazine depletes dopamine-antipsychotic medication e.g. olanzapine is a dopamine antagonist)
• Drugs that enhance GABA-red action of the thalamus (benzodiazepenes)
• Speech and physiotherapy