Lec 19-Huntingtons and Ballism Flashcards
1
Q
Huntington’s disease
A
- George Huntington 1872 (chorea)
- Hereditary (Autosomal dominant) disorder
- Each child of affeceted parent has 50% chance of inheriting the disorder
- 1 in 10-20,00
- 34-42 years, average 37yrs
- Generalised shrinkage and thinning of cortex and basal ganglia
- Disease progresses over 10 to 25 years
2
Q
Huntington’s disease I
A
-
Physical symptoms- hyperkinetic disorder
- Uncontrolled quick jerk involuntary movement
- Slurred speech
- Difficulty in swallowing
-
Emotional symptoms
- Personality changes, depression, mood swings, obsessive
-
Cognitive symptoms
- Loss of attention, difficulting making decisions, loss of recall
- General have an intoxicated demeanour
3
Q
Huntington’s Disease II
A
- Neurodegenerative disease
- Early motor symptoms are due to a loss of GABA/enkephalin containing medium spiny neurones of the striatum
- Later loss of whole striatonigral projection
- Dementia and psychiatric problems due to loss of neurones in the cortex
- Why selective loss?- disruption of the energy metabolism may contribute
- Degeneration by excitotoxic cell death
4
Q
Huntington’s disease (Early stage)
A
- Excess of movement with uncontrollable and relatively rapid motor patterns (chloroform)
- Primary pathology in the early stage is the loss of striatal output of the indirect pathway
- => Overactive thalamocortical pathway
- => Involuntary movement
- Loss of striatal cells, No GABA released so no inhibition of GPe, More GABA released onto STN so activity goes down
- STN does not release glutamate, so less stimulation of SNr/GPi
- Less GABA released onto thalamocortical motor loop so increased activity hence hyperkinetic
5
Q
Late phase
A
- Imbalance of DA, ACh, GABA systems
- Increased DA
- Decreased GABA
- Decreased ACh
- L-DOPA, amphetamine potentiate increases symptoms
- D2 antagonist (neuroleptics) help
6
Q
A hereditary disorder
A
- In 1993, Gene responsible for HD was identified on chromosome 4
- Gene produces a normal protein called Huntingtin
- Individuals that developed HD >40 CAG repeats which encodes for glutamine
- More CAG repeats the earlier symptoms appear
- Predictive testing for the disease
7
Q
Huntingin Protein
A
- Mutant form found in nucleus
- Only appears in certain groups of neurones
- Crucial for embryonic development
- CURRENT RESEARCH HYPOTHESES
- Apoptosis- programmed cell death
- NGF, BDNF supress suicide programme
8
Q
Drug therapy
A
- Limited to symptomatic and support therapies
- Current treatments cannot reverse, stop or slow disease progression
- BZ’s: for GABA-potentiation effect at GABAA receptor- Maximise effect of GABA released from remaining neurones
- Neuroleptics: D2 antagonist (But TD risk) or tetrabenazine (DA reflector)
- Inhibition of neurotoxicity: NMDA inhibitors, antioxidants, inhibitors of Ca channels, NOS
- Future: surgery or foetal striatal implants
9
Q
Ballism
A
- Hyperkinetic disorder- Violent, flailing movements of large areas of the body
- Specific loss of subthalamic nucleus
- Stroke
- Hemi-ballismus on one side of the body results from large unilateral lesions in the opposite subthalamus
10
Q
Drug therapy- Ballism
A
- Limited to symptomatic and support therapies
- Current treatment cannot reverse, stop or slow disease progression
-
BZ’s: for GABA-potentiation effect at GABAA receptor-
- Maximise effect of GABA released from remaining neurones
- Neuroleptics: D2 antagonist (But TD risk) or tetrabenazine (DA reflector)
- Inhibition of neurotoxicity: NMDA inhibitors, antioxidants, inhibitors of Ca channels, NOS
- Future: surgery or foetal striatal implants
11
Q
Ballism- mechanism
A
12
Q
Treatment of ballism
A
- Large doses of neuroleptics (D2 antagonists)
- BZ’s