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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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11
Q

Ballism- mechanism

A
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12
Q

Treatment of ballism

A
  • Large doses of neuroleptics (D2 antagonists)
  • BZ’s
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