Lecture 28: Huntington’s Disease Flashcards
Huntington’s disease characteristics
Involuntary extrapyramidal movements (chorea, athetosis) [basal ganglia dysfunction]
Cognitive decline
Emotional disturbances
15 year progression to hospitalised
Sufferers -> often succumb to aspiration pneumonia
Onset: ~40yo
Type and cause of disorder
Autosomal dominant neurological disorder
Cause: Expanded CAG region in gene IT15 (chromosome 4 short arm)
Wildtype: 35 repeats
Gene carrier: 35-40 repeats
Huntington’s disease if normal life: > 40 repeats
Longer repeats -> more likely to get earlier and more aggressively
Aetiology and genetics
- autosomal dominant
- very rare -> new mutation cause
- long expansion = early onset, short expansion = late onset
- no visible symptoms early in life despite genetic injury early as well
Hungtingtin (htt) protein
- function
- weight
- inclusions
- relevance to disease
Protein transport involvement, antiapoptotic function, increase some neurotrophins level (BDNF)
~ 350kDa
Inclusions - should be removed but accumulate regardless
Most cells/neurons -> no have inclusions when die so relevance to disease is still debated
Pathology
- macroscope
- microscope
- Cerebral atrophy, atrophy of putamen, caudate nucleus & globus pallidus
- GABAergic neurons (basal ganglia) preferentially affected
MSNs (striatum - caudeate nucleus & putamen) -> lost early in disease
Non-GABAergic interneurons: relatively spared
Neuropeptide Y neurons (no GABA/ glutamate receptors): completely spared
Basal ganglia characteristic differential pattern receptors loss as disease progresses
HD grading (Vonsattel grade)
- how it is given
- what do the grades mean
CN - caudeate nucleus
Only given after passed away. Counting number of neurons relative to astrocytes & looking at caudeate nucleus when cut
Grade 0 - minimal apparent change
0 - 1 : lose lots of neurons before major changes seen
Grade 1 - 50% neuronal loss in CN
Obvious visible shrinkage
Grades 2 (CN convex) - 3 (CN concave) - major neuronal loss
Grade 4 (very rare) - 95% neuronal loss in CN
Major CN shrinkage and cortical tissue loss
Neurochemistry of HD circuitry
EGP - external globus pallidus, IGP- Internal globus pallidus, SNr - Substantia Nigra Pars reticulata, SUT - subthalamic nucleus
Indirect pathway : go through subthalamic nucleus instead of through GP
1. Glutametargic fibres (cortex) synapse with 3 neurons in striatum (EGP, IGP, SNr)
2. GABAergic inhibitory neurons (striatum - EGP) - removed
3. GABAergic (EGP - SUT) neurons - fire more
4. Glutamatergic excitatory neuron (SUT - IGP) - reduced activity due to constant firing from inhibitory neuron
5. GABAergic neuron (IGP - VAVL thalamus) - reduce inhibitory activity due to less firing from excitatory neuron
6. Glutamatergic neuron (VAVL - motor cortex) - fire as much as it likes - due no inhibition [hyperexcitability (cortex)]
7. Hyperexcite UMN hyperexcite LMN -> hyperactivity muscle
Hyperexcitability (Cortex) leads to hyperactivity (muscle)
Grades of HD and event that occurs
Grade 0 - cannabinoid receptors lost -> GABAergic cells die -> hyperexcitability
Grade 1 - GABA cells loss in grade 0 + GABA cells to SN loss
Grade 3 - GABA cells to IGB loss -> (Parkinsonian)
Early on in disease (first 5-6 years) -> Huntington’s like symptoms
Later on towards end in disease -> Parkinson’s like symptoms (stiff, rigid, rapid movements disappear)
Drugs that have been tried to alleviate this disorder
Minocycline -> trial done because seem to do better but made it worse
Coenzyme Q & Q10 -> need to consume a lot to get into brain but no work effectively
Latriperidine -> not effective at trial phase 3
Creatine monohydrate -> trials show no effect, large amount needed to go to brain
GABA agonists -> most do not get prescribed beyond trial (can affect many systems), not successful
Antidepressants -> very successful, dealing with cognitive & mood effects of Huntington’s disease
