Huntington's Flashcards
Where is degeneration in HD?
BG and cortex
Impacts many pathways biochemically
What is the inheritance of huntingtons?
- Autosomal dominant
- 100% penetrance
- 4p
- HTT, 67 exons, 3144 A.A.s
What is the genetic defect responsible for HD?
CAG –> Q –> glutamine 36-122 –> destabilizes the DNA and proteins
What number of CAG repeats is associated with HD?
36-41 May or may not have
40-60 adult onset
60 or greater juvenile onset
Can a parent who does not have the disease make a child that does?
Yes, a copy of 36-40 may make more repeats, genetic anticipation
What modifies HD severity?
Variants in the NMDA receptor influence disease severity
What causes Huntington protein agreagtion?
The glutamine repeat makes it insoluble and stuff gets stuck in the aggregates
What is the excitotoxicity hypothesis in HD pathology?
Over exposure to glutamate causes - pathological change in neurons, ion influx,energy depletion –> cell death
NMDARs are a subclass of receptors relevant to neuronal cell death
- relatively high permeability to Ca and slow activation/deactivation
- loss of NMDARs in HD patients
What is the most common inherited neurodegenerative disorder?
HD
What is the age of onset and bias of HD?
35-50. Earliest is 2
Life expectancy is 20yrs after onset
Effects all races and sexes equally
What is the pathogenesis of HD?
- Loss of neurons in BG –> less motor control
(BG also in prefrontal loops and limbic loops) - Lose spiny striatal neurons that dampen motor activity –> increased motor output (choreoathetosis) crazy movements
What are gross features of HD?
- small brain
- atrophic striatum (caudate) and frontal lobe
- dilated lateral and third ventricle
What are the grades of HD?
0-1: only microscopic changes
2: some atrophy but caudate still convex
3: more atrophy, caudate is flat
4: so much caudate atrophy that it becomes concave
What are microscopic changes of HD?
- loss of striatal neurons, especially medium spiny neurons
- tons of fibrillation gliosis
- degeneration = severity of clinical
- Huntington aggreation
- caudate has no neurons, lots of astrocytes
What does the huntington protein stained with and look like?
- ubiquitin stain in caudate (brown)
- basket like structure - long sticky proteins that catch other proteins
What is ELSI?
Ethical, legal, and social implications
What is the treatment for HD?
None, cannot slow or cure
Only treat symptoms
What is the exclusion test?
Px does not want to know but wants to know if offspring will have it
What makes up the striatum?
Caudate + putamen + nucleus accumbens
What is the lenticular nucleus?
Putamen and globus pallidus
What pathway is out of control in HD?
BG - direct pathway
Hyperactive
What pathway is out of control in PD?
BG - indirect
Hyperacitve
What happens in the BG pathway in HD?
Loss in caudate and putamen with gliosis –> loss of Nigrostriatal GABA projection neurons –> decreased GPi inhibition of thalamus –> increased movement
What are treatments of HD?
Dopamine blockers and depleters
- Haloperidol - D2 antagonist (FGA)
- Risperidone - SGA motor and psychiatric
- Clozaril - DA antagonist, risk of agranulocytosis
- Tetrabenazine - Monoamine depleting agent stopping transport into vesicles (best in striatum)
- Valproic acid - enhances GABA effects
- Lithium - serotonin reuptake, NE, D2
- Benzos - chorea, but increase sedation
