Huntingtons disease

Question 1

what is huntingtons disease?

Answer 1

hyperkinetic disorder
no gender predominance
onset 30-50yrs
death 10-20yrs post neuro onset

Question 2

what is the symptomatic profile of huntingtons

Answer 2

physical= chorea (invol mvm in fingers, feet, face, trunk)
loss coord + balance
slurred speech
difficulty swallowing/eating
continual muscular contractions
cog, emotional + psychosis as well

Question 3

describe how huuntingtons is a single gene disease

Answer 3

huntington gene
dominant autosomal
defective neural protein may assemble into aggreagtes, causing damage to neural tissue

Question 4

describe mutations to the huntingtons gene

Answer 4

abnormally expandedd CAG region, econ 1 HTT gene
encodes protein huntingtin, a 3144 aa neuronal protein
healthy gene has <30 repeats, huntingons has 40-80

Question 5

what are the functional consequences of CAG repeats

Answer 5

<26 = no disease (normal)
27-35 = not develp symptoms, kids at risk (intermediate)
36-39 = may/not develop symptoms, esp in old age (reduced penetrance)
40+ =have disease

Question 6

describe general HD pathology

Answer 6

loss striatal medium spiny neurons (MSNs) in striatum. containing D2 rec, in basal ganglia
progressive atrophy striatum (caudate), ventricle enlargement
affects neurons indirect pathway
widespread cortical atrophy + thinning

Question 7

describe the brain ciruitary stuff inhibiton/excitatory things

Answer 7

loss D2 receptor carrying MSNs = dec inhibition on globus pallidus externa => inhibit subthalamic nuclei => cant stim gpi/snr => excite thalamus => hyperexcitability

Question 8

how do excess cag repeats lead to neurotoxicity

Answer 8

excess cag => polyQ formation (makes protein prone to misold/aggreagtion) => insoluble protein aggregates => neuronal intranucelar inclusions (NIIs) -> neurotoxicity

Question 9

what happens when polyq is inserted into mouse genome

Answer 9

tremors, abnormal gait, learning deficit by 6 mnths
brain polQ aggregates
cell los in basal ganglia

Question 10

what is the common theme across ndegn diseases

Answer 10

accumulation of some protein that forms some sort of toxic plaque

Question 11

testing for huntingtons disease

Answer 11

genetic testing
brain scan
unified huntingtons disease rating scale = assessment of feature and progression of hd
4 domains = motor function, cog function, behavioural abnormalities, functional capacity

Question 12

Huntingtons treatment

Answer 12

no treatment to stop progression
pharmacological agent to reduce symptoms:
- antipsychotics for hallucinations/delusions
- antidepressant
- benxo = muscle relax
- anti-parkinsonian agent for rigidity
- tetrabenazine for chorea

Question 13

describe tetrabenazine (TBZ)

Answer 13

fda approved for chorea
mode of action = VMAT-2 inhibitor
VMAT usually transports monoamines from cytoplams into presynaptic storage vesicles = protection from degradation by monomaine oxidase
TBZ = inhibit VMAT = reduces storage of monoamines like dopamine = depletion