Huntington's Disease Flashcards
How common is HD in the caucasian population?
1/10,000 – 1/20,000
30-50 yrs
What is juvenile HD?
before 20yrs with behavioural disturbances & learning difficulties
How is HD inherited?
Autosomal dominant pattern of inheritance -> only need one mutated allele from a single parent
What is the mutation associated with HD?
expanded CAG trinucleotide repeat in HTT gene (chromosome 4) -> produces mutant huntingtin protein with an elongated polyglutamine tract
How much is the CAG repeat typically expanded?
10-35 times
What is anticipation?
the severity of the disease tends to increase and symptoms appear at an earlier age in successive generations.
What does the mutated huntingtin protein lead to?
Toxic effects on nerve cells
disruption of cellular processes
Formation of protein aggregates within cells
What are 5 motor symptoms of HD?
Chorea
Dysarthria
Dysphagia
Bradykinesia
Dystonia -> abnormal posture
What are 5 cognitive symptoms of HD?
Depression
Dementia
Seizures
Compulsive behaviour
Apathy
What brain region is the anatomical basis of chorea?
Basal ganglia
What part of the brain becomes enlarged in HD?
Frontal horns of lateral ventricles
Which brain regions become atrophied?
caudate and putamen
What brain regions degernate?
Frontal & temporal cortices
What are the 5 grade classifications of HD?
Grade 0 – clinical evidence but no gross or microscopic abnormalities
Grade 1 – moderate fibrillary astrocytosis at microscopic level
Grade 2 – macroscopic changes in caudate & putamen
Grade 3 – lateral segment of globus pallidus showing fibrillary astrocytosis
Grade 4 – shrunken caudate, widen anterior horn of lateral ventricle & smaller nucleus accumbens
What other changes are seen in stage 3 and 4?
loss of thalamus, sub-thalamic, nucleus accumbens, white matter & cerebellum
What is the exact neuropathology of HD?
Projection from caudate & putamen to globus pallidus is diminished -> decreases tonic inhibition from GP to subthalamic nucelus -> thalamic excitation of cortex is increased -> inappropriate motor activity -> chorea
What 4 ways can HD be detected?
Imaging -> loss of grey & white matter volume
Diffusion weighted MRI
Functional MRI
PET
What compensatory mechanisms occur in pre manifest stage?
Neuroplasticity & network reconfiguration
What drug is used to treat chorea?
Tetrabenazine
What is the MoA of terabenazine?
Inhibitor of synaptic vesicular monoamine transporter 2 -> depletes DA, 5-HTT, NE, hitamine
What are 3 other drugs used to treat HD symptoms?
Atypical neuroleptics -> DA blocking
Antidepressants
Gene therapy (research focus)
What is the indirect pathway in HD?
medium spiny neurons that project to GP degenerate
What do medium spiny neurons inhibit?
Activity of external GP cells
In HD these cells now become abnormally active
What do the abnormally active external GP cells reduce?
Excitatory output of subthalamic nucleus to internal GP -> reduces inhibitory outflow of BG -> upper motor neurons activated
Which non-motor BG loops are disrupted?
Emotional & cognitive loops deteriorate
What mouse model is used to look at HD?
R6/1
How was this HD mouse model treated?
Suppression of HTT using antisense oligonucleotides to act on neurotransmission & protein clearance
What behavioral tests did the R6/1 mouse do?
balance beam/maze
What 3 brain regions did they look at in thre R6/1 mouse?
mPFC, striatum & hippocampus
What did they measure?
Tyrosine hydroxylase expression -> correlates to DA and NA clearance
What did they find in the ASO treated R6/1 mouse?
Improved balance, spatial memory, recognition memory, motor coordination
Increased TH
