Huntington's Disease Flashcards
Memory for HD lecture (25 cards)
Describe inheritance of HD
Inherited NDD
Autosomal dominant CAG triplet repeat expansion in the huntingtin gene on chr 4
What is the cause of HD?
Known- due to production of mutant mHTT protein with abnormally long polyglutamine repeat
What is onset for HD?
~37 years old, it is dependent on CAG repeat length
death occurs 15-20 yrs after disease onset
What is the effect of more than 56 CAG repeats
junvenile HD
severe prognosis and early onset
Long the CAG repat the earlier the disease onset is
What are the three heterogenous features of HD?
1.Motor dysfunction
2.Behavioural dysfunction
3.Cognitive dysfunction
What are the movement symptoms of HD and its disease course
Chorea
* Motor incoordination
* Dystonia (muscle contortions)
* Oculomotor disturbance (eye
movement)
Phase to phase transition
Hyperkinetic phase (prominent chorea)
to Hypokinetic phase (bradykinesia, dystonia,
balance and gait problems)
What are the cognitive features of HD?
Planning and judgement
Impulse control
Emotional processing
Multi-tasking
Flexibilty
What are the psychiatic features of HD?
Irritability
Depression and anxiety
Aggressiveness
OCD behaviour- Increased suicidal risk and incidence
Psychosis
Hypersexuality
Combination of psychiatric and cognitive features cause the greatest disability, functional decline and distress to relatives
* Problem with accessing the appropriate services and resources, as they fall within both Neurology and Psychiatry
Definition of biomarker
A “biomarker” is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention.
What are the checklists for a biomarker
- Sensitive to disease effects along time period - hard to do for HD as no early clinical signs
2.Biomarkers must be reproducible within and between sites
3.Biomarkers should be able to track changes over time
Biomarkers must be linked to clinically meaningful measures of function
Which biomarker method is the best indicator for disease progression and future onset
Brain imaging
What brain changes could become clinical endpoints
Brain volume change in caudate and putamen, and white matter
What does diffusion MRI reveal about HD
Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset
Why are caudate and putamen affected in HD?
brain regions are highly susceptible to the toxic effects of the mutant huntingtin protein.
Differences in brain changes between HD and PD
PD- Loss of DA neurons in substantia nigra
HD- Genetic disorder- mHTT and CAG repeats
Similarities between PD and HD?
Both have striatum basal ganglia affected
What cell type is affected in HD?
Medium spiny neurons (GABAergic) in the striatum
Test for cognitive biomarkers
- Symbol digit modality test
- Stroop test
What were the staging for HD?
Stage 0: Cag repeats >40
stage 1: Biomarkers of pathogensis- see effects of volume decrease in caudate and putamen
Stage 2: Clinical sign and symptoms- conduct total motor score and symbol digit modality test
Stage 3: Functional change- Total functional capacity and independce scale.
Example of fluid biomarkers of HD?
Plasma NFL
levels higher in every disease stage compared to controls- associated with CAG repeat number
What is somatic CAG repeat expansion
Major driver for HD onset and progression.
HTT repeat is somatically unstable.
Greater somatic expansion occurs with longer initial CAG repeat length.
A recent postmortem study suggests that neurons may experience
decades of ….
‘biologically quiet’ somatic CAG repeat expansion with neuronal damage triggered by a cascade of repeat-length dependent transcriptional dysregulation events in medium spiny neurons (MSNs) only when the CAG reaches a threshold of ~15 repeats.
What does the YAS study say are the earliest signs of HD brain changes? 1 main 2 extra
Normal brain function was reported
CSF plasma Nfl levels are the most sensitive measure and could be used to measure disease progression.
Also
decrease PENK
Decrease Putamen and caudate volume
