Huntington's Disease

Question 1

Describe inheritence of HD

Answer 1

Inherited NDD
Autosomal dominant CAG triplet repeat expansion in the huntingtin gene on chr 4

Question 2

What is the cause of HD?

Answer 2

Known- due to production of mutant mHTT protein with abnormally long poilyglutamine repeat

Question 3

What is onset for HD?

Answer 3

~37 years old, it is deoendent on CAG reoeat length
death occurs 15-20 yrs after disease onset

Question 4

What is the effect of more than 56 CAG repeats

Answer 4

junvenile HD
severe prognosis and early onset
Long the CAG repat the earlier the disease onset is

Question 5

What are the three features of HD

Answer 5

1.Motor dysfucntion
2.Bhevioural dysfunction
3.Gognitive dysfunction

Question 6

What are the movement symptoms of HD and its disease course

Answer 6

Chorea
* Motor incoordination
* Dystonia (muscle contortions)
* Oculomotor disturbance (eye
movement)

Hyperkinetic phase - hypokinetic phase

Question 7

What are the cognitive features of HD?

Answer 7

Planning and judgement
Impulse control
Emotional processing
Multi-tasking
Flexibilty

Question 8

What are the psychiatic features of HD?

Answer 8

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

Question 9

Defenition of biomarker

Answer 9

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.

Question 10

What are the checklists for a biomarker

Answer 10

Biomarkers must be sensitive to disease effects: given the progression of HD, from the
premanifest stage to early HD, and then advanced stages, it becomes difficult to develop
biomarkers early in the disease course, as there are no clinical signs!
Biomarkers must be reproducible within and between sites
Biomarkers should be able to track changes over time
Biomarkers must be linked to clinically meaningful measures of function

Question 11

Which biomarker method is the best indicator for disease progression and future onset

Answer 11

Brain imaging

Question 12

Test for cognitive biomarkers

Answer 12

1. Symbol digit modality test
2. Stroop test

Question 13

What were the staging for HD?

Answer 13

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.

Question 14

Example of biomarkers of HD?

Answer 14

Plasma NFL levels higher in every disease stage compared to controls- asscoiated with CAG repeat number

Question 15

What is somatic CAG repeat expansion

Answer 15

Major driver for HD onset and progression.
HTT repeat is somatically unstable

• Expansion of tens or even hundreds of repeats are observed in the most vulnerable striatal neurons; 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 ~150
repeats.

Question 16

When does neurodegeneration start in Huntington’s disease? YAS study

Answer 16

window for prevention

• Normal brain function was reported
• Rise in sensitive measures of neurodegeneration in preHD
• CSF NfL seems to be a sensible measure to monitor disease
  progression
• These findings can be used to inform decisions on when to initiate a
  potential future intervention to prevent or delay further
  neurodegeneration while function is intact

Question 17

Current treatments for HD?

Answer 17

Symptomatic treatment only:
Chorea
ü Tetrabenazine (sleep
problems, depression,
anxiety and restlessness
as side effects)
ü Neuroleptics
(olanzapine, risperidone
and quetiapine), with
sedation and weight gain
as side effects
ü Physiotherapy

Psychological/psychiatric
disturbances
ü Cognitive Behavioural
Therapy (CBT)
ü Psychodynamic
therapy
ü SSRI (citalopram,
fluoxetine, paroxetine
and sertraline),
mirtazapine
ü Neuroleptics