Huntington's Disease

Question 1

What is chorea?

Answer 1

“dance-like” movements

Question 2

Huntington’s mean age of onset?

Answer 2

30-50 years

Question 3

Genetic mutation and inheritance pattern of Huntington’s disease (HD)?

Answer 3

Mutation of Huntingtin gene (HTT) on short arm of chromosome 4 (4p16.3)

Autosomal Dominant

Question 4

Describe specifics of mutation in HD?

Answer 4

Improper expansion of CAG trinucleotide in Huntingtin-HTT gene (expanded CAG repeats in HD)

Question 5

Correlation between CAG repeats and HD development

Answer 5

= 28 : normal range (won’t develop HD)

29-34: (won’t develop HD but next gen is at risk)

35-39: (some, but not all will develop HD; next gen at risk)

> /= 40: will develop HD

Question 6

Physiology vs Abnormality of HTT gene?

Answer 6

Physiologically: HTT codes for Huntingtin protein

HD: mHTT (mutant) codes for abnormal protein w/ large glutamine blocks

Question 7

Outcome of mutation in HD?

Answer 7

Gradual damage to neurons (possibly by inducing apoptosis)

Degeneration and death of medium spiny GABA-ergic neurons in caudate and putamen -> increased DA release -> movements

(GABA inhibits DA neurons)

Question 8

Neuropathological changes in HD individuals?

Answer 8

General atrophy (widening sulci, narrowing gyri, enlarged ventricles)

Basal ganglia atrophy

Question 9

Prognosis of HD?

Answer 9

PROGRESSIVE DISORDER

Death within 10-15 years of symptom onset

Question 10

Symptoms in early and late HD

Answer 10

EARLY: (mild)

• choreic movements (jerking of trunk/arms/face)]- masked as socially acceptible movements
• depression, clumsiness, lack of concentration, short term memory lapses

LATE (prog. decline)

• choreic movements (worsens until total incapacitation)
• loss of coordination + balance
• difficulty swallowing
• cognitive decline/dementia

Question 11

How to measure HD symptoms?

Answer 11

Unified Huntington Disease Rating Scale (UHDRS)

• tongue protrusion (can’t)
• max. chorea
• gait (reduced mobility)
• dysarthria (mute)
• retropulsion pull test (falls)
• cognitive assessment (dementia)
• behavioural assessment (depression)
• functional capacity (full time nursing care)

Question 12

HD on MRI?

Answer 12

Atrophy in caudate and putamen

Question 13

HD on 11C-Raclopride PET

Answer 13

D2 receptor loss in caudate + putamen (normally expressed by medium spiny GABA neurons)

Reduced PET signal in caudate and putamen

Question 14

Mechanism of using 11C-Raclopride on PET scans

Answer 14

It’s a ligand for D2 receptor (reversible binding) = indirect marker for neuronal loss in HD (can cross BBB)

11-C attaches to Raclopride which binds to D2; 11-C only detected where there is D2

[need to account for background tracer in blood]

Question 15

Management strategies for HD?

Answer 15

• pharmacological
• psychotherapy
• speech therapy
• physical therapy
• occupational therapy
• experimental treatments/novel therapies

Question 16

Pharmacological management of HD and mech. of action?

Answer 16

Tetrabenazine (only available drug)

Tetrabenazine inhibits vesicular monoamine transporter (VMAT) -> reduced DA packaging into vesicles -> reduced synaptic release of DA -> reduced movements

Question 17

Examples of experimental/novel treatments of HD

Answer 17

• RNA interference (antisense oligonucleotides, RNA interference compounds)
• DNA targeting gene therapies (zinc-finger transcriptional repressors, CRISPR/Cas9)
• cell transplantation therapy

Question 18

RNA interference mechanism

Answer 18

(e.g. antisense oligonucleotides aka ASOs, RNA interference compounds)

Targets mRNA HTT and its translation. Aims to increase degradation of transcript

Question 19

DNA gene therapies mechanism

Answer 19

(e.g. zinc-finger transcriptional repressors, CRISPR/Cas9)

Targets DNA and aims to accelerate degradation of transcript

Question 20

Mechanism of cell transplantation therapy in HD?

Answer 20

[in HD: death of caudal neurons and disruption of basal ganglia-cortical pathways]

Cell transplantation (via stereotactic injection) aims to restore basal ganglia-cortical circuits and improve HD symptoms

Question 21

Outcomes of cell transplantation therapy in trials?

Answer 21

Varied success

Transplanted DA neurons can integrate successfully]- increase in 11C-Raclopride PET signal