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Flashcards in Huntington's Disease Deck (21)
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What is chorea?

"dance-like" movements


Huntington's mean age of onset?

30-50 years


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

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

Autosomal Dominant


Describe specifics of mutation in HD?

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


Correlation between CAG repeats and HD development

= 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


Physiology vs Abnormality of HTT gene?

Physiologically: HTT codes for Huntingtin protein

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


Outcome of mutation in HD?

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)


Neuropathological changes in HD individuals?

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

Basal ganglia atrophy


Prognosis of HD?


Death within 10-15 years of symptom onset


Symptoms in early and late HD

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


How to measure HD symptoms?

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)


HD on MRI?

Atrophy in caudate and putamen


HD on 11C-Raclopride PET

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

Reduced PET signal in caudate and putamen


Mechanism of using 11C-Raclopride on PET scans

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]


Management strategies for HD?

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


Pharmacological management of HD and mech. of action?

Tetrabenazine (only available drug)

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


Examples of experimental/novel treatments of HD

- RNA interference (antisense oligonucleotides, RNA interference compounds)

- DNA targeting gene therapies (zinc-finger transcriptional repressors, CRISPR/Cas9)

- cell transplantation therapy


RNA interference mechanism

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

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


DNA gene therapies mechanism

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

Targets DNA and aims to accelerate degradation of transcript


Mechanism of cell transplantation therapy in HD?

[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


Outcomes of cell transplantation therapy in trials?

Varied success

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