Huntington's Disease Flashcards
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?
PROGRESSIVE DISORDER
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
