DYSTONIA

Question 1

what is dyskinesia

Answer 1

• A wide family of involuntary hyperkinetic movements

Question 2

what are the three types of dyskinesia

Answer 2

1. dystonia
2. chorea/athetosis
3. ballism

Question 3

what is dystonia

Answer 3

sustained muscle contractions leading to altered postures

• Characterised by involuntary, sustained, muscle contractions that cause painful, contorted postures.

Question 4

what is chorea/athetosis

Answer 4

rapid/slow transient involuntary movements

Question 5

what is ballism

Answer 5

repetitive large-amplitude involuntary movements

Question 6

3 subdivisions of dystonia

Answer 6

• Inherited or acquired:
• Isolated vs combined:
• Focal vs generalised

Question 7

what are the three current treatments for dystonia

Answer 7

1. pharmacological (generalised)
2. toxin-based (focal)
3. surgical (generalised)

Question 8

drugs used for dystonai

Answer 8

primary: TRIHEXYPHENIDYL (muscarinic AChR antagonist)

plus:
- levodopa
- VMAT2 inhibitors (tetrabenazine)
- Baclofen
- benzodiazepines

Question 9

what is Torsin 1A

Answer 9

an AAA + ATPase localised to the ER and nuclear envelope mutations cause DYT1-TOR1A

Question 10

torsin dystonia gene name:

Answer 10

DYT1 - which encodes an ATP-binding protein

Question 11

mutation in DYT1 and dystonia (penetrance and mutative type)

Answer 11

autosomal dominant - partially penetrant - carriers have 30% chance of inheritance.

• deletion (of GAG) - causes loss of single AA
• potentially loss-of-fucntion or dominant negative.

Question 12

Mutated form of Torsin

Answer 12

WT torsinA primarily localises to the ER
TorsinAE (mutated) mislocalises to the perinuclear space.

Question 13

mislocalised mutant TORSIN in animal models

Answer 13

associated with abnormal protrusion of nuclear membrane called ‘blebs’

Question 14

mutated torsin in patient derived cells

Answer 14

• In patient derived cells, the nuclear lamina protein Lamin B1 (LMNB1) is upregulated and downregulation rescues the cellular phenotypes caused by TOR1AGAG
• TorsinA could be involved in nucleocytoplasmic transport.

Question 15

Torsin1a homologues and the ER stress pathway.

Answer 15

• The ER runs quality control on proteins it produces, identifying and degrading misfolded proteins.
• Accumulation of misfolded proteins causes ER stress.
• Sufficient ER stress can trigger the unfolded protein response (UPR), which can suppress protein synthesis to save the cell, or trigger apoptosis

TorsinA negetively tunes ER stress in C. Elegans.

Question 16

what is the integrated stress response (ISR)

Answer 16

is what the ER stress pathway is part of, responds to various forms of stress throughout the cell and can translationally reprogram the cell, suppress protein synthesis, or initiate apoptosis.

Question 17

dystonia associated genes that form part of the integrated stress response pathway (2)

Answer 17

1. PKR
2. ATF4

Question 18

neural circuit basis of dystonia

Answer 18

• Disruptions to a number of brain regions can lead to altered cortico-striatal-thalamic signalling.

Question 19

organisation of BG and striatum

Answer 19

• Two main output nuclei, the globus palidus internus (GPi) and susbantia nigra pars reticulata (SNpr) inhibit movement.
• The direct pathway – facilitates movement by inhibiting output from the GPi
• The indirect pathway – inhibits movement by increasing inhibitory output.

Question 20

dystonia and striatum

Answer 20

• Cholinergic interneurons in the striatum constitutively engage the integrated stress response (which is usually transiently engaged in response to stress).
• Because this is an area directly associated with dysfunction in dystonia in various models – you see abnormalities in volume/metabolic activity – so this is again converging as a strong candidate.

Question 21

dystonia and LTP

Answer 21

• altered plasticity and inhibition in a mouse model of DYT1 dystonia
• enhanced LTP and reduced synaptic downscaling at cortico-striatal synapses
• DBS rectifies altered plasticity in dystonic patients
• DBS suppresses enhanced plasticity.

Question 22

cerebellum and dystonia

Answer 22

altered cerebello-thalamic pathways of mouse model of DYT1 dystonia.

Question 23

CPG and dystonia

Answer 23

properties of spinal central pattern generators altered in dystonia.

in mouse model - knockout TOR1A gene in spinal circuit - leads to spinal symptoms.
- you will see an increase in co-contractions

Question 24

3 types of mutation in dystonia and their penetrance and age of onset

Answer 24

TOR1A approx 30%, 0 - 40
THAP1 approx 50% 20-40
GNAL approx 90%, 40 to 80.

Question 25

dystonia as a two hit disorder

Answer 25

Genetic defect causes endophenotype of a network vulnerability to some insult that may occur during critical developmental disorder, if you experience this you develop dystonia, but if you don’t then you are non-symptomatic

Question 26

dystonia as neurodevelopmental disorder

Answer 26

Loss of gene TOR1A has a pathogenic effect during a specific developmental window leading to pretty much irreversible damage, but in the adult brain this LoF is well tolerated.