Huntington's Disease Essay

Question 1

Huntington’s disease (HD)

Answer 1

relatively rare, inherited disorder with a worldwide prevalence of 5 per 100,000 (Medina et al. 2022)

Question 2

Repeat length expansion disorder

Answer 2

caused by mutation in HTT gene, the function of HTT protein remains relatively unclear

Question 3

Polyglutamine expansion (>36 CAG repeats)

Answer 3

mutant HTT protein aggregation and formation of dense intraneuronal inclusion bodies which ultimately compromise cell viability and neuronal survival

Question 4

Mean age of HD onset

Answer 4

30-50 years, with average life expectancy of 17-20 years

Question 5

Juvenile HD

Answer 5

Onset before 20 years of age
Behavioural disturbances
Learning difficulties at school

Question 6

HD primarily characterised by

Answer 6

Motor, cognitive and psychiatric impairments
Metabolic and mitochondrial dysfunction
Aberrant inflammatory response

Question 7

Motor dysfunction most common manifestation

Answer 7

with Huntington’s chorea defined as non-rhythmic jerking movements of arms and legs

can also include facial grimacing, shoulder raising and finger extensions

Question 8

Chorea is present while individual is awake

Answer 8

disappearance during sleep linked to antiinflammatory properties of sleep

Question 9

As HD progresses

Answer 9

difficulty talking and swallowing can lead to patients becoming mute and risk of choking

Question 10

Mild cognitive symptoms

Answer 10

irritability
incoordination
depression

eventually leading to dementia and epileptic seizures

Question 11

Psychiatric symptoms may appear during

Answer 11

pre-manifest stage
with apathy the only neuropsychiatric symptom shown to consistently progress with disease

Question 12

Suicide rates second leading cause of death in HD

Answer 12

following respiratory related complications

Question 13

The anatomical basis of chorea

Answer 13

primarily thought to involve the basal ganglia

Question 14

HD brains present with enlargement of lateral ventricles and

Answer 14

thus atrophy of the dorsal striatal regions, caudate and putamen

Question 15

Associated degeneration of frontal and temporal cortices

Answer 15

potenial cause for cognitive and behavioural deficits

Question 16

5 grade classification scale for HD pathology

Answer 16

Grade 0 - clinical HD features without microscopic abnormalities
Grade 4 - yellow/brown shrunken caudate, widened anterior horn of lateral ventricle and smaller nucleus accumbens

Question 17

Recent MRI advances

Answer 17

confirmed early pathological findings of grey matter volume decline in C&P and loss of white matter in striatum and cortex

Question 18

Pathophysiological mechanism behind hyperkinetic activity in HD

Answer 18

involves loss of GABAergic medium spiny interneurons of caudate and putamen. Loss of inhibitory outflow to the EGP leads to decreased activity of indirect pathway of basal ganglia. EGP cells become abnormally active which reduces excitatory outputs of subthalamic nucleus to the IGP. Loss of inhibitory outflow of BG shifts balance in favour of direct pathway and thalamic overexcitation of the frontal cortex.

Question 19

In contrastm deterioration of cognitive and emotional function in HD

Answer 19

associated with non-motor basal ganglia loops

Question 20

WHO predicts 2040, ndegn surpass cancer emphasising need for treatments to improve quality of life

Answer 20

Tetrabenazine - only licensed for chorea
Reversible inhibitor of VMAT2
Degrades and depletes dopamine
SE: depression, sleep distrubances, anxiety

Question 21

Antidepressants for cognitive symptoms

Answer 21

In recent years researchers increasingly aware of potential therapies extending beyond CNS

Metformin
Sanchis et al. 2019
Trujillo Del Rio et al, 2022

Question 22

Gene therapy

Answer 22

Forefront of current research
ASO promising
Single stranded synthetic DNA molecules
Selectively bind to target mRNA
Produce RNAH-mediated degradation of target

Previous studies ASO reduce mHTT in transgenic R6/1 mouse model (Kordasiewicz et al. 2012)

Phase III trials discouraging
Further research required