Huntington's Disease Essay Flashcards
(22 cards)
Huntington’s disease (HD)
relatively rare, inherited disorder with a worldwide prevalence of 5 per 100,000 (Medina et al. 2022)
Repeat length expansion disorder
caused by mutation in HTT gene, the function of HTT protein remains relatively unclear
Polyglutamine expansion (>36 CAG repeats)
mutant HTT protein aggregation and formation of dense intraneuronal inclusion bodies which ultimately compromise cell viability and neuronal survival
Mean age of HD onset
30-50 years, with average life expectancy of 17-20 years
Juvenile HD
Onset before 20 years of age
Behavioural disturbances
Learning difficulties at school
HD primarily characterised by
Motor, cognitive and psychiatric impairments
Metabolic and mitochondrial dysfunction
Aberrant inflammatory response
Motor dysfunction most common manifestation
with Huntington’s chorea defined as non-rhythmic jerking movements of arms and legs
can also include facial grimacing, shoulder raising and finger extensions
Chorea is present while individual is awake
disappearance during sleep linked to antiinflammatory properties of sleep
As HD progresses
difficulty talking and swallowing can lead to patients becoming mute and risk of choking
Mild cognitive symptoms
irritability
incoordination
depression
eventually leading to dementia and epileptic seizures
Psychiatric symptoms may appear during
pre-manifest stage
with apathy the only neuropsychiatric symptom shown to consistently progress with disease
Suicide rates second leading cause of death in HD
following respiratory related complications
The anatomical basis of chorea
primarily thought to involve the basal ganglia
HD brains present with enlargement of lateral ventricles and
thus atrophy of the dorsal striatal regions, caudate and putamen
Associated degeneration of frontal and temporal cortices
potenial cause for cognitive and behavioural deficits
5 grade classification scale for HD pathology
Grade 0 - clinical HD features without microscopic abnormalities
Grade 4 - yellow/brown shrunken caudate, widened anterior horn of lateral ventricle and smaller nucleus accumbens
Recent MRI advances
confirmed early pathological findings of grey matter volume decline in C&P and loss of white matter in striatum and cortex
Pathophysiological mechanism behind hyperkinetic activity in HD
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.
In contrastm deterioration of cognitive and emotional function in HD
associated with non-motor basal ganglia loops
WHO predicts 2040, ndegn surpass cancer emphasising need for treatments to improve quality of life
Tetrabenazine - only licensed for chorea
Reversible inhibitor of VMAT2
Degrades and depletes dopamine
SE: depression, sleep distrubances, anxiety
Antidepressants for cognitive symptoms
In recent years researchers increasingly aware of potential therapies extending beyond CNS
Metformin
Sanchis et al. 2019
Trujillo Del Rio et al, 2022
Gene therapy
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
