Huntington's disease Flashcards
LO
- Describe the pathology associated with Huntington’s disease.
- Understand the principle of the CAG tract (poly-glutamine (Q) expansion) and its consequence for Huntingtin (the Huntington disease protein).
- Describe the key determinants and potential consequences of different mis-folding intermediates.
- Use Huntington disease to introduce the idea of loss or gain of function mutation.
- List routes by which the misfolded protein affects cellular function.
- Address the potential for selective degeneration of neuronal type and compartment.
- Consider the evidence for huntingtin protein propagation.
What are the main characteristics of HD?
- Autosomal dominant (50% of children from infected parents will get it)
- Hereditary
- Neurodegenerative
Tell me 4 main characteristics/ facts about HD?
- everyone with the mutated gene will get HD
- probability of each offspring inheriting the affected gene in 50%
- inheritance is independent of gender
- characterised by cognitive, behavioural, and motor dysfunction
Brief history
Recognised as an inherited disorder in 1872 when a 22-year-old American doctor, George Huntington, wrote a paper called: On Chorea.
(https://en.wikisource.org/wiki/On_Chorea)
“Chorea” comes from the Latin and Greek words meaning dances (involuntary/uncontrollable movements/muscle jerks and twitches)
What is the gene responsible in HD?
IT15 gene
everybody expresses this gene but those who inherit the expansion of the gene are the ones with HD
IT15 gene found on chromosome 4 and this gene expresses the Hungtingtin protein
When was the IT15 gene identified and when did genetic tests become available?
It was first identified in 1983
Predictive genetic tests become available from 1993
Tell me about the expansion of the IT15 gene that leads to HD
Poly Q repeats (repeats of glutamine (Q))
Normal conditions: 10-35 repeats
Huntington’s disease: > 36 repeats
Tell me about the poly Q expansion and anticipation
repeat expansion
effect replication –> anticipation. When DNA polymerase replicates DNA there can be an error due to glutamine repeats which can lead to expansion of that region
therefore, child could inherit more repeats than parent due to expansion of CAG repeat
this is more prevalent in male’s parents due to sperm generation, which leads to a high chance of expansion of this region being given to offspring
Tell me about the age of onset with HD
Strong inverse relationship between the age of onset of HD and the number of CAG repeats.
more repeats= earlier age of onset
mild be able to modify process, if direct linear relationship, then you’d think you could modify, so as not linear then suggests there could be factors (genetic/ environmental) that could be modified
cannot map age an individual will show symptoms of disease
Explain the different interpretations of genetic testing for CAG repeats
HD has 100% penetrance: if individuals have ≥ 40 repeats they have the disease.
Symptoms start between the ages of 30-50 years (40+ CAG), although late onset (36-39 CAG) and juvenile manifestation (60+ CAG) also occur.
Prognosis usually between 15-20 years from onset of symptoms.
>60 juvenile form of HD and this is more aggressive and leads to EOHD
people don’t die due to HD they die because of other factors that HD cause
Tell me about the prevalence of HD
Increase in the prevalence of HD over the past two decades.
Family history - likely excluded sporadic or de novo cases (5-8%).
Prevalence studies (genetic and clinical) show:
Higher prevalence:
- America, Australia & most European & Western countries:
- (10.6-13.7:100,000)
Lower prevalence:
- Asia & Africa (0.5:100,000 in Japan & China)
Tell me about the symptoms of HD, what are the main areas infected?
The symptoms usually vary widely between people, even families
this sympton variety means that some people may not be aware they have HD
Changes usually affect three main areas:
1. Movement: Involuntary & Voluntary (physical)
2. Behaviour: Changes in behaviour and personality (physical)
3. Cognitive: Difficulties with planning and thinking (overlaps with other ND diseases so can often be misdiagnosed)
What sympton is usually the most obvious first symptom?
Movement disorder
What symptom is the one which gives patients and carers the most concern?
Behavioural disorder
What is the symptom that people find effects them most in daily life?
Cognitive disorder
Tell me some of the physical symptoms
The symptoms of HD are like having ALS, PD & AD simultaneously.
- Motor deficits (jerky/fidgety motor).
- May seem clumsy or stumble more than usual.
- Voluntary movements are affected.
- Abnormal eye movement.
- Speech becomes slurred.
- As disease progresses, swallowing problems become common.
- Weight loss (excessive movements and malnutrition through dysphagia) and central effects on appetite.
- Incontinence.
- Involuntary movements cannot be consciously suppressed and stop only with sleep.
Tell me some of the cognitive symptoms of HD
- Memory and concentration problems
- Hard to plan and think ahead, difficult to switch between tasks.
- Lack of motivation – appear lazy.
- Reduced ability to read facial expression.
- Emotional changes –subtle changes to mood/behaviour.
- Aggressive, demanding, stubborn and self-centred.
- Impulsive or irrational, behaving in a disinhibited way or obsessive with things. depression, anxiety, and anger.
- Relationships at high risk.
- May lead to social isolation.
- Respiratory/cardiac/suicide (major reasons for mortality – 3-13%).
Tell me about the neuropathology of the disease
basal ganglia is the main site of neuronal loss in HD. mainly the striatal part
all work together and communicate with cortex (in red box and two below). neurons within striatum which are affected early on
Normal conditions
putamen is an inhibitory nucleus which releases the inhibitory NT GABA
GABA has dampening effect on globus pallidus which leads to release of LESS GABA which leads to thalamus having an increased activity, which sends signals to increase movement
Huntington’s disease
These inter-connected areas are associated with different types of activity including movement, learning, thinking, planning, motivation & emotion. As the cells in these parts of the brain reduce in number, changes occur in how they function, resulting in the various symptoms of HD.
if cells loss due to HD.
less neurons to interact with in cortex
so, putamen effect decreases
so, inhibition onto globus pallidus is reduced which means that this remains more active and its activity increases
more GABA onto thalamus which reduces this activity and therefore movement
What aspects of the basal ganglia are mostly affected by HD?
- striatum (caudate nucleus and Putamen)
- Globas pallidus
- subthalamic nucleus
- Substantia nigra
What are two cell types which are affected in HD?
MSNs (medium spiny neurons)
ASNs (aspiny striatal neurons)
Tell me about MSNs
- main and earliest striatal cell type affected in HD
- Vulnerable projection neurons
- long axons
- medium cell body
- prone to excitotoxicity
- inhibitory
Tell me the NT associated with MSNs
GABA
Calbindin
Substance P
Enkephalin
Dynorphin
TGF alpha