Huntingtons Disease Flashcards
What is Huntingtons disease?
Autosomal dominant, hereditary, Neurodegenerative Disease
What the probability it’s passed onto offspring?
50%
How can you characterise Huntingtons disease?
A cognitive behavioural and motor dysfunction.
What is the faulty gene in huntingtons?
HTT gene (IT15)
Where is Huntingtin gene located?
On chromosomes 4
How many repeats are needed to cause Huntingtons?
36 or more
What is the codon repeated in Huntingtons disease?
CAG- produces glutamines.
What do the Huntington repeats produce?
Extra glutamine residues
What are the stages of clinical progression in Huntingtons?
Pre-symptomatic
Predromal
Manifest
What is the pre-symptomatic stage of Huntingtons disease?
Stage before symptoms show
What is the predromal stage of Huntingtons disease?
When symptoms begin to appear
What is the manifest stage of Huntingtons disease?
Stage with clear symptoms
What three ways do Huntingtons symptoms show?
It affects:
Movement (usually first symptom)
Behaviour
Cognitive
Name some physical symptoms of Huntingtons?
Motor deficits
Weight loss
Abnormal eye movement
Slurred speech
Incontinence
Involuntary movement
What are the cognitive symptoms of Huntingtons disease?
Memory problems
Concentration problems
Emotional changes
Aggressive
What grades are there of loss of medium spiny neurons in Huntingtons disease
0-4
What’s grade 0/1 of loss of medium spiny neurons in Huntingtons?
Indistinguishable from a normal brain. Only selective loss of neurons in caudate nucleus and putamen
What’s grade 2 of loss of medium spiny neurons in Huntingtons?
Enlargement of lateral ventricle, loss of cortico-striatal projection neurons. Severe striatal atrophy.
What’s grade 3/4 of loss of medium spiny neurons in Huntingtons?
Severe HD cases with atrophy of the striatum and wide cell loss on other cortical, hippocampal cerebellum and hypothalamic regions.
What happens when you have polyQ Huntingtin?
Forms an abnormal shape and subsequently aggregates forming inclusion bodies in neurons.
What are inclusion bodies?
Collections of insoluble proteins (Huntingtons)
What is loss of function (LOF)?
When mutant proteins are no longer able to perform normal functions.
What is gain of function (GOF)?
Extra activity that a mutants proteins gains from mutation
What is mtHTT and HTT?
Mutant Huntingtin and Huntingtin
What does mtHTT do?
Inhibits gene transcription and also histone modification limiting transcription further.
How does HD cause mitochondrial dysfunction?
Leads to enhanced sensitivity to mPTP, leading to pore opening a reduction in membrane potential and subsequent apoptosis.
What is an example of Huntingtons LOF?
HTT blocks procaspase-9 by direct binding, when mutated this doesn’t occur leading to higher risk and susceptibility to apoptosis.
What therapeutic strategies are there for Huntingtons?
Anti-sense oligonucleotide- allele selective drugs that bind to and target single poly-morphisms for degradation such as in Huntingtons.
