4. Huntington's Disease Flashcards
who first described Huntingtons disease
George Huntington
name 4 symptoms of HD
involuntary bowing, grimacing or twisting
facial or vocal tics
difficulty with speech or swallowing
psychiatric problems of hallucination or delusions
what happens to the lateral ventricles in HD
they are enlarged and filled with CSF
by what % of brain weight is lost in HD
<30% of brain weight is lost
where is severe loss of neurons in HD
caudate-putamen
name another histopathological feature of HD
gliosis
describe how motor movement is altered at the onset of HD
glutamate excitotoxicity drives the death of GABAergic in the caudate putamen - this lack of inhibition hyper activates the thalamus leading to increased motor movement at the onset of HD
what type of neurotransmission is also altered in HD and at what stage
at the onset - dopamine increases
at later stages - dopamine decreases
what happens if you administer L-dopa to a HD patient
symptoms are aggravated (because there is already an excess of dopamine)
what can alleviate the symptoms of HD
dopamine antagonists
what type of genetic disease is HD
autosomal DOMINANT
from which parent is the disease severity increased if you inherit their dominant allele
inheritance from the father is likely to result in more severe disease
what is the prevalence of HD
5-10/100,000 of the UK
is there a sex bias in HD
no, males and females are equally affected
what is the typical age of onset for HD
40-50 years old
what percentage of HD cases do children constitute
10%
what genetic phenomenon does HD exhibit, what does this mean?
genetic anticipation
- this means the disease phenotype worsens over generations: disease becomes more severe and age of onset gets earlier
what gene encodes Huntingtin
gene IT-15
where is huntingtin found
in the brain and testes
what is the function of Huntingtin
unknown
what is the hypothesised functions of huntingtin
either a transcription factor or plays a role in endocytosis
how do we know that huntingtin is essential for normal embryonic developemtn
huntingtin KO mice is embryonic lethal
what determines if someone develops HD
the length of CAG repeats - repeated insertion of the CAG trinucleotide
what does CAG stand for
cytosine
adenine
guanine
what is a normal repeat length for CAg
10-35
what repeat length determines late onset
36-39
what CAG repeat length determines adult-juvenile onset
40+
what happens when mutant huntingtin (with many CAG repeats) is cleaved
it generates a much larger N-terminal fragment that can’t interact with the C-terminus
what properties does a large N-terminal fragment confer
aggregation properties
what happens when there is an extra-long n-terminus
it becomes misfolded and becomes oligomeric and eventually form a fibrillar structure
which is the most toxic state of huntingtin aggregates
there is much debate it is not known
in HD there is a change in distribution, where is it now found and what are they called
found in the nucleus
called nuclear inclusions
describe the experimental research conducted by Scherzinger et al. 1999
- 20-27 CAG repeats do not form fibrils
- more than 30 repeats do form fibrils, with the more repeats aggregating faster and at lower concentrations
what else did Scherzinger find as to the cause of HD
huntingtin inclusions form before neurological symptoms and neurodengeration occurs - suggests they may be the cause
list 3 drugs in the pipeline for treating HD
depletion or stabilisation of monoamines
antioxidants
silencing IL-15 gene with anti-sense oligonucleotides
stem cells
what may be the risks of silencing IL-15
its risky as we don’t know the physiological role of huntingtin
