4. Huntington's Disease

Question 1

who first described Huntingtons disease

Answer 1

George Huntington

Question 2

name 4 symptoms of HD

Answer 2

involuntary bowing, grimacing or twisting
facial or vocal tics
difficulty with speech or swallowing
psychiatric problems of hallucination or delusions

Question 3

what happens to the lateral ventricles in HD

Answer 3

they are enlarged and filled with CSF

Question 4

by what % of brain weight is lost in HD

Answer 4

<30% of brain weight is lost

Question 5

where is severe loss of neurons in HD

Answer 5

caudate-putamen

Question 6

name another histopathological feature of HD

Answer 6

gliosis

Question 7

describe how motor movement is altered at the onset of HD

Answer 7

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

Question 8

what type of neurotransmission is also altered in HD and at what stage

Answer 8

at the onset - dopamine increases
at later stages - dopamine decreases

Question 9

what happens if you administer L-dopa to a HD patient

Answer 9

symptoms are aggravated (because there is already an excess of dopamine)

Question 10

what can alleviate the symptoms of HD

Answer 10

dopamine antagonists

Question 11

what type of genetic disease is HD

Answer 11

autosomal DOMINANT

Question 12

from which parent is the disease severity increased if you inherit their dominant allele

Answer 12

inheritance from the father is likely to result in more severe disease

Question 13

what is the prevalence of HD

Answer 13

5-10/100,000 of the UK

Question 14

is there a sex bias in HD

Answer 14

no, males and females are equally affected

Question 15

what is the typical age of onset for HD

Answer 15

40-50 years old

Question 16

what percentage of HD cases do children constitute

Answer 16

10%

Question 17

what genetic phenomenon does HD exhibit, what does this mean?

Answer 17

genetic anticipation

• this means the disease phenotype worsens over generations: disease becomes more severe and age of onset gets earlier

Question 18

what gene encodes Huntingtin

Answer 18

gene IT-15

Question 19

where is huntingtin found

Answer 19

in the brain and testes

Question 20

what is the function of Huntingtin

Answer 20

unknown

Question 21

what is the hypothesised functions of huntingtin

Answer 21

either a transcription factor or plays a role in endocytosis

Question 22

how do we know that huntingtin is essential for normal embryonic developemtn

Answer 22

huntingtin KO mice is embryonic lethal

Question 23

what determines if someone develops HD

Answer 23

the length of CAG repeats - repeated insertion of the CAG trinucleotide

Question 24

what does CAG stand for

Answer 24

cytosine
adenine
guanine

Question 25

what is a normal repeat length for CAg

Answer 25

10-35

Question 26

what repeat length determines late onset

Answer 26

36-39

Question 27

what CAG repeat length determines adult-juvenile onset

Answer 27

40+

Question 28

what happens when mutant huntingtin (with many CAG repeats) is cleaved

Answer 28

it generates a much larger N-terminal fragment that can't interact with the C-terminus

Question 29

what properties does a large N-terminal fragment confer

Answer 29

aggregation properties

Question 30

what happens when there is an extra-long n-terminus

Answer 30

it becomes misfolded and becomes oligomeric and eventually form a fibrillar structure

Question 31

which is the most toxic state of huntingtin aggregates

Answer 31

there is much debate it is not known

Question 32

in HD there is a change in distribution, where is it now found and what are they called

Answer 32

found in the nucleus called nuclear inclusions

Question 33

describe the experimental research conducted by Scherzinger et al. 1999

Answer 33

- 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

Question 34

what else did Scherzinger find as to the cause of HD

Answer 34

huntingtin inclusions form before neurological symptoms and neurodengeration occurs - suggests they may be the cause

Question 35

list 3 drugs in the pipeline for treating HD

Answer 35

depletion or stabilisation of monoamines antioxidants silencing IL-15 gene with anti-sense oligonucleotides stem cells

Question 36

what may be the risks of silencing IL-15

Answer 36

its risky as we don't know the physiological role of huntingtin