Neuro - Huntingtons disease

Question 1

When was it classed as a separate class of disorders?

Answer 1

1990s

Question 2

What was the first disease discovered?

Answer 2

Fragile X

Question 3

How many diseases have been currently identified?

Answer 3

18 - may be more

Question 4

Can trinucleotide repeats be inherited?

Answer 4

Yes - increased repeat size can be due to paternal transmission - ‘classic anticipation’

Question 5

What are the 8 clinical features of trinucleotide repeat disorders?

Answer 5

Almost all exhibit ataxia

• Chorea which is involuntary movement
• Dystonia - muscles contractions
• Dysarthria - difficulty in speaking (due to muscles)
• Akathisia - ‘inability to sit’ want to move
• Seizure
• Tremor
• Dementia

Question 6

Are trinucleotide repeat disorders degenerative?

Answer 6

Yes - progressively degenerative

Question 7

What does the larger the expansion mean?

Answer 7

The earlier the onset

Question 8

What are the 2 types of triplet expansion?

Answer 8

Type 1 and 2

Question 9

What are the repeats in type 1?

Answer 9

Always CAG

Question 10

What is the pathological threshold of type 1?

Answer 10

35-40 where above this is pathological

Question 11

What are the repeats in type 2?

Answer 11

Repeat codon varies

Question 12

What is the pathological threshold of type 2?

Answer 12

100+ - larger than type 1

Question 13

Which type is always translated?

Answer 13

Type 1

Question 14

Which type is transcribed but not translated?

Answer 14

Type 2

Question 15

Which type is autosomal dominant?

Answer 15

Type 1

Question 16

Is type 2 autosomal dominant?

Answer 16

No the inhertance varies

Question 17

Are inclusions seen in type 1?

Answer 17

Yes

Question 18

Are inclusions seen in type 2?

Answer 18

No

Question 19

Are type 1 neurodegenerative?

Answer 19

Yes

Question 20

Are type 2 neurodegenerative?

Answer 20

Variable - often pleiotropic phenotypes

Question 21

How does gene expansion occur?

Answer 21

Previously thought through double-stranded break repair by homologous recombination, crossover or non-homologous end joining.

But now suggested loop formation from single-stranded repair where there are 3 models for loop incorporation into duplex DNA involving mismatch repair machinery

Question 22

What is the most common type 1 disease?

Answer 22

Huntington’s

Question 23

Is Huntington’s nuclear or cytoplasmic localized?

Answer 23

Cytoplasmic

Question 24

What is the normal CAG repeat in Huntington’s

Answer 24

3-34

Question 25

What is the expanded CAG repeat in Huntington's?

Answer 25

36-121

Question 26

How first described Huntington's disease and when?

Answer 26

George Huntington in 1872

Question 27

What is the prevalence of Huntington's

Answer 27

4-10/100,000 - rare

Question 28

What are the clinical features of HD?

Answer 28

Initially minimal where patients can suppress/mask the irregular movements Chorea in 90% of cases Dysarthria, Bradykinesia, Dysphagia Cognitive decline - loss of recent memory, difficulty concentrating and judgement errors and various psychiatric symptoms, changes in personality, aptahy, social withdrawl, depression, agitiation, mania, delusions, hallicinations or psychosis Progressive to death with 15-20 years

Question 29

How long after onset is death in HD?

Answer 29

15-20 years due to respiratory failure but also infection/suicide

Question 30

What age is the age of onset in HD?

Answer 30

~40 years with repid onset

Question 31

Where are cells lost in HD?

Answer 31

Cerebral cortex and corpus striatum

Question 32

What are the neurotransmitters which are altered in medium sized spiny neurones HD?

Answer 32

GABA and enkephalin

Question 33

Where do you get distruped signaling from in HD?

Answer 33

Thalamus and motor cortex caused by impair communication to muscles

Question 34

Is Huntington's autosomal dominant?

Answer 34

Yes it is genetic

Question 35

Which chromosome is Huntington's found on?

Answer 35

Chromosome 4 locus IT15

Question 36

Which exon are the CAG repeats found?

Answer 36

1 - at N-terminus

Question 37

Are there known sporadic cases of HD?

Answer 37

Yes

Question 38

What else does the Huntington's gene contain?

Answer 38

WW repeats and caspase cleavage sites

Question 39

Do we know the function of the protein in HD?

Answer 39

No it is unassigned

Question 40

Where is the polyglutamine repeat located in the protein?

Answer 40

Near the N-terminus

Question 41

What motifs does Huntington contain?

Answer 41

Number of HEAT-repeat motifs and nuclear export signal - implies ability to enter/leave the nucleus

Question 42

Which 4 components of the cell is WT Huntington's associated with?

Answer 42

ER MT Mitochondria Synaptic vesicles

Question 43

Where is the mutated form of Huntingon's know to form aggregated in?

Answer 43

Cytoplasm and nucleus

Question 44

Which terminal of Huntington's is found in neuronal intracellular inclusions?

Answer 44

N-terminal

Question 45

How is Huntington's disgonosed?

Answer 45

Clinical assessment - neurological testing, motor imerisistence, uses Unified Huntingson's Disease Rating Scale Family history of HD Neuroimaging - EEG/CT/MRI scans get changes in certain regions Genetic screening - CAG length

Question 46

What is the treatment for HD?

Answer 46

Movement disorder medication e.g. tetrabenazine for chorea Psychiatric disorder medication e.g. Tricyclic or SSRI antidepressants for depression, Haloperidol for psychosis and hallucinations, Phenothaizine or benzodiazepines for movement and anxiety and Lithium for mood swings

Question 47

What are HDAC? and how can they be used in HD?

Answer 47

Class of enzymes which allow histones to wrap the DNA more tightly preventing transcription Mutant Huntingtin inhibits acetylation (acetyltransferase activity) of histones H3 and H4 HDAC inhibitors in HD - Works in mouse models and Selisistat has recently found to be safe in Phase II trial of HD

Question 48

Clues in the function of Huntingtin

Answer 48

Required during developement - K.O. mice die at 7.5 days Interacts with several proteins involved in intracellular trafficking, vesicle endocytosis/membrane trafficking, and trancription/histone acetylation