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ATU 1 > Neuro - Huntingtons disease > Flashcards

Neuro - Huntingtons disease Flashcards

1
Q

When was it classed as a separate class of disorders?

A

1990s

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2
Q

What was the first disease discovered?

A

Fragile X

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3
Q

How many diseases have been currently identified?

A

18 - may be more

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4
Q

Can trinucleotide repeats be inherited?

A

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

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5
Q

What are the 8 clinical features of trinucleotide repeat disorders?

A

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
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6
Q

Are trinucleotide repeat disorders degenerative?

A

Yes - progressively degenerative

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7
Q

What does the larger the expansion mean?

A

The earlier the onset

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8
Q

What are the 2 types of triplet expansion?

A

Type 1 and 2

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9
Q

What are the repeats in type 1?

A

Always CAG

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10
Q

What is the pathological threshold of type 1?

A

35-40 where above this is pathological

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11
Q

What are the repeats in type 2?

A

Repeat codon varies

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12
Q

What is the pathological threshold of type 2?

A

100+ - larger than type 1

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13
Q

Which type is always translated?

A

Type 1

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14
Q

Which type is transcribed but not translated?

A

Type 2

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15
Q

Which type is autosomal dominant?

A

Type 1

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16
Q

Is type 2 autosomal dominant?

A

No the inhertance varies

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17
Q

Are inclusions seen in type 1?

A

Yes

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18
Q

Are inclusions seen in type 2?

A

No

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19
Q

Are type 1 neurodegenerative?

A

Yes

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20
Q

Are type 2 neurodegenerative?

A

Variable - often pleiotropic phenotypes

21
Q

How does gene expansion occur?

A

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

22
Q

What is the most common type 1 disease?

A

Huntington’s

23
Q

Is Huntington’s nuclear or cytoplasmic localized?

A

Cytoplasmic

24
Q

What is the normal CAG repeat in Huntington’s

25
Q

What is the expanded CAG repeat in Huntington’s?

26
Q

How first described Huntington’s disease and when?

A

George Huntington in 1872

27
Q

What is the prevalence of Huntington’s

A

4-10/100,000 - rare

28
Q

What are the clinical features of HD?

A

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

29
Q

How long after onset is death in HD?

A

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

30
Q

What age is the age of onset in HD?

A

~40 years with repid onset

31
Q

Where are cells lost in HD?

A

Cerebral cortex and corpus striatum

32
Q

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

A

GABA and enkephalin

33
Q

Where do you get distruped signaling from in HD?

A

Thalamus and motor cortex caused by impair communication to muscles

34
Q

Is Huntington’s autosomal dominant?

A

Yes it is genetic

35
Q

Which chromosome is Huntington’s found on?

A

Chromosome 4 locus IT15

36
Q

Which exon are the CAG repeats found?

A

1 - at N-terminus

37
Q

Are there known sporadic cases of HD?

38
Q

What else does the Huntington’s gene contain?

A

WW repeats and caspase cleavage sites

39
Q

Do we know the function of the protein in HD?

A

No it is unassigned

40
Q

Where is the polyglutamine repeat located in the protein?

A

Near the N-terminus

41
Q

What motifs does Huntington contain?

A

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

42
Q

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

A

ER
MT
Mitochondria
Synaptic vesicles

43
Q

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

A

Cytoplasm and nucleus

44
Q

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

A

N-terminal

45
Q

How is Huntington’s disgonosed?

A

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

46
Q

What is the treatment for HD?

A

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

47
Q

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

A

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

48
Q

Clues in the function of Huntingtin

A

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

ATU 1 (11 decks)

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