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Neuromuscular > Htt 1 > Flashcards

Htt 1 Flashcards

1
Q

Prevalence?

A

4-10 per 10,000

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2
Q

Effect on brain

A

Selective degeneration of neutrons in caudate and putamen with less severe atrophy in the cerebral cortex

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3
Q

Symptoms?

A

Involuntary movements
Psychiatric disturbance -mood swings, rigid thoughts
Dementia

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4
Q

Age of onset and length of disease?

A

Peak 40-45 yrs

Runs a course over 15-20 years

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5
Q

Differential diagnosis?

A 
Hd like 1 (HDL1) = PRNP gene 
HD like 2 (HDL2) = JPH3
DRPLA =ATN1
SCA17 =HD4
Frederich ataxia = fxn
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6
Q

Allele classifications

A

Normal <27
Intermediate 27-35
HD allele (reduced penetrance) 36-39
HD allele >39

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7
Q

Predictive testing protocol?

A

-3 counselling sessions involving 2 members of staff over several months

  • must be over 18
  • written informed consent taken
  • follow up contact and support is offered after results are taken
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8
Q

PGD?

A

Embryo cultured to 8 cell stage- biopsy- only implant those without HD

Can also do exclusion testing

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9
Q

Management of HD?

A

Managed by MDT
Speech therapy
Dietician -High calorie diet
OT to make home adaptions

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10
Q

Symptoms of juvenile HD?inheritance pattern and symptoms?

A

> 60 repeats
Nearly always paternally inherited
Schooling problems, decreased facial movements

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11
Q

Expansion?

A

CAG repeat tract in exon 1 of HTT gene

Translated into a polyglutamine tract with novel deleterious functions

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12
Q

Age of onset variability?

A

70% related to repeat length and 30% environmental

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13
Q

Why is anticipation more likely paternally?

A

Expansion of unstable CAG repeat during spermatogenesis

Can occur pre and post meiotic

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14
Q

Features of partial penetrance?

A

Chance of being a symptomatic at 65 = >40%, at 75= >30%

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15
Q

Features of intermediate range?

A

Frequency estimated 1-7%
Below affected range but risk of expansion
Risk of expansion to disease in 1 generation= 0.1-1%

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16
Q

Can you offer PND to intermediate allele range?

A

Yes

17
Q

What increases risk of expansion in intermediate allele?

A
  • FH of intermediate allele expanding
  • age/sex of parent
  • poly GLu2645del surrounding HTT
  • where 3’CAA has changed to CAG= more unstable
18
Q

What are NIIs?

A

Neuronal Intranuclear Inclusions
Aggregation of abnormal polyglutamine expansions in neuronal nuclei
Contain Huntington and ubiquitin
More in juvenile

19
Q

Pathogenesis of HD

A

1) mutant HTT forms abnormal protein confirmations
2) mutant HTT is truncated by caspase 6 cleavage producing toxic n-terminal fragments
3) toxicity of HTT affected by post-translational modification and nuclear localisation

20
Q

Departments that can refer?

A

Neurologists
Psychiatrists
Specialists in care have of the elderly

*under 16 must go via clinical genetics

21
Q

Test types

A

1) confirmation of a diagnosis of HD if affected family member - need copy of report and pos sample
2) presymptomatic testing via clin gen (pos fam if possible)
3) prenatal via clin gen (direct and exclusion)

22
Q

Pcr method?

A 
Cy5-CAG PCR
1 primer fluoresecently labelled
2 primer pairs 
HD1A+HD3- avoid snp under primer
HD1alt+HD2 (used in 1a+3 shows two close/homo alleles)
23
Q

What are the possible results from a single allele?

A
  • a true homozygote
  • a normal allele with 1 unamplifiable large expansion
  • a normal allele and small expansion that has not been amplified due to poly under HD3 primer
24
Q

Where does HD1alt+HD2 amplify?

A

Includes CCG repeat that is 3’ to CAG

** these primers are not used to determine CAG repeat.

25
Q

What next if after HD1alt+Hd2 still homo?

A

TP- PCR, southern blotting

26
Q

Describe tp-pcr?

A

P1 is fluoresently labelled
P4 binds CAG repeat
P3 amplifies the different sized products generated by p1+4
Long extension time allows large allele to be amplified

27
Q

Describe southern blot

A

Pst1 enzyme

4GP1.7 probe

28
Q

Who is predictive testing offered to?

A

People at 50% or 25% prior risk
Requires genetic counselling and consent
If molecularly confirmed family member not available caveat in report- other diagnosis possible

29
Q

What is recommbination risk across HD gene?

A

~2%

Small risk of double recombination- affected individual with a low risk haplotype

Neuromuscular (2 decks)

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