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Flashcards in Htt 1 Deck (29):
1

Prevalence?

4-10 per 10,000

2

Effect on brain

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

3

Symptoms?

Involuntary movements
Psychiatric disturbance -mood swings, rigid thoughts
Dementia

4

Age of onset and length of disease?

Peak 40-45 yrs
Runs a course over 15-20 years

5

Differential diagnosis?

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

6

Allele classifications

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

7

Predictive testing protocol?

-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

8

PGD?

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

Can also do exclusion testing

9

Management of HD?

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

10

Symptoms of juvenile HD?inheritance pattern and symptoms?

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

11

Expansion?

CAG repeat tract in exon 1 of HTT gene
Translated into a polyglutamine tract with novel deleterious functions

12

Age of onset variability?

70% related to repeat length and 30% environmental

13

Why is anticipation more likely paternally?

Expansion of unstable CAG repeat during spermatogenesis

Can occur pre and post meiotic

14

Features of partial penetrance?

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

15

Features of intermediate range?

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

16

Can you offer PND to intermediate allele range?

Yes

17

What increases risk of expansion in intermediate allele?

-FH of intermediate allele expanding
-age/sex of parent
-poly GLu2645del surrounding HTT
-where 3'CAA has changed to CAG= more unstable

18

What are NIIs?

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

19

Pathogenesis of HD

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

Departments that can refer?

Neurologists
Psychiatrists
Specialists in care have of the elderly

*under 16 must go via clinical genetics

21

Test types

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

Pcr method?

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

What are the possible results from a single allele?

- 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

Where does HD1alt+HD2 amplify?

Includes CCG repeat that is 3' to CAG
** these primers are not used to determine CAG repeat.

25

What next if after HD1alt+Hd2 still homo?

TP- PCR, southern blotting

26

Describe tp-pcr?

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

Describe southern blot

Pst1 enzyme
4GP1.7 probe

28

Who is predictive testing offered to?

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

What is recommbination risk across HD gene?

~2%
Small risk of double recombination- affected individual with a low risk haplotype