Htt 1 Flashcards
Prevalence?
4-10 per 10,000
Effect on brain
Selective degeneration of neutrons in caudate and putamen with less severe atrophy in the cerebral cortex
Symptoms?
Involuntary movements
Psychiatric disturbance -mood swings, rigid thoughts
Dementia
Age of onset and length of disease?
Peak 40-45 yrs
Runs a course over 15-20 years
Differential diagnosis?
Hd like 1 (HDL1) = PRNP gene HD like 2 (HDL2) = JPH3 DRPLA =ATN1 SCA17 =HD4 Frederich ataxia = fxn
Allele classifications
Normal <27
Intermediate 27-35
HD allele (reduced penetrance) 36-39
HD allele >39
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
PGD?
Embryo cultured to 8 cell stage- biopsy- only implant those without HD
Can also do exclusion testing
Management of HD?
Managed by MDT
Speech therapy
Dietician -High calorie diet
OT to make home adaptions
Symptoms of juvenile HD?inheritance pattern and symptoms?
> 60 repeats
Nearly always paternally inherited
Schooling problems, decreased facial movements
Expansion?
CAG repeat tract in exon 1 of HTT gene
Translated into a polyglutamine tract with novel deleterious functions
Age of onset variability?
70% related to repeat length and 30% environmental
Why is anticipation more likely paternally?
Expansion of unstable CAG repeat during spermatogenesis
Can occur pre and post meiotic
Features of partial penetrance?
Chance of being a symptomatic at 65 = >40%, at 75= >30%
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%
Can you offer PND to intermediate allele range?
Yes
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
What are NIIs?
Neuronal Intranuclear Inclusions
Aggregation of abnormal polyglutamine expansions in neuronal nuclei
Contain Huntington and ubiquitin
More in juvenile
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
Departments that can refer?
Neurologists
Psychiatrists
Specialists in care have of the elderly
*under 16 must go via clinical genetics
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)
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)
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
Where does HD1alt+HD2 amplify?
Includes CCG repeat that is 3’ to CAG
** these primers are not used to determine CAG repeat.
What next if after HD1alt+Hd2 still homo?
TP- PCR, southern blotting
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
Describe southern blot
Pst1 enzyme
4GP1.7 probe
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
What is recommbination risk across HD gene?
~2%
Small risk of double recombination- affected individual with a low risk haplotype
