HD

Question 1

Clinical features of HD

Answer 1

Progressive neurodegenerative disorder

1. Movement - chorea, dystonia
2. Psychiatric - depression, mood swings
3. Dementia

Question 2

Average age of onset for HD

Answer 2

35-50 years. Juvenile HD <20 years

Question 3

Cause of HD

Answer 3

> 39 CAG expansion in exon 1 of HTT gene at 4p16.3

Question 4

Intermediate alleles in HD

Answer 4

27-35 CAG

Have potential to expand into disease range in single generation

Question 5

What effects risk of expansion for intermediate alleles?

Answer 5

1. Length of CAG tract - the longer the greater the risk
2. Age and sex of transmitting parents - greater risk for males >36 years
3. Family history
4. Sequence surrounding CAG repeat, polymorphisms etc

Question 6

Molecular pathogenesis of HD

Answer 6

HTT translated into protein with extended polyglutamine tract; aggregates in neuronal nuclei to form neuronal intranuclear inclusions - interefere with transcription factors
Aggregate HTT protein contains toxic N-terminal fragments

Question 7

Genetic testing for HD

Answer 7

PCR to size CAG repeat - primers flanking tract

products separated by capillary electrophoresis

Question 8

Presence of one peak in HD testing - what could this mean?

Answer 8

1) patient is hom for same sized CAG expansion
2) SNP under primer binding site caused dropout of one allele
3) patient has one normal allele and one allele not identifiable by the test (ie too large - juvenile)

Question 9

Presence of one peak in HD testing - reflex test?

Answer 9

Use second set of primers that flank CAG repeat AND adjacent (CCG)n repeat tract; highly polymorphic- allows you to ensure that two peaks are present (not for sizing)
If juvenile HD, could do TP-PCR for large expansions

Question 10

Exclusion testing in HD - when is it used?

Answer 10

When fetus has 25% chance of being affected (ie affected grandparent) but parent doesnt wish to know their HD status

Question 11

Limitations of HD exclusion testing

Answer 11

1) Will only determine which grandparental haplotype has been inherited; not whether it was the disease causing allele or not so max information on risk is 0% or 50%. BUT it avoids a prenatal test for those at 0%
2) risk of recombination across HTT is 2%
3) testing may not be informative
4) relies on grandparental sample availability