Huntington's Disease7

Question 1

Where do HD referrals often come from?

Answer 1

Neurology, psychiary, medicine for the elderly, clinical genetics (if predictive)

Question 2

Three main components of HD?

Answer 2

Movement disorder (chorea)
Psychiatric disturbance
Dementia

Question 3

Brain changes in HD?

Answer 3

Degeneration of the basal ganglia and caudate nucleus

Brain appears smaller mainly in frontal lobes

Question 4

Frequency of classic HD?

Answer 4

3-10 per 100,000

Question 5

Approx what % of clinically diagnosed HD are phenocopies?

Answer 5

1%

Question 6

Cause of HD?

Answer 6

Expansion of CAG repeat tract in exon 1 of the HTT gene (chr 4)

Question 7

Phenomenon where the disorder presents earlier/has more severe symptoms in subsequent generations

Answer 7

Anticipation

Question 8

Age of onset and course?

Answer 8

between 30 and 60, course runs between 15-20 years

Question 9

Definition of juvenile onset?

Answer 9

Under 20

Question 10

Allele classification:
a) normal
b) intermediate
c ) HD allele reduced penetrance
d) HD allele

Answer 10

a) <27
b) 27-35
c) 36-39
d) >39

Question 11

Number of repeats:

a) classic HD
b) juveline HD

Answer 11

a) 40-65

b) >65 and can be up to 250

Question 12

How does juveline HD present?

Answer 12

Don’t have chorea, usually have rigidity, decreased facial movements and decreased school performance

Question 13

How is juveline HD usually inherited?

Answer 13

Nearly always paternally inherited (allele has a tendency to increase in size particularly when inherited from father)

Question 14

What are the potential pitfalls for clinicians/counsellors?

Answer 14

Reduced penetrance alleles- patients may get symptoms later in life and may not- difficult to counsel

Intermediate range- individuals will not get HD but repeat has ability to expand in future generations- should consider PND and risk for other family members

Question 15

Testing protocol for predictive testing?

Answer 15

3 counselling sessions involving 2 members of staff over a period of months

Question 16

Under what circumstances is predictive testing offered?

Answer 16

Individuals at 25%/50% prior risk (if >18 years old)

Question 17

When does diagnostic testing need to be referred to clinical genetics?

Answer 17

Individuals <16

Question 18

Why does prenatal testing require careful discussion with parents?

Answer 18

If they test during pregnancy then decide against termination- effectively done a PST without consent

Question 19

What is exclusion testing?

Answer 19

Form of PGD- test foetus to see if it has inherited haplotype from affected grandparent. Means you can avoid testing HTT gene in parent if they do not want a predictive test- their risk remains 50%

Question 20

Turnaround time?

Answer 20

10 days both diagnostic and predictive

Question 21

Testing methods for HD?

Answer 21

Fluorescent PCR and TP-PCR

Question 22

F-PCR can detect alleles up to what size?

Answer 22

115 repeats

Question 23

What does a single allele in F-PCR represent?

Answer 23

Either a true homozygote, or a normal allele + an unamplifiable large expansion, or a small expansion that has not been amplified due to a polymorphism under one of the primers

Question 24

What is the second primer set in F-PCR used for?

Answer 24

To resolve patients who have 2 normal alleles of the same size (uses CCG repeat upstream of CAG)

Question 25

When is triplet-primed PCR used?

Answer 25

Whe only one normal allele can be detected by both PCRs

Question 26

What are the three primers in TP-PCR?

Answer 26

Flurouscently labelled forward primer binds to upstream sequence

Reverse primer which binds to the CAG at multiple sites; has a non-specific 5’. Limited concentration; becomes exhausted after first few PCR cycles

Tail primer P3 which is specific to the 5’ of the reverse primer and allows further amplification of the products from the forward and reverse primers

Question 27

What does the final pool of products in triplet-primed PCR represent?

Answer 27

The whole repeat- gives a distinct trace on capillary electrophoresis

Question 28

What does triplet-primed PCR NOT do, and what can be used instead?

Answer 28

Does not size the expansion; southern blot may be used for sizing

Question 29

Report writing considerations for HD

Answer 29

1. Autosomal dominant- both males and females can be affected
2. Result consistent with phenotype?
3. Size of CAG must be stated
4. Information about F-PCR test must be stated in the technical information section
5. At-risk family members should be offered testing
6. Should state that prenatal testing is available to affected individuals
7. Genetic counselling should be offered to those who have a positive test or are considering testing