triplet repeat disorders

Question 1

what is HDD?

Answer 1

it is a neurological disorder affecting around 8000 people in the UK - rare and complex illness where symptoms appear between 35 and 50 will uncontrolled muscle movements and dementia. The deterioration is rapid.

Question 2

what is life expectancy with HDD?

Answer 2

around 20 years after symptoms begins - no cure

Question 3

what is the inheritance mode of HDD?

Answer 3

autosomal dominant - 50% chance of offspring - faulty gene that can be tested for

Question 4

why is genetic testing in HDD controversial?

Answer 4

it can be beneficial or negative

Question 5

what is the main clinical feature of HDD?

Answer 5

progressive neurodegenerative disorder with motor, cognitive and psychiatric disturbances - movements, memory and mood

Question 6

what is involved in the muscular disorder in HDD?

Answer 6

chorea, bradykinesia, dystonia, swallowing, choking, dysarthria

Question 7

what is involved in mood in HDD?

Answer 7

depression, apathy, aggression, euphoria, anxiety and psychotic symptoms

Question 8

what is involved in cognition in HDD?

Answer 8

dementia, memory loss, rigidity of thought and loss of executive functioning

Question 9

what is the mean onset and range of HDD and the median survival time?

Answer 9

mean onset is 35 to 44 years and range is 2-80 years. The median survival time is 15-18 years after onset

Question 10

what is the genetic inheritance of HDD?

Answer 10

it is autosomal dominant with complete penetrance that is age dependent

Question 11

what is the basis of genetics in HDD?

Answer 11

the HTT gene is at 4q16.3 on chromosome 4 - the normal gene contains within 1 exon a run of CAG trinucleotide repeats of no more than 26. In HDD the CAG is a polyglutamine expansion of over 40 repeats. If there is repeats of 36-39 there is reduced penetrance.

Question 12

what is the normal huntingtons protein?

Answer 12

it is widely expressed in different tissues with an unknown function. There are around 20-26 repeats.

Question 13

what is the abnormal huntingtons protein?

Answer 13

it is a polyglutamine/polyQ expansion of over 40 repeats. These will aggregate and curl up resulting in a loss of protein structure and function. The basal ganglia especially the caudate nucleus is affected.

Question 14

what is anticipation?

Answer 14

it is a phenomenom that is associated with triplet repeat disorders where the age of onset of the disorder occurs at an earlier age and with more severity as it is passed from one generation to the next due to expansion in repeats. It is often linked with a specific parental inheritance.

Question 15

when is the anticipation risk high in HDD?

Answer 15

through paternal inheritance

Question 16

what are other disorders that result in anticipation and when?

Answer 16

Fragile X (XL-R) and myotonic (AD)dystrophy through maternal inheritance

Question 17

what is juvenile HDD?

Answer 17

it is a rare disorder where the onset of HDD is under 20 years of age due to an expansion of 60+ repeats usually paternally inherited and therefore the child may start to present before the father has any symptoms.

Question 18

what are clinical signs of juvenile HDD?

Answer 18

the first signs will not be chorea and restlessness, they will be motor - bradykinesia, social and mood - friends and decline in social interactions and memory - decline in school work.

Question 19

what is the risk of juvenile HDD?

Answer 19

siblings may also have it - although if they are well they can still have a 50% chance of having adult HDD

Question 20

what is the basis of juvenile HDD?

Answer 20

each sperm will have a different size of expansion in it

Question 21

what are the genetic tests for HDD?

Answer 21

if they are symptomatic whether they have a Fx or not they will have a diagnostic test that looks at the size of expansion. If they are asymptomatic but have a Fx then will do a predictive test.

Question 22

what is the point of predictive testing?

Answer 22

to offer prophylactic treatment, identify disease early and start treatment and offer prenatal testing - only the last applies in HDD

Question 23

what are other diseases where predictive test is possible?

Answer 23

BRCA, HNPCC and myotonic dystrophy

Question 24

what is the treatment of HDD?

Answer 24

no cure therefore testing offers no medical advantage - only symptomatic - medication for chorea and mood etc

Question 25

why might someone want a test?

Answer 25

make decision about care, future career, children, want to know and inform family

Question 26

why might someone not want to test?

Answer 26

do not want to worry and think will be fine, do not want children to have, know or worry about HDD

Question 27

what can a test not predict?

Answer 27

the age of onset, speed of progression, order or balance of symptoms and symptom hunting

Question 28

what are the prenatal option for HDD?

Answer 28

normal birth, prenatal testing at 11-12 weeks through CVS, exclusion testing (do not want to know themselves but do not want baby to be at risk), pre-implantation genetic testing, sperm or egg donor or adoption

Question 29

how many people will have testing?

Answer 29

15-20% of the people at 50% risk

Question 30

what is the test?

Answer 30

blood test - around 2 week to process