triplet repeat disorders Flashcards
what is HDD?
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.
what is life expectancy with HDD?
around 20 years after symptoms begins - no cure
what is the inheritance mode of HDD?
autosomal dominant - 50% chance of offspring - faulty gene that can be tested for
why is genetic testing in HDD controversial?
it can be beneficial or negative
what is the main clinical feature of HDD?
progressive neurodegenerative disorder with motor, cognitive and psychiatric disturbances - movements, memory and mood
what is involved in the muscular disorder in HDD?
chorea, bradykinesia, dystonia, swallowing, choking, dysarthria
what is involved in mood in HDD?
depression, apathy, aggression, euphoria, anxiety and psychotic symptoms
what is involved in cognition in HDD?
dementia, memory loss, rigidity of thought and loss of executive functioning
what is the mean onset and range of HDD and the median survival time?
mean onset is 35 to 44 years and range is 2-80 years. The median survival time is 15-18 years after onset
what is the genetic inheritance of HDD?
it is autosomal dominant with complete penetrance that is age dependent
what is the basis of genetics in HDD?
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.
what is the normal huntingtons protein?
it is widely expressed in different tissues with an unknown function. There are around 20-26 repeats.
what is the abnormal huntingtons protein?
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.
what is anticipation?
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.
when is the anticipation risk high in HDD?
through paternal inheritance
what are other disorders that result in anticipation and when?
Fragile X (XL-R) and myotonic (AD)dystrophy through maternal inheritance
what is juvenile HDD?
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.
what are clinical signs of juvenile HDD?
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.
what is the risk of juvenile HDD?
siblings may also have it - although if they are well they can still have a 50% chance of having adult HDD
what is the basis of juvenile HDD?
each sperm will have a different size of expansion in it
what are the genetic tests for HDD?
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.
what is the point of predictive testing?
to offer prophylactic treatment, identify disease early and start treatment and offer prenatal testing - only the last applies in HDD
what are other diseases where predictive test is possible?
BRCA, HNPCC and myotonic dystrophy
what is the treatment of HDD?
no cure therefore testing offers no medical advantage - only symptomatic - medication for chorea and mood etc
why might someone want a test?
make decision about care, future career, children, want to know and inform family
why might someone not want to test?
do not want to worry and think will be fine, do not want children to have, know or worry about HDD
what can a test not predict?
the age of onset, speed of progression, order or balance of symptoms and symptom hunting
what are the prenatal option for HDD?
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
how many people will have testing?
15-20% of the people at 50% risk
what is the test?
blood test - around 2 week to process
