Huntington's Disease Flashcards
What type of genetic condition is Huntington’s?
Autosomal dominant
What percentage of Huntington’s has juvenile onset below age 21 and what is it associated with?
5% - Westphal variant
What is the mean age of motor onset in Huntington’s?
45 years old
What are the two phases of Huntington’s?
▪️Premanifest (presymptomatic, prodromal)
▪️Manifest (motor onset)
Where is huntingtin protein usually found?
▪️Most tissue
▪️Highest activity in the brain ▪️Predominantly extranuclear in neurons
How does a huntingtin gene mutation cause disease?
▪️Expanded, unstable CAG repeats
▪️Translates to polyglutamine repeat in HD protein
How many CAG repeats is classes as normal and not pathogenic?
<35
What is seen with 29-35 CAG repeats?
▪️Paternal meiotic instability
▪️Non pathogenic
▪️Rarely expands into disease range
▪️Increased risk of children with HD
What is seen with 36-39 CAG repeats?
▪️Pathogenic but reduced penetrance
▪️Risk increases by ~25% with each one
(36 ~ 25%, 37 ~ 50%, 38 ~ 75%, 39 ~ 90%)
How many CAG repeats is classed as pathogenic and will always cause HD?
> 39
What is preimplantation diagnostic genetic testing (PDG) ?
▪️Remove cell from early IVF embryo
▪️Test single cell
▪️Re-implant unaffected embryos
▪️Similar success rate to IVF (20-30%)
What are the disadvantages of predictive testing for HD?
▪️Emotional impact
▪️Cannot unlearn result
▪️Discover non-paternity
▪️Discrimination
▪️Long-term adjustment - hopelessness, suicide risk
What employment and insurance issues may someone at risk of HD face?
▪️Exckuded from firearms work and high-speed driving in police
▪️Army now cannot discriminate or insist on a test
▪️DVLA must be informed if symptomatic
▪️Must disclose test results to apply for life insurance
When would diagnostic testing for HD be performed?
▪️If presenting with chorea in mid-life (commonest cause)
▪️Positive family history of progressive motor, cognitive or affective disturbance
▪️Family history of HD
▪️Absence of family history (e.g. non-paternity, anticipation)
When should diagnostic testing be done in patients with a family history of HD?
▪️To confirm clinical diagnosis
▪️ONLY when motor abnormalities are consistent with HD to avoid inadvertently predictive testing
What are the main issues of diagnostic testing?
▪️Is it presymptomatic testing?
▪️Pressure from relatives to have test
▪️If no previous experience, may be unaware of genetic risk
▪️At what age do you start testing?
What are some other genetic HD-like disorders?
▪️Inherited prion disease
▪️Spinocerebellar ataxia type 1-3 and 17
▪️DRPLA
▪️Neuroferritinopathy
What is the most common cause of chorea presenting in midlife?
Huntington’s disease
What differential diagnoses could you consider for chorea?
▪️Acquired chorea (e.g. Sydenham’s, SLE, APS, pregnancy, MS, metabolic disturbance, HIV, Lyme)
▪️Drug-induced (30%)
What drugs have been shown to induce chorea?
▪️Anticonvulsants
▪️Oral contraceptive
▪️Antiparkinsonian drugs
▪️Tricyclic antidepressants
▪️Stimulants
▪️Neuroleptics (and withdrawal)
▪️Carbon monoxide, manganese, mercy, thallium
What are the main targets for symptomatic treatments for movement disorder?
▪️Dopamine receptor blockade
▪️Presynaptic dopamine depletion
▪️Glutamate antagonism
What is typically used to block dopamine receptors in HD?
Typical and atypical neuroleptics (e.g. olanzapine, risperidone, sulpiride)
What can tetrabenazine be used for in HD?
Presynaptic dopamine depletion
What can amantadine be used for in HD?
Glutamate antagonism (inhibit activity of glutamate receptors)
