Huntington's Disease

Question 1

What type of genetic condition is Huntington’s?

Answer 1

Autosomal dominant

Question 2

What percentage of Huntington’s has juvenile onset below age 21 and what is it associated with?

Answer 2

5% - Westphal variant

Question 3

What is the mean age of motor onset in Huntington’s?

Answer 3

45 years old

Question 4

What are the two phases of Huntington’s?

Answer 4

▪️Premanifest (presymptomatic, prodromal)
▪️Manifest (motor onset)

Question 5

Where is huntingtin protein usually found?

Answer 5

▪️Most tissue
▪️Highest activity in the brain ▪️Predominantly extranuclear in neurons

Question 6

How does a huntingtin gene mutation cause disease?

Answer 6

▪️Expanded, unstable CAG repeats
▪️Translates to polyglutamine repeat in HD protein

Question 7

How many CAG repeats is classes as normal and not pathogenic?

Answer 7

<35

Question 8

What is seen with 29-35 CAG repeats?

Answer 8

▪️Paternal meiotic instability
▪️Non pathogenic
▪️Rarely expands into disease range
▪️Increased risk of children with HD

Question 9

What is seen with 36-39 CAG repeats?

Answer 9

▪️Pathogenic but reduced penetrance
▪️Risk increases by ~25% with each one

(36 ~ 25%, 37 ~ 50%, 38 ~ 75%, 39 ~ 90%)

Question 10

How many CAG repeats is classed as pathogenic and will always cause HD?

Answer 10

> 39

Question 11

What is preimplantation diagnostic genetic testing (PDG) ?

Answer 11

▪️Remove cell from early IVF embryo
▪️Test single cell
▪️Re-implant unaffected embryos
▪️Similar success rate to IVF (20-30%)

Question 12

What are the disadvantages of predictive testing for HD?

Answer 12

▪️Emotional impact
▪️Cannot unlearn result
▪️Discover non-paternity
▪️Discrimination
▪️Long-term adjustment - hopelessness, suicide risk

Question 13

What employment and insurance issues may someone at risk of HD face?

Answer 13

▪️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

Question 14

When would diagnostic testing for HD be performed?

Answer 14

▪️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)

Question 15

When should diagnostic testing be done in patients with a family history of HD?

Answer 15

▪️To confirm clinical diagnosis
▪️ONLY when motor abnormalities are consistent with HD to avoid inadvertently predictive testing

Question 16

What are the main issues of diagnostic testing?

Answer 16

▪️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?

Question 17

What are some other genetic HD-like disorders?

Answer 17

▪️Inherited prion disease
▪️Spinocerebellar ataxia type 1-3 and 17
▪️DRPLA
▪️Neuroferritinopathy

Question 18

What is the most common cause of chorea presenting in midlife?

Answer 18

Huntington’s disease

Question 19

What differential diagnoses could you consider for chorea?

Answer 19

▪️Acquired chorea (e.g. Sydenham’s, SLE, APS, pregnancy, MS, metabolic disturbance, HIV, Lyme)
▪️Drug-induced (30%)

Question 20

What drugs have been shown to induce chorea?

Answer 20

▪️Anticonvulsants
▪️Oral contraceptive
▪️Antiparkinsonian drugs
▪️Tricyclic antidepressants
▪️Stimulants
▪️Neuroleptics (and withdrawal)
▪️Carbon monoxide, manganese, mercy, thallium

Question 21

What are the main targets for symptomatic treatments for movement disorder?

Answer 21

▪️Dopamine receptor blockade
▪️Presynaptic dopamine depletion
▪️Glutamate antagonism

Question 22

What is typically used to block dopamine receptors in HD?

Answer 22

Typical and atypical neuroleptics (e.g. olanzapine, risperidone, sulpiride)

Question 23

What can tetrabenazine be used for in HD?

Answer 23

Presynaptic dopamine depletion

Question 24

What can amantadine be used for in HD?

Answer 24

Glutamate antagonism (inhibit activity of glutamate receptors)

Question 25

What medications can be used for the akinetic rigid variant on HD?

Answer 25

▪️L-dopa
▪️Baclofen
▪️Clonazepam

Question 26

What percentage of HD patients present with psychiatric problems?

Answer 26

30%

Question 27

What are the most common psychiatric presentations of HD?

Answer 27

▪️Anxiety and depression (5x suicide risk)
▪️Apathy
▪️OCD
▪️Irritability
▪️Impulsivity
▪️Psychotic symptoms

Question 28

What primary psychiatric disorders are most commonly diagnosed in individuals with HD in the absence of family history?

Answer 28

▪️Personality disorder and neurosis
▪️Mood disorder
▪️Schizophrenia
▪️Forensic presentation

Question 29

What medications can be used for anxiety and depression in HD?

Answer 29

SSRIs and NRIs (e.g. mirtazepine, citalopram, fluoxetine)

Question 30

What is usually used to treat OCD symptoms in HD?

Answer 30

Behavioural interventions and SSRIs

Question 31

What medications are typically used to treat irritability, impulsivity, and psychotic symptoms in HD?

Answer 31

Neuroleptics (e.g. olanzapine, sulpiride, amisulpiride, risperidone)

Question 32

When do cognitive deficits typically present in HD and how do you test for it?

Answer 32

Up to 10 years before manifest HD

Most sensitive test = test of psychomotor speed

Question 33

What brain areas are primarily affected by HD?

Answer 33

Striatal neurons in the caudate

Question 34

What forms of cognitive impairment are most commonly seen in HD?

Answer 34

▪️Dysexecutive syndrome (difficulties with planning, reasoning, mental flexibility, decision-making, attention and concentration)
▪️Personality changes - typically impulsive, irritable, loss of emotional response

Question 35

What other issues must be considered when supporting someone with HD?

Answer 35

▪️Dental care
▪️Weight, feeding and swallowing
▪️Communication
▪️Sleep
▪️Family planning
▪️Legal considerations (power of attorney, capacity, driving, work)
▪️Care needs

Question 36

What are the current main areas of HD research?

Answer 36

▪️Lab mouse models
▪️Disease modifying treatments for pre-manifest and carriers - clinical trials
▪️Biomarkers of progression