Huntingdon's disease

Question 1

What is HD?

Answer 1

Autosomal dominant neurodegenerative disorder, presenting in middle age with chorea and dementia

Question 2

What is the cause of HD

Answer 2

Huntingtin gene (HTT) on chromosome 4p16.3 contains trinucleotide repeats of CAG.

CAG is repeated 10-30 times in a row.

People with Huntingdon’s disease have increased CAG repeats:

• incomplete penetrance 36-39
• complete penetrance >40

Question 3

Describe the pathophysiology in HD

Answer 3

• There is GABAergic neuronal cell death
• Dysregulation of the glutamate-mediated basal ganglia activity means there is increased motor output and hyperkinetic movements.
• Abnormal proteins (gene mutation) aggregates in the caudate and putamen cells of the basal ganglia.
• Atrophy (tissue loss) in the striatum and cortex and expansion of the lateral ventricles that comes with the neuronal cell death.

Question 4

What are the implications of excessive CAG repeats?

Answer 4

CAG codes for glutamine - Extra CAG repeats will lead to a toxic gain of function.

Question 5

How do the CAG repeats change over generations?

Answer 5

Extra CAG repeats are inserted due to default of the DNA polymerase enzyme during DNA replication. As a person develops from zygote  foetus  adult, there will be lots of rounds of replications/ increased opportunities for REPEAT EXPANSION.

With each generation, there will be an increased number of CAG repeats which means an earlier onset of disease with each generation.

Question 6

When is the average age of onset of HD?

Answer 6

30-40 years old

Question 7

What does anticipation mean WRT HD?

Answer 7

Repeat expansion occurs more in spermatogenesis therefore if paternal side affected, more likely to be early onset of Huntingdons.

Question 8

Name some symptoms and signs of HD (broken into motor, psychiatric and cognitive)

Answer 8

Motor symptoms-

• Hypotonia
• Hyperreflexia
• Chorea (face, head, neck, tongue, trunk, extremities)- jerky dyskinetic movements
• Athetosis (slow involuntary snake-like movements)
• Dystonia
• Gait abnormalities
• Slow, abnormal eye movements
• Speech impairments

Psychiatric-

• Apathy
• Depression
• Irritability
• Aggressions
• Disinhibition

Cognitive-

• Dementia
• Memory loss
• Loss of concentration
• Fits

Question 9

What investigations would you do for HD?

Answer 9

1. Take a good family history
2. Do a neuro examination, motor and mental state exam too
3. Genetic analysis- note how many CAG repeats there are. Be aware if higher than 36, higher than 39 is diagnostic
4. MRI/CT- visualise atrophy in the striatum and dilation of the ventricles

Question 10

What are some complications of HD?

Answer 10

Most patients die within 10-20 years of diagnosis.

Depression –> suicide

Dysphagia –> aspiration pneumonia (common cause of death in Huntingdons)

Question 11

What is the treatment of HD?

Answer 11

No curative treatment- provide with counselling for patient and family to reduce anxiety.

Chorea- treat the symptoms

• Neuroleptics (dopamine receptor antagonists)- reduces dopaminergic input which reduces basal ganglia output.
• Tetrabenazine- presynaptic vesicular monoamine transporter (type II) inhibitors. Will increase the synaptic metabolism of dopamine. The decrease in dopamine will reduce basal ganglia output/ hyperkinetic output.

Can also provide assistive equipment like helmets, padded reclining chairs etc for chorea. Get therapy for speech difficulties. Use hip protectors for gait impairment.