Huntington's disease

Question 1

What is the epidemiology of Huntington’s disease (HD)?

Answer 1

Rare

Highest occurring in western European descent and lowest in black Africans

Men and women affected equally

Question 2

What is the aetiology and pathophysiology of HD?

Answer 2

Autosomal dominant disorder

Shows full penetrance

Defect on the Huntingtin gene (HTT) on chromosome 4:

i) Normally codes for amino acid glutamine and contains repeats of the trinucleotide sequence CAG
ii) In affected individuals there are more CAG repeats and the gene grows → surpasses a threshold → disease

36-40 repeats – disease present with reduced penetrance
>40 repeats – disease exists with full penetrance

The number of repeats is inversely proportional to the age that the disease presents and proportional to its severity: with hundreds of repeats → onset may be before age 20 and is thus called juvenile HD

The protein produced causes neuronal damage through unknown mechanisms but cerebral and caudate nucleus and putamen atrophy due to the loss of GABA-nergic and cholinergic neurons

Dopamine levels are normal

Question 3

What is anticipation and why is it significant?

Answer 3

Means that repeats can lengthen between generations leading to a worse phenotype over time within the same family

Genetic counselling is available to assess affected individuals and their families

Parents often present after childbearing age and the child may/may not want to know

If 1 parent is affected, there is a 50% chance of an affected child

Question 4

How does HD progress?

Answer 4

Age of onset typically 35-50

Initially symptoms may be sporadic but then become progressive or present simultaneously

Question 5

How does HD present?

Answer 5

Early signs may be personality change, self-neglect, apathy with clumsiness, fidgeting with fleeting facial grimaces
Behavioural problems may lead to family conflict, marital breakdown and job loss before a formal diagnosis has been made
Depressed mood is very common, possible bipolar or schizophrenia

Progressive chorea, rigidity and dementia +/- seizures

Chorea - jerky, involuntary movements affecting the shoulders, hips and face; gait problems; motor impersistence i.e. muscle contractions cannot be sustained - is initially mild but may become severe

As the disease progresses, chorea is gradually replaced by dystonia and Parkinsonian features

Dysarthria, dysphagia and abnormal eye movements; tics and myoclonus

HD-related cardiomyopathy and skeletal muscle wasting

Death

Question 6

How do you investigate HD?

Answer 6

Clinical + family pedigree

CT/MRI:
Often performed to rule out alternative diagnosis
HD will show a squaring off of the ventricle edges – ‘boxcar ventricles’ - where the caudate nucleus has atrophied

Question 7

How do you manage HD?

Answer 7

Typically only supportive + counselling to patient ± family

Chorea:
Benzodiazepines, valproic acid, dopamine-depleting agents (eg, tetrabenazine)
Potential use of atypical anti-psychotics can be used to reduce chorea and agitation but not slow disease progression

Patients with predominant bradykinesia and rigidity may benefit from levodopa or dopamine agonists instead

Depression:
SSRIs +/- ECT in severe
Suicide peaks @ diagnosis then again when function starts to be lost

Death is usually from intercurrent illness e.g. pneumonia; or suicide