Medicine – Huntington Disease

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterised by a combination of chorea, psychiatric disturbance, and progressive cognitive decline. Symptoms most commonly begin in adult life, often between about 30 and 50 years of age, although onset can occur earlier or later.

Because the disorder is autosomal dominant, an affected person usually has an affected parent, although the family history may occasionally appear negative because of early parental death, unrecognised disease, or a new mutation.

1. Inheritance

Huntington disease is inherited in an autosomal dominant pattern.

This means that an affected individual has a 50% chance of transmitting the pathogenic variant to each child, regardless of the child’s sex.

Both males and females can therefore be affected and can transmit the disease.

2. Genetic Defect

Huntington disease is caused by expansion of a CAG trinucleotide repeat in the HTT gene on chromosome 4.

The CAG sequence codes for glutamine, so the mutation produces an abnormally long polyglutamine tract in the huntingtin protein.

The abnormal protein ultimately causes progressive neuronal dysfunction and death.

3. Anticipation

Huntington disease demonstrates anticipation.

This means that the disease can present at an earlier age in successive generations when the CAG repeat expands further.

Anticipation is particularly associated with paternal transmission, because repeat expansion is more likely during spermatogenesis.

Therefore:

More CAG repeats → generally earlier disease onset.

4. Neuropathology

The most characteristic pathological changes involve degeneration of neurons within the striatum, especially the:

Caudate nucleus.

Putamen.

Loss of striatal neurons disrupts the normal basal-ganglia control of movement and contributes to chorea and other motor abnormalities.

5. Caudate Atrophy

As the disease progresses, marked caudate nucleus atrophy may develop.

On brain imaging this can produce enlargement of the frontal horns of the lateral ventricles.

This is a classic structural feature of advanced Huntington disease.

6. Age of Onset

Symptoms classically begin between approximately 30 and 50 years of age.

However, there is considerable variation.

Some patients develop disease later in life, while those with very large CAG expansions can present much earlier.

7. Juvenile Huntington Disease

Disease beginning before about 20 years of age is called juvenile Huntington disease.

Unlike classic adult Huntington disease, juvenile cases may show more:

Rigidity.

Bradykinesia.

Dystonia.

Seizures.

Chorea may actually be less prominent.

This juvenile phenotype is sometimes called the Westphal variant.

8. Chorea

Chorea is the characteristic movement disorder of classic Huntington disease.

It consists of involuntary, irregular, unpredictable, flowing movements that seem to move randomly from one part of the body to another.

The movements are not rhythmic.

They may affect the:

Face.

Arms.

Legs.

Trunk.

9. Appearance of Chorea

Early chorea may initially look like normal restlessness or fidgeting.

Patients may incorporate involuntary movements into apparently purposeful actions, sometimes making them difficult to recognise initially.

As disease progresses, the movements become more obvious and may interfere with walking, speech, eating, and daily activities.

10. Other Motor Features

Huntington disease is not limited to chorea.

Patients may also develop:

Dystonia.

Abnormal eye movements.

Dysarthria.

Dysphagia.

Impaired gait and balance.

In advanced disease, chorea may become less prominent while rigidity and bradykinesia increase.

11. Cognitive Decline

Progressive cognitive impairment is a central component of Huntington disease.

Early abnormalities commonly involve executive function, including difficulty with:

Planning.

Organisation.

Problem solving.

Attention.

Mental flexibility.

As the disease progresses, cognitive impairment may eventually develop into dementia.

12. Dementia

Dementia usually develops gradually as neurodegeneration progresses.

Unlike Alzheimer’s disease, early problems may be dominated by executive dysfunction and slowed thinking rather than severe early loss of episodic memory.

Eventually, multiple cognitive domains become affected.

13. Psychiatric Features

Psychiatric symptoms are extremely important and may precede the obvious movement disorder.

These can include:

Depression.

Irritability.

Anxiety.

Apathy.

Impulsivity.

Obsessive or compulsive behaviour.

Psychosis in some patients.

Therefore, Huntington disease should be considered a motor, cognitive, and psychiatric disorder.

14. Family History

A positive family history strongly supports the diagnosis because Huntington disease is autosomal dominant.

A typical history may reveal a parent or grandparent who developed unusual movements, personality changes, psychiatric illness, or progressive dementia during adulthood.

However, an apparently negative family history does not completely exclude the disease.

15. Genetic Testing

The diagnosis can be confirmed by molecular genetic testing demonstrating an expanded CAG repeat in the HTT gene.

Testing an individual who already has compatible symptoms is called diagnostic genetic testing.

16. Predictive Genetic Testing

Because Huntington disease usually develops in adulthood, an asymptomatic adult with an affected parent may request predictive testing.

This is a major decision because a positive result predicts a high likelihood of future disease before symptoms appear.

Predictive testing therefore requires careful genetic counselling, informed consent, and psychological support.

17. Treatment Principles

There is currently no treatment that reliably reverses the underlying neurodegeneration.

Management therefore focuses on:

Controlling abnormal movements.

Treating psychiatric symptoms.

Maintaining nutrition and swallowing safety.

Physiotherapy and mobility support.

Speech and language therapy.

Genetic counselling.

Psychological and social support.

18. Treatment of Chorea

The older note lists chlorpromazine to relieve chorea.

Dopamine-blocking antipsychotic drugs can indeed reduce choreiform movements, particularly when the patient also has behavioural disturbance or psychosis.

However, chlorpromazine is not generally regarded as the principal modern treatment specifically for Huntington chorea.

19. Tetrabenazine

Tetrabenazine is an important treatment for troublesome Huntington-related chorea.

It inhibits vesicular monoamine transporter type 2 (VMAT2), reducing storage and release of monoamines such as dopamine.

The resulting reduction in dopaminergic activity helps suppress choreiform movements.

20. Deutetrabenazine

Deutetrabenazine is a related VMAT2 inhibitor that may also be used to treat Huntington chorea.

Drug selection depends on availability, individual symptoms, adverse-effect risk, and specialist assessment.

21. Antipsychotic Drugs

Antipsychotic drugs may be especially useful when chorea occurs together with:

Psychosis.

Severe agitation.

Aggressive behaviour.

Some atypical antipsychotics are often preferred over older drugs such as chlorpromazine because treatment can be tailored according to adverse effects and psychiatric symptoms.

22. Depression and Suicide Risk

Depression is common in Huntington disease and requires active treatment.

Patients can also have an increased risk of suicidal thoughts and behaviour, particularly around diagnosis and during periods of declining function.

Psychiatric assessment and ongoing support are therefore essential components of care.

23. Dysphagia and Nutrition

Progressive motor dysfunction may cause dysphagia.

At the same time, continuous involuntary movements can increase energy expenditure.

Patients may consequently develop significant weight loss and nutritional problems.

Swallowing assessment and nutritional support become increasingly important as disease advances.

24. Huntington Disease – Note Form

Inheritance: autosomal dominant.

Gene: HTT gene on chromosome 4.

Mutation: CAG trinucleotide repeat expansion.

Anticipation: increasing CAG repeat length can cause earlier onset in later generations, particularly with paternal transmission.

Typical onset: approximately 30–50 years, although highly variable.

Main movement disorder: chorea.

Chorea: irregular, involuntary, non-rhythmic flowing movements.

Cognition: progressive executive dysfunction followed by dementia.

Psychiatric features: depression, irritability, apathy, behavioural disturbance and sometimes psychosis.

Family history: usually positive because of autosomal dominant inheritance.

Pathology: degeneration of the caudate and putamen.

Imaging: caudate atrophy may lead to enlargement of the frontal horns of the lateral ventricles.

Diagnosis: genetic demonstration of expanded CAG repeats in HTT.

Treatment of chorea: VMAT2 inhibitors such as tetrabenazine or deutetrabenazine are important modern options.

Antipsychotics: may reduce chorea and are particularly useful when psychiatric or behavioural symptoms coexist.

Chlorpromazine: can suppress chorea but is an older treatment and is not usually the main modern first-choice drug specifically for chorea.

Key Clinical Pattern

Remember Huntington disease as:

Autosomal dominant + adult onset + chorea + psychiatric disturbance + progressive dementia.

The genetic mechanism is:

Chromosome 4 HTT gene → CAG repeat expansion → abnormal huntingtin protein → striatal neurodegeneration.

The classic pathological structure is:

Caudate nucleus atrophy.

And the major treatment update is:

Troublesome chorea → think VMAT2 inhibition, especially tetrabenazine or deutetrabenazine, rather than chlorpromazine alone.