Huntington's disease

Huntington’s disease (HD) is an autosomal-dominantly inherited, neurodegenerative condition characterised by chorea, dystonia and cognitive changes.

Symptoms tend to develop between the ages of 20-40, choreiform movements are characteristic. It is a progressive disorder that often results in death within 20 years of onset.

HD is caused by an increased number of cysteine-adenosine-guanine (CAG) trinucleotide repeats within the huntingtin gene on chromosome 4. Treatment is aimed at reducing symptoms and preserving quality of life, currently there are no intervention cure or halt disease progression.

HD is estimated to have a prevalence of 2-5 per 100,000 worldwide.

Onset tends to be in middle-age with the onset for many between 30-50 however it may develop at an earlier or later age.

It appears to be less common in asian populations where the normal number of CAG trinucleotide repeats is lower.

HD is caused by an abnormal expansion of the CAG trinucleotide in the huntingtin gene (located on chromosome 4).

A trinucleotide refers to a codon, a sequence of three nucleotides that code a specific amino acid. In the case of the CAG trinucleotide it codes for glutamine. A trinucleotide repeat refers to a section of DNA that contains multiple repeats of the same trinucleotide in sequence.

The number of CAG repeats is key to the development of HD. 28 or less CAG repeats is considered normal. Between 28 and 35 there is an increased risk of disease occurring in their offspring (due to expansion of the repeats).

Those with 36 to 39 repeats have variable penetrance, with some developing symptoms though this tends to be at an older age. 40 repeats or more invariably results in disease, the more repeats the earlier the onset of disease.

The condition follows an autosomal dominant inheritance. ‘Anticipation’ is seen between successive generations - this refers to expansion of the CAG trinucleotide repeats resulting in the development of disease at an earlier age in offspring.

HD is characterised by choreiform movements (and other motor symptoms), psychiatric features and cognitive decline.

Motor features

HD is characterised by the progressive development of chorea. Chorea refers to abnormal, abrupt, involuntary movements. Initially these movements may be subtle and passed off as fidgetiness or restlessness. Parakinesia may be seen, these refers to choreiform movements that the individual attempts to incorporate into a purposeful movement. Over time they progressively worsen becoming significant uncontrollable flailing of the limbs.

Dysphagia and speech difficulties develop as the disease worsens. Poor coordination of the muscles controlling swallowing increases the risk of aspiration and resulting pneumonia.

Dystonia develops and with time parkinsonian features (e.g. bradykinesia, rigidity). As disease further develops an akinetic-rigid syndrome develops replacing chorea type movements.

Psychiatric features

Change in mood is common in patients with HD and this may precede motor symptoms. Depression is relatively common and there is an increased risk of suicide.

Other manifestations include paranoia, delusions, irritability, agitation, sleep disturbance and behaviour detrimental to close personal relationships.

Cognitive impairment

As the disease progresses cognitive decline is seen. The ability to make complex decisions and multi-task are affected. With time significant memory loss features and dementia develops.

HD is diagnosed by the identification of the number of CAG repeats through polymerase chain reaction (PCR) analysis and capillary or gel electrophoresis.

Initially, a blood sample is taken from the patient and used for PCR analysis. Within PCR, molecular primers (short fragments of DNA) are used to flank the CAG repeat region located in exon 1 of the HTT gene on chromosome 4. A forward and a reverse primer are used, which contain short DNA sequences complementary to the targeted genetic region.

Through the PCR process, hydrogen bonds between complementary base pairs in DNA break allowing the primers to bind to their target regions. At this point, DNA polymerase synthesises new strands, which includes the CAG repeat region. The whole cycle is then repeated many times to amplify the specified genetic region with the CAG repeat, which generates thousands to millions of copies.

Once this is complete samples are then run through a capillary or gel electrophoresis. In gel electrophoresis, the main principle is that negatively charged DNA will migrate through the gel to the positively charged end. Smaller fragments of DNA will pass further through the gel, meaning that smaller CAG repeats will pass further than larger CAG repeats.

The patients sample is run alongside control samples that have well defined CAG repeat sizes. Once completed, two bands should appear on the gel that represent the patients two alleles (CAG repeat numbers). These can be compared to the control bands to determine each CAG repeat number.

Management involves input from multiple teams including neurologists, physiotherapists, psychiatrists and palliative care specialists.

HD is a complex neurodegenerative disease that affects patients motor function, cognition, mental health and independence. The disease is heterogenous and progressive, management must be tailored to the individual and their stage of disease.

Pharmacological therapies aim to alleviate motor symptoms, treat psychological disturbances and maintain independence. At present there are no treatments that halt the progression of this disease.

In the later stages advanced care directives should be considered and increased input from palliative care services arranged.

Pharmacological treatment of chorea

• VMAT2 inhibitors (e.g. tetrabenazine): Vesicular monoamine transporter type 2 inhibitors are dopamine depleting agents used in the treatment of patients with troublesome chorea. It can however result in the features of parkinsonism. They are also associated with an increased risk of depression and suicidality. It may also worsen other psychological disturbances and as such must be avoided in patients suffering with any of these factors. Patients who are initiated on therapy should be warned of the side-effects and closely monitored.
• Other medications: Anti-psychotics (e.g. risperidone) can be used to help treat chorea. It may also be of use in those with psychotic features. Benzodiazepines (e.g. clonazepam) can be used to treat chorea in the short term.

Therapies

Physio (and occupational) therapy forms significant component of HD care. The input changes as the disease and symptoms progress. Early on this is focused on aerobic and resistance training. As the disease develops physiotherapy helps with planning and sequencing of tasks, maintaining mobility (whilst possible) and avoiding falls. Later care is orientated around optimising respiratory function, reducing aspiration and maintaining comfort.

Speech and language therapists can offer assistance in managing difficulty with communication if and when this occurs. Techniques to aid articulation and strategies to improve communication may be taught.

Neuropsychiatric management

Depression and low mood are common and should be screened for regularly. SSRI’s (e.g. citalopram) can be used to treat depression. Alongside or in place of this, talking based therapies (e.g. CBT) can be considered.

Patients at risk of self-harm or suicide should be urgently discussed with the relevant crisis team to develop an appropriate management plan.

Psychosis occurs more commonly in patients with HD. Anti-psychotics may be used to treat this, they may also help with the management of chorea.

Palliative care

Palliative care specialists have expertise in managing troublesome symptoms (such as pain) and optimising quality of life. As such their input can be valuable even before the disease enters its end-stages.

They are a key part of holistic care and help to ensure a patients spiritual, family and personal needs are met and cared for.

HD is without cure and is normally fatal 15-20 years after the onset of symptoms.

Though optimal therapy can help to preserve quality of life for longer, currently no treatment halts disease progression. Patients progress at different rates which are difficult to predict but it is known patients developing symptoms early (juvenile HD) tend to show much faster progression.

In the end-stage of disease, aspiration pneumonia and trauma (secondary to falls) are common causes of death. Suicide is also more common than in the general population, particularly at diagnosis and as independence begins to reduce.

Last updated: July 2021