Huntington's disease

What is Huntington's disease?

Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, inco-ordination, cognitive decline and behavioural difficulties. Huntington's disease is associated with cell loss within the basal ganglia and cortex. Huntington's disease was first described by George Huntington in 1872. Huntington's disease is associated with increases in the length of a cysteine-adenosine-guanine (CAG) triplet repeat present in a gene called 'huntingtin' (HTT) located on chromosome 4p16.3.¹ There are many symptomatic Huntington's diseasetreatments but no as yet, there are no therapies that alter disease progression.

Epidemiology

• Huntington's disease prevalence is estimated at between 1 in 10,000 and 1 in 20,000.

• HD is the most common hereditary neurodegenerative disorder . It is the most common genetic cause of chorea .

• The mean age at onset of Huntington's disease symptoms is 30-50 years.

• In some cases Huntington's disease symptoms start before the age of 20 years with behavioural disturbances and learning difficulties at school - juvenile Huntington's disease (JHD); this is more common when the condition has been inherited from the father.¹

Huntington's disease presentation

Typically, onset of Huntington's disease symptoms is in middle age but the disorder can manifest at any age. There is often a prodromal phase of mild psychotic and behavioural symptoms before the development of chorea. Clinical and neuroradiological abnormalities can be demonstrated in gene-positive individuals before the onset of manifest HD, even as far as 15 years before the disease onset .

• 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 significantly higher in HD gene carriers than in the general population and in individuals with HD it has been reported to be as common as 69%.²

• HD then leads to progressive chorea, rigidity and dementia. It is frequently associated with seizures.

• Chorea is initially mild but may be severe and cause uncontrollable limb movements.

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

• Dysarthria, dysphagia and abnormal eye movements are common. There may also be other movement disorders - eg, tics and myoclonus.

• HD patients can develop a wide array of dysfunction, including HD-related cardiomyopathy and skeletal muscle wasting.²

HD is associated with increasing depression, bradykinesia, cognitive impairment and aggression as the disease progresses . Behavioural difficulties include apathy or lack of initiative, dysphoria, irritability, agitation or anxiety, poor self-care, poor judgment and inflexibility. Late Huntington's disease symptoms include spasticity, clonus, supranuclear gaze palsy and extensor plantar responses. The rate of cognitive decline is very variable.

JHD (6% of all cases of HD) is defined as an age of onset of younger than 20 years. It causes Parkinsonian features, dystonia, pyramidal tract signs, dementia and epilepsy. Chorea is often mild and may be absent.

Differential diagnosis

• Neuroacanthocytosis: a group of genetic conditions that are characterised by movement disorders and acanthocytosis (abnormally-shaped red blood cells).

• Tardive dyskinesia and other causes of chorea.

• Other causes of dementia.

Investigations

• MRI and CT scans in moderate-to-severe HD show a loss of striatal volume and increased size of the frontal horns of the lateral ventricles; however, scans are usually unhelpful for diagnosis of early disorder .

• If genetic testing is considered then extensive genetic counselling in a specialised unit is required in view of the implications of an untreatable, familial, progressive, neurodegenerative disease.

• Testing for alternative causes of movement disorders (including systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, thyroid disease and Wilson's disease) and dementia.

Huntington's disease testing

• Genetic testing for Huntington's disease is available at regional genetics clinics (contact details are available in the linked Huntington's Disease Association information sheet).

• The clinics follow an agreed genetic counselling procedure which is usually spread over at least three sessions to help the person decide whether or not to go ahead with the Huntington's disease test.

• Two separate blood samples are taken to double-check the results. The affected parent's blood may also be tested to check the original diagnosis of HD.

• One section of the Huntington's gene contains cytosine, adenine and guanine repeated a number of times. In the faulty gene there are many repetitions.

• Four types of results are recognised:²
  

  • Under 27 repetitions is unequivocally normal.

  • Between 27-35 repetitions is normal but there is a small chance that the repeat may increase in future generations.

  • Between 36-39 repetitions is abnormal but there is a chance the person may be affected very late in life or even not at all.

  • Over 40 repetitions is unequivocally abnormal.

• Although the test can tell whether the person is carrying the HD mutation, it cannot tell when the disease itself will start to develop.

Huntington's disease treatment and management³

• Currently available drug therapy has no effect on the progression of disability.

• Hyperkinesias and psychiatric symptoms may respond well to pharmacotherapy but neuropsychological deficits and dementia remain untreatable.

• Standards of care:

  • Patients, their families and carers require a great deal of physical and emotional support.

  • The care of someone with HD is complex and involves many specialties including neurology, general practice, psychiatry,⁴ speech and language therapy, physiotherapy,⁵ clinical genetics, neuropsychology and dietetics, as well as social work and palliative care. However, there is little research on this aspect of HD.

  • The European Huntington's Disease Network hosts relevant guidelines for the care of people with Huntington's disease including physiotherapy and nutrition.⁶

• Chorea:
  

  • Medication should be considered if the patient is uncomfortable or distressed by chorea.

  • Tetrabenazine and second generation neuroleptics should be considered the antichoreic drugs of choice according to International guidelines.³ Comorbidity - eg, depression, will guide choice.

  • An algorithm for the drug treatment of chorea has been developed from international expert opinion.²

  • Monotherapy is preferable, if possible.

• Patients with predominant bradykinesia and rigidity may benefit from levodopa or dopamine agonists in addition to physiotherapy.

• Depression:²

  • Needs prompt recognition and treatment.

  • Selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitor (SNRI) are first-choice antidepressants. Refractory depression may require ECT treatment.

  • There is a significantly higher occurrence of suicidal ideation (19.76%) and suicidal plans (2.1%) than the general population.⁷ The risk is highest initially when the patient recognises the first symptoms of HD; the second 'danger period' occurs as independence starts to be lost.

• Psychosis:

  • Antipsychotic medications may be necessary. Newer atypical antipsychotics are preferable in view of their lower incidence of extrapyramidal side-effects.

  • Antipsychotics may also be needed in the treatment of obsessive-compulsive behaviours and irritability when psychotherapy and behavioural management strategies have proved inadequate.²

• Neural and stem cell transplantation have been studied in humans but only in small studies and guidelines do not yet mention their use.

• Deep brain stimulation is a new approach for palliative treatment of choreatic movements, dystonia and stiffness, but the role of other clinical features and of disease progression needs to be elucidated.⁸ There is a need for more reliable criteria that may guide the selection of HD patients suitable for this treatment.

Predictive genetic testing allows for early identification of HD carriers and observational studies are increasing knowledge of the pathophysiology and natural progression of HD. In addition the development of sensitive measurements that allow earlier diagnosis are expected to provide the ideal time for the use of disease-modifying therapy, such as gene silencing.⁹

Huntington's disease prognosis¹⁰

• Huntington's disease is currently a relentlessly progressive, neurodegenerative disorder which takes its course over 15-20 years.

• The number of CAG repeats not only provide information on the age of clinical onset but also predict the age of death. The larger the CAG repeat sizes, the greater is the rate of deterioration of motor, cognitive, and functional measures.

• The clinical features develop steadily with severe increase in choreic movements and dementia.

• Death is usually from an intercurrent illness - eg, pneumonia.

• Suicide is the second most common cause of death.