Huntington's disease is associated with cell loss within the basal ganglia and cortex. It is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties.¹ Huntington's disease was first described by George Huntington in 1872. The disease is associated with increases in the length of a CAG (cysteine-adenosine-guanine) triplet repeat present in a gene called 'huntingtin' located on chromosome 4p16.3.²

Epidemiology

• The prevalence in most European countries ranges from between 4 and 8 per 100,000 people.³

Presentation

• Typically, onset of symptoms is in middle-age but the disorder can manifest at any age.¹
• There is often a prodromal phase of mild psychotic and behavioural symptoms which may last for up to ten years before the development of chorea. Early signs may be personality change, self neglect, apathy with clumsiness, fidgeting with fleeting facial grimaces.
• Huntington's disease then leads to progressive chorea, rigidity and dementia. It is frequently associated with seizures.
• Dysarthria, dysphagia and abnormal eye movements are common. There may also be other movement disorders, e.g. tics and myoclonus.
• 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.
• Behavioural difficulties include apathy or lack of initiative, dysphoria, irritability, agitation or anxiety, poor self-care, poor judgment and inflexibility.¹
• Late features include spasticity, clonus, supranuclear gaze palsy and extensor plantar responses.
• The rate of cognitive decline is very variable. Early changes include behavioural changes and then progresses to impaired intellectual function and memory disturbances.
• Juvenile Huntington's disease (6% of all cases of huntington's disease) 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.
• Tardive dyskinesia.
• Other causes of chorea:⁴
  • Hereditary: e.g. Wilson's disease.
  • Sporadic: e.g. drugs, pregnancy, senile chorea, vascular disease, thyrotoxicosis, systemic lupus erythematosus and the lupus anticoagulant syndrome, polycythaemia rubra vera, AIDS and Sydenham's chorea.
• Other causes of dementia.

Investigations

• MRI and CT scans in moderate-to-severe Huntington's disease show a loss of striatal volume and increased size of the frontal horns of the lateral ventricles, but scans are usually unhelpful for diagnosis of early disorder.¹
• If genetic testing is considered then extensive genetic counselling in a specialist unit is required in view of the implications of an untreatable, familial, progressive, neurodegenerative disease.
• Testing for alternative causes of movement disorders (including SLE, antiphospholipid antibody syndrome, thyroid disease and Wilson disease) and dementia.

Predictive testing⁵

• Genetic testing 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 test.
• 2 separate blood samples taken to double check the results. The affected parent’s blood may also be tested to check the original diagnosis of Huntington’s disease.
• One section of the Huntington’s gene contains cytosine, adenine and guanine repeated a number of times. In the faulty gene there are many repeats.
• Four types of results are recognised:
  • Under 27 repeats is unequivocally normal.
  • Between 27-35 repeats is normal but there is a small chance that the repeat may increase in future generations.
  • Between 36-39 repeats is abnormal but there is a chance the person may be affected very late in life or even not at all.
  • Over 40 repeats is unequivocally abnormal.
• Although the test can tell whether the person is carrying the Huntington’s disease mutation, it cannot tell when the disease itself will start to develop.

Associated diseases

• Depression, significant personality change and symptomatic schizophrenia are all common in patients with Huntington's disease.⁶

Management

• Current 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.⁷
• Patients, their families and carers require a great deal of physical and emotional support.
• Chorea: benzodiazepines, valproic acid, dopamine-depleting agents (e.g.tetrabenazine) and neuroleptics may be useful.
• Patients with predominant bradykinesia and rigidity may benefit from levodopa or dopamine agonists.
• Depression: needs prompt recognition and treatment with SSRIs or alternative antidepressants. Refractory depression may require ECT treatment.
• Psychosis: antipsychotic medications may be necessary. Newer atypical antipsychotics are preferable in view of their lower incidence of extrapyramidal side effects.
• Neural and stem cell transplantation is a potential future treatment.

Prognosis

• Relentlessly neurodegenerative disorder. The clinical features develop progressively with severe increase in choreic movements and dementia.
• Death is usually from an intercurrent illness, e.g. respiratory tract infection.

Document references

1. Walker FO; Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28. [abstract]
2. Huntington Disease, Online Mendelian Inheritance in Man (OMIM)
3. Harper PS; The epidemiology of Huntington's disease. Hum Genet. 1992 Jun;89(4):365-76. [abstract]
4. Quinn N, Schrag A; Huntington's disease and other choreas. J Neurol. 1998 Nov;245(11):709-16. [abstract]
5. Huntington’s Disease Association; Predictive Testing for Huntington’s Disease.
6. Shiwach R; Psychopathology in Huntington's disease patients. Acta Psychiatr Scand. 1994 Oct;90(4):241-6. [abstract]
7. Bonelli RM, Hofmann P; A systematic review of the treatment studies in Huntington's disease since 1990. Expert Opin Pharmacother. 2007 Feb;8(2):141-53. [abstract]

Internet and further reading

• HDBuzz - Huntington's disease research and patient website

Acknowledgements