Huntington Disease

Essentials of Diagnosis

• Gradual onset and progression of chorea and dementia or behavioral change

• Family history of the disorder

• Responsible gene identified on chromosome 4

General Considerations

• Inherited in an autosomal dominant manner and occurs throughout the world, in all ethnic groups, with a prevalence rate of about 5 per 100,000

• The gene responsible for the disease has been located on the short arm of chromosome 4

  • There is an expanded and unstable CAG trinucleotide repeat at 4p16.3

  • Longer repeat lengths correspond to earlier age of onset and faster disease progression

• Offspring should be offered genetic counseling

• Genetic testing permits presymptomatic detection and definitive diagnosis of the disease

Symptoms and Signs

• Clinical onset is usually between 30 and 50 years of age

• Initial symptoms

  • May consist of either abnormal movements or intellectual changes

  • However, both ultimately occur

• Earliest mental changes

  • Often behavioral, with irritability, moodiness, antisocial behavior, or a psychiatric disturbance

  • However, a more obvious dementia subsequently develops

• Dyskinesia

  • May initially be no more than an apparent fidgetiness or restlessness

  • However, choreiform movements and some dystonic posturing eventually occur

• A parkinsonian syndrome with progressive rigidity and akinesia (rather than chorea) sometimes occur in association with dementia, especially in cases with childhood onset

Differential Diagnosis

• Chorea developing with no family history of choreoathetosis should not be attributed to Huntington disease, at least not until other causes of chorea have been excluded clinically and by appropriate laboratory studies

• In younger patients, self-limiting Sydenham chorea develops after group A streptococcal infections on rare occasions

• Other nongenetic causes of chorea

  • Stroke

  • Systemic lupus erythematosus and antiphospholipid antibody syndrome

  • Paraneoplastic syndromes

  • Infection with HIV

  • Various medications

• If progressive intellectual failure is the sole presentation, it may not be possible to distinguish Huntington disease from other causes of dementia unless there is a characteristic family history or a dyskinesia develops

• Dentatorubral-pallidolysian atrophy

  • A clinically similar autosomal dominant disorder

  • Uncommon except in persons of Japanese ancestry

  • Manifested by chorea, dementia, ataxia, and myoclonic epilepsy

  • Due to a mutant gene mapping to 12p13.31

Imaging Studies

• CT scanning or MRI usually demonstrates cerebral atrophy and atrophy of the caudate nucleus in established cases

• Positron emission tomography (PET) has shown reduced striatal metabolic rate

Medications

• Dopamine receptor blockers, such as phenothiazines or haloperidol, may control the dyskinesia and any behavioral disturbances

• Haloperidol

  • Initial dose is 1 mg orally once or twice daily

  • Dose is increased every 3 or 4 days, depending on the response

• Tetrabenazine

  • Interferes with the vesicular storage of biogenic amines

  • Used to treat the dyskinesia; however, not indicated for treatment of levodopa-induced dyskinesias

  • Starting dose: 12.5 mg two or three times daily, increasing by 12.5 mg every 5 days depending on response and tolerance

  • Usual maintenance dose: 25 mg three times daily

  • Side effects include depression, postural hypotension, drowsiness, and parkinsonian features

  • Should not be given within 14 days of taking monoamine oxidase inhibitors

• Deutetrabenazine

  • Effective in reducing chorea

  • Starting dose: 6 mg once daily orally, increased to 6 mg twice daily after 1 week and by 6-mg increments weekly thereafter, to a maximum of 24 mg twice daily

• Reserpine

  • Similar in its actions to tetrabenazine and may be helpful

  • However, reserpine has more peripheral effects and a worse side-effect profile than tetrabenazine

  • Daily dose is built up gradually to between 2 and 5 mg orally, depending on the response

• Atypical antipsychotic agents such as quetiapine (increasing from 25 mg daily up to 100 mg twice daily as tolerated) may be tried

• Amantadine in a daily dose of 200–400 mg is sometimes helpful for chorea

• Behavioral disturbances may respond to clozapine

• Attempts to compensate for the relative gamma-aminobutyric acid (GABA) deficiency by enhancing central GABA activity or to compensate for the relative cholinergic underactivity by giving choline chloride have not been therapeutically helpful

Therapeutic Procedures

• Deep brain stimulation has been used successfully to treat chorea in a small number of patients

Prevention

• Genetic counseling is important to prevention

Prognosis

• There is no cure for Huntington disease

  • Progression cannot be halted

  • Treatment is purely symptomatic

• Usually fatal within 15–20 years

When to Refer

• All patients should be referred