Huntington disease (HD) is a trinucleotide repeat autosomal dominant neurodegenerative disorder characterized by involuntary movements manifesting as chorea, psychiatric disturbance, and cognitive decline.

HD

Huntington chorea

Chorea: hallmark physical manifestation of HD. Chorea refers to involuntary, random, irregular, fragmented, purposeless movements that flow from one body part to the next.

• Body parts affected: limbs, trunk, neck, face, and tongue.
• Velocity varies from fast (mimicking myoclonus) to slow (mimicking dystonia).
• Intensity, frequency, and amplitude may vary from subtle low-amplitude movements in upper face to dramatic large-amplitude movements in the limbs and trunk.
• May initially be mistaken for fidgeting.
• Patients may deny its presence even when obvious to others and may disguise their chorea by incorporating it into a voluntary movement.
• Chorea in HD often involves the upper face and forehead, which is less often involved in other forms of chorea such as tardive dyskinesia.
• Cognitive decline
• Progressive cognitive decline eventually leading to subcortical dementia found in all HD patients.
• Cognitive domains affected: Executive function, planning, working memory, and attention.
• Behavioral affects
• Depression, irritability, anxiety, and impulsivity common
• Some experience obsessive-compulsive symptoms
• Apathy common and worsens over course of disease
• Psychosis is uncommon
• High rates of suicide
• HD prodrome
• May begin up to 10 years before a clinical diagnosis.
• Manifests as subtle motor and nonmotor symptoms not sufficiently significant to yield a clinical diagnosis.
• Cognitive and behavioral symptoms such as depression may precede overt motor symptoms by years and may lead to significant morbidity or even mortality from suicide.
• (Fig. E1). When there is a writhing quality, it is referred to as choreoathetosis. Chorea is present early on and tends to decrease in end stages of disease.
• Dancelike, lurching gait (Fig. E2), often caused by chorea.
• Westphal variant: Typical of juvenile-onset HD and presenting with a parkinsonian syndrome of cognitive dysfunction, bradykinesia, and rigidity.
• Oculomotor abnormalities are common early on and include increased latency of response, hypometric saccades, and insuppressible eye blinking.
• Motor impersistence is common. Patients cannot keep their tongue sticking without moving it in and out of the mouth or cannot hold on to thumb of the examiner for prolonged period of time.
• Psychiatric disorders (can be present early on): Depression is commonly seen, as well as obsessive-compulsive behaviors and aggression associated with impaired impulse control.

• Trinucleotide repeat disorder; repeat of CAG, which codes for glutamine.
• The responsible gene is the huntingtin gene (HTT), located on chromosome 4. Its function is not known.

• Drug-induced chorea: Dopamine agonists, stimulants, anticonvulsants, antidepressants, and oral contraceptives have all been known to cause chorea.
• Tardive dyskinesia.
• Sydenham chorea: Decreased incidence with decline of rheumatic fever.
• Benign hereditary chorea: Autosomal dominant with onset in childhood; nonprogressive and without associated dementia or behavioral problems.
• Senile chorea: Possibly vascular in origin.
• Wilson disease: Autosomal recessive; tremor, dysarthria, and dystonia are more common presentations than chorea. A total of 95% of patients with neurologic manifestations will have Kayser-Fleischer rings.
• Postinfectious.
• Systemic lupus erythematosus: Can be the presenting feature of lupus (rare).
• Chorea gravidarum: Presents during first 4 to 5 mo of pregnancy and resolves after delivery.
• Paraneoplastic: Seen most commonly in small cell lung cancer and lymphoma.
• C9orf72 mutation: Originally described as a leading cause of frontotemporal dementia-amyotrophic lateral sclerosis; it is also the most common phenocopy of HD in people of European origin.
• Huntington disease-like syndrome 2: This is the most common HD-like syndrome caused by GTC/CAG triplet expansions in the JPH3 gene encoding junctophilin-3 and found exclusively in people of African descent.
• Dentatorubral pallidoluysian atrophy (DRPLA): This autosomal dominant trinucleotide CAG expansion disorder is due to a mutation in the atrophin-1 gene (ATN1) on chromosome 12p13. It presents like HD but also causes seizures. It is seen mostly in people of Japanese origin but also has been found among individuals from the Haw River valley of North Carolina.
• Chorea/acanthocytosis: Due to mutation in VPS13A. Presents with orobuccolingual chorea and acanthocytes on blood smear. McLeod syndrome is an X-linked form.

Onset of symptoms in an individual with an established family history requires no additional investigation.

• Genetic testing for CAG repeat numbers. Genetic testing should be ordered only with appropriate pretesting and posttesting genetic counseling.
• If no CAG repeat is in the huntingtin gene, other genetic mutations may be producing a phenocopy of HD. Consider additional genetic tests, such as spinocerebellar ataxia type 17, the C9orf2 hexanucleotide repeat (in people of European descent), the GTC/CAG triplet expansions in the JPH3 gene encoding junctophilin-3 (in people of African descent).
• Also obtain CBC with smear, erythrocyte sedimentation rate, electrolytes, serum ceruloplasmin, 24-h urinary copper excretion, thyroid panel, antinuclear antibody, liver function tests, HIV, and antistreptolysin O titer. Consider paraneoplastic markers.

• CT scan or MRI scan (Fig. E3) will show atrophy, most notably in the caudate and putamen. In some cases, the striatal atrophy causes a characteristic appearance of the lateral ventricles on imaging termed “boxcar ventricles.” The cortex is involved to a lesser extent. A normal scan does not exclude the diagnosis.
• Positron emission tomography studies show reductions in striatal glucose metabolism and loss of dopamine D₂ receptor-bearing neurons in the striatum (Fig. E4), and increased brain lactate levels.

• Supportive counseling
• Physical and occupational therapy
• Speech language pathology
• Home health care
• Genetic counseling

• Chorea does not need to be treated unless it is disabling.
• Tetrabenazine and deutetrabenazine are both approved by the FDA for the symptomatic treatment of chorea seen in HD. They are both a reversible inhibitor of the vesicle monoamine transporter type 2 (VMAT-2), impairing presynaptic dopamine release by blocking packaging of monoamines into presynaptic storage vesicles. Side effects include parkinsonism and severe depression. Deutetrabenazine appears to have a lower incidence of neuropsychiatric adverse effects than tetrabenazine. Both drugs are expensive and have no effect on disease progression.
• Neuroleptics, typical or atypical, can be used for symptomatic management of neuropsychiatric issues and chorea at low doses (e.g., haloperidol 1 to 10 mg/day).
• Amantadine (up to 300 to 400 mg divided three times daily).
• Depression with suicidal ideation is common; may improve with tricyclic antidepressants or SSRIs.
• Recent trials involving intrathecal administration of IONIS-HTT_Rx, an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentration of mutant huntingtin in patients with early HD, have shown dose-dependent reductions in concentration of mutant huntingtin without serious side effects.

Relentless course of variable duration leading to progressive disability and death

• Neurology for diagnosis and treatment of chorea
• Psychiatry to treat behavioral consequences such as depression and anxiety
• Genetic counseling
• Speech language pathology to evaluate swallow function

Huntington Disease (Patient Information)